Shikha Baghel Chauhan

Indu Singh
Ajmer Singh Grewal
Rajwinder Kaur
Editors

Lipid Based Nanocarriers

for Drug Delivery
Copyright © 2024 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by
any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written
permission of the Publisher.

We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this
publication. Please visit [Link] and search by Title, ISBN, or ISSN.

For further questions about using the service on [Link], please contact:

Copyright Clearance Center

Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: info@[Link]

NOTICE TO THE READER

The Publisher has taken reasonable care in the preparation of this book but makes no expressed or implied warranty of any
kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential
damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any
special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this
material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the
extent applicable to compilations of such works.

Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no
responsibility is assumed by the Publisher for any injury and/or damage to persons or property arising from any methods,
products, instructions, ideas or otherwise contained in this publication.

This publication is designed to provide accurate and authoritative information with regards to the subject matter covered
herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional
services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A
DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR
ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

Library of Congress Cataloging-in-Publication Data

ISBN: 979-8-89113-920-6

Published by Nova Science Publishers, Inc. † New York

Contents

Preface ..................................................................................................................... vii

Chapter 1 Introduction to Lipid Nanocarriers: A Promising Approach
in Drug Delivery ........................................................................................... 1
Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh,
Shikha Baghel Chauhan, Indu Singh, Rishab Bhanot,
Rupam Sharma and Ajmer Singh Grewal
Chapter 2 Solid Lipid Nanoparticles for Drug Delivery........................................... 11
Harwinder Kaur, Parneet Kaur, Narinderpal Kaur
and Pallavi Bassi
Chapter 3 Nanoemulsions ........................................................................................... 25
Kirti Goel, Purav Gupta, Karan Goel,
Jasmine Chaudhary and Akash Jain
Chapter 4 Niosome Drug Delivery System: A Versatile Approach
for Enhanced Therapeutic Efficacy.......................................................... 45
Mithun Bhowmick, Pratibha Bhowmick Rideb Chakraborty
and Naureen Afrose
Chapter 5 Lipid Nanocarriers in Cosmetics .............................................................. 63
Meghna Dheek, Shikha Baghel Chauhan and Indu Singh
Chapter 6 Herbal Drug Loaded Nano Lipid Carriers:
Enhancing Bioavailability and Therapeutic Efficacy ............................. 77
S. Neelufar Shama
Chapter 7 Lipid-Based Nano Carriers for Drug Delivery........................................ 97
Manasvi Saini, Gaurav Chaudhary,
Chaitanay Vinayak Narayan, Swati Verma,
Lovy Sharma and Shalini K. Shawney
Chapter 8 Nanomedicine: Transforming Healthcare through Precision,
Theranostics, and Future Frontiers ....................................................... 111
Ashish Verma, Pradeep Kumar Sharma and Amit Singh
Chapter 9 Lipid Nanocarriers in Ocular Drug Delivery ........................................ 127
Hiti, Varneet Sandhu, Sonia Dhiman
and Thakur Gurjeet Singh
iv Contents

Chapter 10 Therapeutic Valuation and Challenges of Lipid Nanocarriers

in Oral Drug Delivery System ................................................................. 143
Manisha Bhatti and Jasneek Kaur Kaloti
Chapter 11 Lipid-Based Nanoparticles in Cancer Therapy:
Enhancing Efficacy and Minimizing Toxicity ....................................... 157
Abhinav Singhal, Anjali Sharma, Vishnu Mittal,
Devkant Sharma and Prabhjot Singh Bajwa
Chapter 12 Lipid-Based Nanoparticles for Topical and Transdermal D
rug Delivery .............................................................................................. 169
Ashima Ahuja, Yogesh Murti and Meenakshi Bajpai
Chapter 13 Synergy of Nanotechnology and Genetic Therapies:
Lipid Nanocarriers for RNA and DNA Delivery .................................. 181
Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar
and Rajan Swami
Chapter 14 Lipid Nanoparticles for Blood Brain Barrier ........................................ 195
Hitesh Chopra, Kavita Munjal,, Vinod Kumar Gauttam,
Divya Dhawal Bhandari, Sonia Arora, Sonam Yadav
and Mohamed Rahamathulla
Chapter 15 Lipid Nanocarriers for Pulmonary Drug Delivery ............................... 205
Himanshu Sachdeva, Sunishtha Kalra, Balwan Singh,
Praveen Kumar, Yogesh and Govind Singh
Chapter 16 Lipid-Based Nanocarriers for Nutraceuticals Delivery ........................ 225
Upasana Yadav, Arjvee Vaidya, Ashwini Patel,
Shailesh Koradia and Harshkumar Brahmbhatt
Chapter 17 Emergence of Plant-Based Nano-Technology
as Anticancer Approach .......................................................................... 245
Akanksha Dwivedi, Amit Modi, Juhi Bhadoria,
Dipali Trivedi, Anuradha Derashri, Nitin Kolhe,
Rakhi Khabiya, G. N. Darwhekar and Devyani Rajput
Chapter 18 Lipid Nano-Carrier Systems for Inflammatory Diseases ..................... 263
Sayak Khawas, Kumar Anand and Neelima Sharma
Chapter 19 Revolutionizing Medication Delivery: Harnessing Solid Lipid
Nanoparticles for Targeted Delivery ...................................................... 279
Riya Singh, Shikha Baghel Chauhan and Indu Singh
Chapter 20 Lipid-Based Nanocarriers: Panacea for Improving Oral
Bioavailability of Lipophilic Drugs ........................................................ 289
Vishal Kumar Parida, Sneha Poddar, Neeraj Mittal
and Teenu Sharma
 Contents v

Chapter 21 Nanoscale Dendrimers in Targeted Drug Delivery:

A Systematic Review ................................................................................ 305
Ajit Kumar Varma, Beena Goyal, Pooja Chaurasia,
Nisha Mandloi and Aakanksha Meval
Chapter 22 Lipid-Based Nanoparticles in Cancer Therapy:
Innovations, Challenges and Future Prospects ..................................... 327
Vani, Simran, Priyanka Kriplani, Bhawna Chopra,
Munish Goyal and Kumar Guarve
Chapter 23 Nano Lipid Carriers: Revolutionizing Herbal Medicine
for Enhanced Therapeutic Outcomes .................................................... 339
Pradeep Kumar Sharma, Prabhu Dayal Rajan and Nitin Kumar
Chapter 24 Nanostructured Lipid Carriers for Drug Targeting:
Innovations and Applications in Pharmaceutical Sciences .................. 353
Vishnu Mittal, Anjali Sharma, Abhinav Singhal,
Devkant Sharma and Prabhjot Singh Bajwa
Chapter 25 Nanostructured Lipid Carriers: Enhancing Herbal
Medicine Delivery .................................................................................... 367
Radha Goel, Rosaline Mishra, Neelam Singh, Anjali Rajora,
Rashmi Singh and Praveen Kumar Gaur
Chapter 26 A Comprehensive Exploration of Nanomedicine’s Current
Landscape and Future Horizons ............................................................ 383
Kallepalli Surya Badarinadh, Priyanka Shukla,
Shikha Baghel Chauhan and Indu Singh
Chapter 27 Nanotechnology in Drug Delivery: Unraveling the Potential
of Nanostructured Lipid Carriers .......................................................... 397
Mayuri Goyal, Shikha Baghel Chauhan, Indu Singh
and Charu Gupta
List of Contributors ............................................................................................................ 413
About the Editors ................................................................................................................ 421
Index ................................................................................................................... 425
Preface

The field of pharmaceutics has undergone a significant transformation in recent decades, driven
by the emergence of nanotechnology and its integration into drug delivery systems. Among the
numerous nanocarrier platforms, lipid-based nanocarriers have garnered substantial attention
among scientific world owing to their unique properties, versatility, and potential to address
the longstanding challenges associated with drug delivery.
This edited book, “Lipid-Based Nanocarriers for Drug Delivery,” aims to provide a
comprehensive overview of the current status, innovations, and future prospects of lipid
nanocarriers in the realm of targeted drug delivery. With contributions from leading experts
and researchers in the field, this book delves into the intricate world of lipid nanocarriers,
exploring their diverse applications in various therapeutic areas.
From the initial chapters, readers will gain a solid foundation in the fundamental principles
of lipid nanocarriers, including their types, advantages, disadvantages, and their role in
revolutionizing drug delivery. Subsequent chapters delve into the specific applications of lipid
nanocarriers in cosmetics, ocular drug delivery, solid lipid nanoparticles, nanomedicines, and
herbal drug-loaded nanoparticles, highlighting their potential in addressing diverse ailments.
As the demand for tailored pharmaceutical dosage forms that mitigate side effects associated
with conventional drug therapy continues to grow, the book emphasizes the critical need for
developing and formulating drug delivery systems capable of achieving targeted drug delivery.
By harnessing the potential of lipid nanocarriers, researchers and pharmaceutical professionals
can optimize drug delivery systems to enhance efficacy while minimizing adverse effects.
Throughout the book, readers will gain insights into the availability and assessment of different
lipids suitable for nanocarrier formulations, along with their roles and significance in ocular
drug delivery, transdermal drug delivery, cancer treatment, and cosmetics. Additionally, the
text offers a thorough examination of nanomedicine formulation and development, providing
readers with a comprehensive understanding of lipid-based nanocarriers and their diverse
applications. Intended as a textbook for advanced courses in lipid nanoparticles for biomedical
applications, this book caters to medical, pharmaceutical, and paramedical students at both
undergraduate and postgraduate levels. Moreover, it serves as a valuable resource for academic
researchers, industry professionals, and all those interested in exploring the boundless potential
of lipid nanocarriers in revolutionizing targeted drug delivery.
viii Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal et al.

In conclusion, “Lipid-Based Nanocarriers for Drug Delivery” offers a comprehensive

exploration of the intricate realm of lipid nanocarriers, bridging the gap between theory and
practice, and paving the way for the development of innovative and effective drug delivery
systems that can enhance patient outcomes and transform healthcare.

Shikha Baghel Chauhan, PhD

Indu Singh, PhD
Ajmer Singh Grewal, PhD
Rajwinder Kaur, PhD
Editors
Chapter 1

Introduction to Lipid Nanocarriers:

A Promising Approach in Drug Delivery

Vaishali1,
Vikas Kumar Singh2
Kallepalli Surya Badarinadh3
Shikha Baghel Chauhan3
Indu Singh3
Rishab Bhanot4
Rupam Sharma4
and Ajmer Singh Grewal5
1Moradabad Educational Trust, Group of Institutions, Faculty of Pharmacy, Moradabad, Uttar Pradesh, India
2Teva API Pvt. Ltd., Gajraula, Uttar Pradesh, India
3Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India
4Department of Pharmacy, Indus International University, Bathu, Una, Himachal Pradesh, India
5Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, India

Abstract

The pharmaceutical sciences have determined that lipid nanocarriers serve as a highly
effective and adaptable platform for medication delivery. Conventional drug delivery
systems have limitations that can be overcome through the innovative utilization of lipids,
known for their biocompatibility and resemblance to natural cell constituents. This
introductory section presents the foundational concepts of lipid nanocarriers and their
significance in contemporary drug delivery methods. Lipid nanocarriers encompass
nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and liposomes as
notable examples. These nanocarriers exhibit a propensity to encapsulate both hydrophobic
and hydrophilic medicines, safeguarding them from degradation while concurrently
enhancing their bioavailability. Lipid-based solutions are appealing due to their
biocompatibility and biodegradability, characteristics that diminish the likelihood of
undesirable side effects and concerns about toxicity. The versatility of lipid nanocarriers in
drug delivery—whether administered orally, topically, transdermally, or intravenously—
stands as a major strength. Their adaptability allows for application in personalized
medicine and targeted therapy for both small compounds and macromolecules, such as
peptides and nucleic acids. The growing attention towards lipid nanocarriers can be


Corresponding Author’s Email: vaishalihi009@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
2 Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh et al.

attributed to the persistent interest in enhancing therapeutic efficacy while mitigating side
effects in the field of medication delivery.

Keywords: lipid nanocarriers, drug delivery systems, nanoparticles, nanostructured lipid

carriers (NLCs), solid lipid nanoparticles (SLNs).

Abbreviations

NLCs Nano Lipid Carriers

SLNs Solid lipid nanoparticles
RES Reticulo Endothelial system
HLB Hydrophilic lipophilic balance

Introduction

Nanotechnology, materials science, and medicine all meet in lipid nanocarriers, making for an
intriguing combination. Poor bioavailability, short drug half-lives, and potential toxicity are
just some of the reasons why alternative drug delivery systems were developed (Torchilin,
2005). Nanoscale structures capable of encapsulating and transporting therapeutic payloads in
a controlled and efficient manner have been developed by researchers who take advantage of
the unique physicochemical features of lipids (Allen & Cullis, 2013). Liposomes are a common
type of lipid nanocarrier. The lipid bilayers that make up these spherical vesicles are capable
of enclosing both hydrophobic and hydrophilic substances (Müller et al., 2000). Lipid bilayers
are designed to resemble biological membranes, making them more biocompatible and
enabling their uptake by cells. Targeted and prolonged medication release is feasible because
liposomes liberate their contents in response to environmental effects like pH, temperature, or
enzyme activity (Müller et al., 2002a). The primary categorizations of lipid nanoparticles
encompass solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs),
constituting two foundational types (Torchilin, 2006). The solid lipids that make up SLNs
permit for long-term storage and accurate dosing. When NLCs are formulated with a
combination of solid and liquid lipids, there is an improvement observed in both drug loading
capacities and release characteristics, comparatively speaking (Torchilin, 2005). Micelles made
of lipids are another important type of lipid nanocarriers. Self-assembling in aqueous solutions,
these nanostructures have a core-shell shape with hydrophobic medicines protected by
hydrophilic lipid layers (Langer, 1998). Micelles have showed promise in increasing
medication solubility and bioavailability and are thus particularly beneficial for delivering
weakly water-soluble medicines. Lipid nanocarriers have several potential applications beyond
the pharmaceutical industry. Their potential in “nanogene delivery,” the transport of genes, has
also been investigated. These nanocarriers can help carry weak nucleic acids through cellular
barriers while protecting them from degradation thanks to their lipid encapsulation. Despite
lipid nanocarriers’ promising future, several obstacles still need to be overcome (Torchilin,
2001). Challenges in formulation include ensuring particles are the same size, keeping them
stable in storage, and regulating their rate of release. In addition, it is still crucial to the
development of lipid nanocarriers to comprehend their interaction with biological systems, such
 Introduction to Lipid Nanocarriers 3

as their potential immunogenicity and long-term safety (Zambaux et al., 1998).

Nanotechnology is a leading edge in the quest for personalised medicine and cutting-edge
therapeutic approaches. Lipid nanocarriers have emerged as a promising nanoscale platform
with the potential to revolutionise medication delivery, diagnostics, and possibly gene therapy.
These highly developed carriers, which have their origins in lipid chemistry and
nanotechnology, provide a promising alternative to the established difficulties of conventional
drug delivery systems. Lipid nanocarriers, which take advantage of lipids special features, offer
a wide variety of options for increasing therapeutic stability, bioavailability, and targeted
distribution, and hence, patient outcomes (Moghimi et al., 2001).

Nanotechnology in the Medical Field

Synergy between nanotechnology and medicine, such as that represented by lipid nanocarriers,
promises game-changing advances in medical care. Amphipathic lipids are the building blocks
of these nanocarriers due to their adaptability (Wagner et al., 1990). Liposomes, lipid
nanoparticles (including nanostructured lipid carriers and solid lipid nanoparticles), and lipid-
based micelles are only few examples of the many nanostructures that can be made because to
lipids’ self-assembly characteristics. These designs each have their own benefits and specific
answers to the many medication delivery problems that exist (Farokhzad & Langer, 2009).

Biomimetic Liposomes for Specific Drug Delivery

The most basic and most well-recognized lipid-based nanocarriers are Liposomes. Therapeutic
substances can be enclosed in liposomes, which are lipid bilayer vesicles with an aqueous core.
Liposome bilayers are very much biocompatible and conducive to biological interactions
because of their prominent similarity to natural cell membranes (Kaur et al., 2016). Because of
its biomimetic property, targeted administration may be possible by modifying the surface with
ligands or antibodies, and cellular absorption is enhanced. In addition, liposomes’ release
kinetics can be adjusted according to characteristics including lipid content and bilayer fluidity,
allowing for the sustained and triggered release of encapsulated payloads (Silva et al., 2012).

Mechanical Stability and Timed Release of Lipid Nanoparticles

The field of lipid-based drug delivery has witnessed significant development and advancements
with the introduction of lipid nanoparticles, specifically SLNs and NLCs. SLNs have
exceptional storage stability because of their lipid composition. As a platform for regulated
drug release, they are desirable for both hydrophobic and hydrophilic medicines (Hu et al.,
2004). The shortcomings of SLNs are overcome and drug loading capabilities are increased
with the advent of NLCs, which blend solid and liquid lipids. These nanoparticles have the
potential for continuous and regulated release of active constituents despite dealing with issues
including poor drug solubility, fast clearance, and low bioavailability (Laurent et al., 2014).
4 Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh et al.

Micelles Comprised of Lipids: A Solution to the Problem of Drug Solubility

Micelles made of lipids are another important type of lipid nanocarriers. These nanostructures
self-assemble in aqueous solutions into a core-shell configuration, where hydrophobic
medicines are encased within the core and a hydrophilic lipid shell surrounds the entire
structure. The main benefit of lipid-based micelles is that they can solubilize medications that
are difficult to dissolve in water (De Jong & Borm, 2008). Lipid-based micelles improve
solubility, stability, and bioavailability by enclosing hydrophobic molecules within the core.
They are convenient for systemic drug delivery because of their diminutive size and ease of
manufacture (Hu & Zhang, 2012).

Beyond Drug Delivery: Gene Therapy and More

Beyond the bounds of traditional drug delivery, lipid nanocarriers explore the new territory of
gene therapy. At molecular levels, lipid nanocarriers have the prospective to recover the
treatment of genetic disorders and various other diseases due to their power to encapsulate and
protect nucleic acids (Wilhelm et al., 2016). These carriers protect DNA and RNA from
destruction and carry them across biological barriers, making it possible to convey genetic
information to specific cells. Crucial role is played by Lipid nanocarriers in the translation of
genetic medicine into practise as the science of gene therapy continues to develop (Müller et
al., 2002a).

Types of Lipid Nanoparticles

To contain and transport therapeutic substances, lipid nanoparticles come up to a broad variety
of sizes and shapes. Liposomes, SLNs, NLCs, and lipid-based micelles are the key classes of
lipid nanoparticles. The medication deliverance applications of each of these types are distinct
due to their individual features and benefits (Jain et al., 2019).

Liposomes
These are bilayer vesicles constituting lipid(s) that can encapsulate both water- and fat-soluble
medications. They are biocompatible and able to interact with biological systems because of
their similarity to cell membranes. Depending on the deliberated use, liposomes can be either
unilamellar or multilamellar, and their sizes can be adjusted accordingly (Jain et al., 2019). The
surface of liposomes can be changed with ligands or antibodies to facilitate targeted drug
administration, and they can encapsulate a wide variety of medicines and biomolecules.
Hydrophilic medications work well in the aqueous core of liposomes, while hydrophobic
pharmaceuticals can be encapsulated in the lipid bilayers (Malam et al., 2009).

Solid Lipid Nanoparticles (SLNs)

SLNs have the potential to increase medication properties such as controlled drug release and
long life/stability. Lipids are dispersed in an aqueous solution and subsequently the particles
are solidified. SLNs improve the bioavailability of poorly soluble medicines and have proven
 Introduction to Lipid Nanocarriers 5

to be highly stable during storage. Their stable lipid matrix can prevent the medicine inside
from degrading and allow for controlled, gradual release.

Nanostructured Lipid Carriers (NLCs)

The greater adaptability of NLCs in comparison to SLNs stems from their composition, which
combines solid and liquid lipids. This improvement compensates for the SLN’s shortcomings,
such as its low drug loading capacity because of the solid lipid’s crystalline structure. The drug
loading, stability, and controlled release offered by NLCs are superior. A larger drug payload
and more uniform drug release are made possible by the absence of big lipid crystals thanks to
the existence of liquid lipids (Malam et al., 2009).

Lipid-Based Micelles
Micelles made of lipids are generated when amphiphilic lipids form a core-shell structure while
self-assembling in water. Utilizing micelles as a solubilizer can enhance the stability and
bioavailability of medications that have low solubility in water. Micelles derived from lipids
are particularly attractive for systemic medication delivery due to their minute size and
straightforward fabrication process (Peer et al., 2007).

Methods of Lipid Nanoparticles Preparation

Emulsification-Solvent Evaporation Method

The emulsification-solvent evaporation method is widely used for making lipid nanoparticles.
In the formulation process, lipids and medication are dissolved in an organic solvent, followed
by the emulsification of the resulting mixture into an aqueous phase with the addition of a
stabilizer. Following the loss of the organic solvent, the lipid nanoparticles crystallise. This
method of encapsulating within the lipid matrix works for both hydrophobic and hydrophilic
drugs. Here’s a rundown of the steps involved (Hu et al., 2002; Müller et al., 2002b).

Microemulsion Method
The microemulsion method is a methodology for generating lipid nanoparticles by combining
oil, water, surfactant, and co-surfactant systems to generate a stable and transparent dispersion.
Incorporating lipids and medicines into these microemulsions paves the way for their
conversion into lipid nanoparticles. This technique is ideal for encapsulating drugs, whether
hydrophobic or hydrophilic. Here’s a quick rundown of what happens (Date & Nagarsenker,
2007; Souto et al., 2004):

High-Pressure Homogenization
Preparing lipid nanoparticles by means of high-pressure homogenization is a common practise.
Large lipid droplets are broken up into smaller particles by applying strong pressure to a lipid-
water solution. Using this technique, you can make lipid nanoparticles more stable and achieve
a narrow particle size distribution (Müller et al., 2002b; Souto et al., 2004).
6 Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh et al.

Hot Homogenization and Ultrasonication

Hot combination of homogenization and ultrasonication is a common technique for making
lipid nanoparticles. Lipids are melted first, then homogenised at high temperature, and then
ultrasonically disrupted to reduce particle size. This technique is especially helpful for
producing lipid nanoparticles with uniform size and high drug loading (Souto et al., 2004).

Solvent Injection Technique

The solvent injection technique is a common method for producing lipid nanoparticles. In this
process, a solution containing dissolved lipids and the medication (if hydrophobic) is rapidly
injected into an aqueous phase containing a stabilizer and surfactant. This results in the creation
of lipid nanoparticles through the rapid diffusion of the organic solvent into the aqueous phase.
Both hydrophilic and hydrophobic medicines can be encapsulated using this approach (Souto
& Müller, 2010; Xia et al., 2014).

Supercritical Fluid Technology

Preparing lipid nanoparticles with supercritical fluid technology is a cutting-edge technique.
The medication and lipids are dissolved in a supercritical fluid like supercritical CO2, and then
precipitate out when the pressure is released. Using this technology, you may precisely regulate
the particle size of your lipid nanoparticles and expose them to only trace amounts of organic
solvents (Attama et al., 2008; Freitas & Müller, 1998; Zhang et al., 2023).

Double Emulsion Method

Utilized for the synthesis of lipid nanoparticles, particularly for encapsulating hydrophilic
medications, the double emulsion method, also recognized as the water-in-oil-in-water
emulsion method, involves dissolving the medication in water. Following this, the medication
is encapsulated within lipid droplets, and the resultant mixture is dispersed in an external
aqueous phase, giving rise to a multiple emulsion structure. The hydrophilic medication is
protected by the double emulsion, which allows the lipid nanoparticles to encapsulate it (Jain
et al., 2019; Jenning et al., 2000).

Coacervation Method
Lipid nanoparticles, inclusive of SLNs and nanostructured lipid companies, can be organized
the use of the coacervation method. Changing variables like temperature, pH, or solvent
composition result in phase separation of lipids and the medication from a solution. Once the
coacervate phase has formed, the medicine and lipids can be extracted and refined into lipid
nanoparticles. This method lets in for a wide range of manipulation of particle homes and
encapsulation of medicine (Butani et al., 2016; Souto & Müller, 2010).

Applications of Lipid Nanocarriers

Topical Route of Administration

Skin-related diseases are prevalent worldwide, and their treatment faces significant challenges,
primarily attributed to the low efficacy of drugs resulting from poor skin penetration or
permeation in conventional formulations. The stratum corneum of the epidermis serves as a
 Introduction to Lipid Nanocarriers 7

major barrier, necessitating the alteration of penetration pathways from transcellular to

paracellular or follicular routes. Lipid nanoparticles, including SLNs and NLCs, have been
developed to enhance skin penetration or permeation. These particulate formulations can be
created by incorporating SLNs or NLCs into conventional formulations. They offer the
advantage of direct preparation in a one-step process, resulting in drug loaded SLNs or NLCs.
Lipid nanoparticles present numerous benefits for topical drug delivery, such as
biocompatibility and biodegradability, controlled and prolonged drug release profiles, close
contact with the skin, strong skin adhesion, skin hydration, and film formation to enhance skin
and dermal penetration (Chen et al., 2017; Garg et al., 2017).

Oral Route
Oral drug administration stands out as the most prevalent route in drug delivery systems, largely
due to its high patient compliance. However, challenges such as limited drug solubility and a
significant hepatic first-pass effect contribute to low oral bioavailability, necessitating effective
solutions. Nanoparticle-based drug delivery systems have emerged as a promising approach to
enhance oral bioavailability. Lipid nanoparticles, including SLNs and NLCs, offer sustained
drug release capabilities, ensuring constant plasma levels. Moreover, nanoparticles with a
higher specific surface area and increased saturation solubility exhibit a faster dissolution rate,
expediting the onset of drug action. Overcoming major barriers in oral drug delivery, such as
glycoprotein efflux pumps and chemical or enzymatic degradation, has been addressed in recent
research. Specific lipids or surfactants used in lipid nanoparticles have demonstrated the
capability to inhibit glycoprotein efflux pumps. Drug-loaded lipid nanoparticles not only reduce
chemical or enzymatic degradation but also facilitate lymphatic transport, circumventing the
liver and avoiding the hepatic first-pass effect (Ghasemiyeh & Mohammadi-Samani, 2018;
Malam et al., 2009).

Ocular Administration
The eye has a very complex and sensitive structure, and there are many obstacles that must be
overcome to reach this special tissue. New drug delivery systems such as lipid nanoparticles
are expected to overcome these problems and increase bioavailability in tissues. Lipid
nanoparticles are used as ocular drug delivery agents that can cross the blood-ocular barrier to
achieve drug release and control, protect the drug from the effects of lacrimal gland enzymes,
and prolong the time and location of drug accumulation in the eye. Treatment of the eye and
the back of the eye is quite difficult. There are many ways to focus on the back of the eye. The
cosmetic method is not a suitable method to target intraocular tissue; Other methods used for
this purpose are transscleral application (subconjunctival and retrobulbar injection), intravitreal
method, subretinal injection, etc. Since most of these procedures are invasive, new drug
delivery systems such as lipid nanoparticles may be an alternative (Chetoni et al., 2016; Liu et
al., 2011; Luan et al., 2014; Sánchez-López et al., 2017).

Parenteral Administration
In the realm of parenteral drug delivery, the development is significantly influenced by the
contributions of nanomedicine and nanotechnology. For this purpose, the most important
features of lipid nanoparticles are ease of mass production, biocompatibility and
biodegradability of the formulation components, control and modification of the drug release
8 Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh et al.

pattern, and prevention of drug release. It reduces and controls blood sugar levels. Medicines
containing lipid nanoparticles can be injected intravenously, subcutaneously, intramuscularly,
or directly into the body. Drug release from lipid nanoparticles can occur through erosion (e.g.,
enzymatic degradation) or contamination, which may promote drug release. Recent studies
have demonstrated the potential of lipid nanoparticles in the integration of peptides and
proteins. In this case, SLN is not a suitable carrier due to its low drug carrying capacity, but
NLC is a suitable alternative. In this way, peptides and proteins can be protected from harsh
environments (Kaur et al., 2016; Pardeike et al., 2016).

Pulmonary Delivery
Pulmonary drug delivery is a new method with many advantages. It is a local delivery and
management method. Lipid nanoparticles containing SLNs and NLCs have been evaluated for
pulmonary delivery. They have the advantages of drug release, biocompatibility and
biodegradability, low toxicity, and better stability than previously developed particle systems.
Delivery of drug-loaded nanoparticles into the lungs results in high local concentrations and
may reduce the risk of disease (Pardeike et al., 2009; Zambaux et al., 1998).

Brain Delivery
Delivering drugs to the brain is one of the main challenges in drug research due to the blood-
brain barrier. Lipid nanoparticles consisting of SLN and NLC are one of the colloidal tablets
used to conquer those issues. The benefit of lipid nanoparticles is that they can boom the
retention time of drugs in mind capillary blood and growth drug gradients from blood to brain,
opening junctions for easy get right of entry to thru the blood brain barrier and drug loaded
lipids. transcytosis of nanoparticles. It includes endothelial cells. Lipid nanoparticles are
suitable for combining lipophilic and hydrophilic tablets, which can be used in many ways.
Preceding research have highlighted the crucial effect of surfactant compatibility on brain drug
transport (Pardeike et al., 2009).

Conclusion

Lipid nanoparticles represent innovative drug delivery systems with several advantages
compared to other colloidal and polymeric nanocarriers. Lipid carriers offer several benefits,
chief among them being their biocompatibility, biodegradability, simplicity of scaling, and
ability to have regulated and customized release patterns. Lipophilic and hydrophilic medicines
can both be transported by lipid nanoparticles. Each of these nanoparticles’ administration
routes has unique benefits and drawbacks that need to be considered. Lipid nanoparticles are
promising drug delivery systems for handing over diverse pharmaceutically essential lively
substances from small molecules to proteins and genes inside the close to future destiny.

References

Allen, T. M., & Cullis, P. R. (2013). Liposomal drug delivery systems: From concept to clinical applications.
Advanced Drug Delivery Reviews, 65(1), 36–48.
 Introduction to Lipid Nanocarriers 9

Attama, A. A., Reichl, S., & Müller-Goymann, C. C. (2008). Diclofenac sodium delivery to the eye: In vitro
evaluation of novel solid lipid nanoparticle formulation using human cornea construct. International
Journal of Pharmaceutics, 355(1), 307–313.
Butani, D., Yewale, C., & Misra, A. (2016). Topical Amphotericin B solid lipid nanoparticles: Design and
development. Colloids and Surfaces. B, Biointerfaces, 139, 17–24.
Chen, J., Wei, N., Lopez-Garcia, M., Ambrose, D., Lee, J., Annelin, C., & Peterson, T. (2017). Development
and evaluation of resveratrol, Vitamin E, and epigallocatechin gallate loaded lipid nanoparticles for skin
care applications. European Journal of Pharmaceutics and Biopharmaceutics: Official Journal of
Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V, 117, 286–291.
Chetoni, P., Burgalassi, S., Monti, D., Tampucci, S., Tullio, V., Cuffini, A. M., Muntoni, E., Spagnolo, R.,
Zara, G. P., & Cavalli, R. (2016). Solid lipid nanoparticles as promising tool for intraocular tobramycin
delivery: Pharmacokinetic studies on rabbits. European Journal of Pharmaceutics and Biopharmaceutics:
Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V, 109, 214–223.
Date, A. A., & Nagarsenker, M. S. (2007). Design and evaluation of self-nanoemulsifying drug delivery
systems (SNEDDS) for cefpodoxime proxetil. International Journal of Pharmaceutics, 329(1), 166–172.
De Jong, W. H., & Borm, P. J. (2008). Drug delivery and nanoparticles: Applications and hazards. International
Journal of Nanomedicine, 3(2), 133–149.
Farokhzad, O. C., & Langer, R. (2009). Impact of Nanotechnology on Drug Delivery. ACS Nano, 3(1), 16–20.
Freitas, C., & Müller, R. H. (1998). Spray-drying of solid lipid nanoparticles (SLNTM). European Journal of
Pharmaceutics and Biopharmaceutics, 46(2), 145–151.
Garg, A., Bhalala, K., Tomar, D. S., & Wahajuddin. (2017). In-situ single pass intestinal permeability and
pharmacokinetic study of developed Lumefantrine loaded solid lipid nanoparticles. International Journal
of Pharmaceutics, 516(1), 120–130.
Ghasemiyeh, P., & Mohammadi-Samani, S. (2018). Solid lipid nanoparticles and nanostructured lipid carriers
as novel drug delivery systems: Applications, advantages and disadvantages. Research in Pharmaceutical
Sciences, 13(4), 288.
Hu, C. M. J., & Zhang, L. (2012). Nanoparticle-based combination therapy toward overcoming drug resistance
in cancer. Biochemical Pharmacology, 83(8), 1104–1111.
Hu, F. Q., Hong, Y., & Yuan, H. (2004). Preparation and characterization of solid lipid nanoparticles containing
peptide. International Journal of Pharmaceutics, 273(1–2), 29–35.
Hu, F. Q., Yuan, H., Zhang, H. H., & Fang, M. (2002). Preparation of solid lipid nanoparticles with clobetasol
propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization.
International Journal of Pharmaceutics, 239(1), 121–128.
Jain, S., Tiwary, A. K., & Jain, N. K. (2019). PEGylated Elastic Liposomal Formulation for Lymphatic
Targeting of Zidovudine. Current Drug Delivery, 5(4), 275–281.
Jenning, V., Gysler, A., Schäfer-Korting, M., & Gohla, S. H. (2000). Vitamin A loaded solid lipid nanoparticles
for topical use: Occlusive properties and drug targeting to the upper skin. European Journal of
Pharmaceutics and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische
Verfahrenstechnik e.V, 49(3), 211–218.
Kaur, P., Garg, T., Rath, G., Murthy, R. S. R., & Goyal, A. K. (2016). Development, optimization and
evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of
drug resistance lung cancer using Box-Behnken design. Drug Delivery, 23(6), 1912–1925.
Langer, R. (1998). Drug delivery and targeting. Nature, 392(6679 Suppl), 5–10.
Laurent, S., Saei, A. A., Behzadi, S., Panahifar, A., & Mahmoudi, M. (2014). Superparamagnetic iron oxide
nanoparticles for delivery of therapeutic agents: Opportunities and challenges. Expert Opinion on Drug
Delivery, 11(9), 1449–1470.
Liu, D., Liu, Z., Wang, L., Zhang, C., & Zhang, N. (2011). Nanostructured lipid carriers as novel carrier for
parenteral delivery of docetaxel. Colloids and Surfaces B: Biointerfaces, 85(2), 262–269.
Luan, J., Zhang, D., Hao, L., Qi, L., Liu, X., Guo, H., Li, C., Guo, Y., Li, T., Zhang, Q., & Zhai, G. (2014).
Preparation, characterization and pharmacokinetics of Amoitone B-loaded long circulating nanostructured
lipid carriers. Colloids and Surfaces B: Biointerfaces, 114, 255–260.
Malam, Y., Loizidou, M., & Seifalian, A. M. (2009). Liposomes and nanoparticles: Nanosized vehicles for
drug delivery in cancer. Trends in Pharmacological Sciences, 30(11), 592–599.
10 Vaishali, Vikas Kumar Singh, Kallepalli Surya Badarinadh et al.

Moghimi, S. M., Hunter, A. C., & Murray, J. C. (2001). Long-circulating and target-specific nanoparticles:
Theory to practice. Pharmacological Reviews, 53(2), 283–318.
Müller, R. H., Mäder, K., & Gohla, S. (2000). Solid lipid nanoparticles (SLN) for controlled drug delivery—
A review of the state of the art. European Journal of Pharmaceutics and Biopharmaceutics: Official
Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V, 50(1), 161–177.
Müller, R. H., Radtke, M., & Wissing, S. A. (2002a). Nanostructured lipid matrices for improved
microencapsulation of drugs. International Journal of Pharmaceutics, 242(1–2), 121–128.
Müller, R. H., Radtke, M., & Wissing, S. A. (2002b). Solid lipid nanoparticles (SLN) and nanostructured lipid
carriers (NLC) in cosmetic and dermatological preparations. Advanced Drug Delivery Reviews, 54, S131–
S155.
Pardeike, J., Hommoss, A., & Müller, R. H. (2009). Lipid nanoparticles (SLN, NLC) in cosmetic and
pharmaceutical dermal products. International Journal of Pharmaceutics, 366(1–2), 170–184.
Pardeike, J., Weber, S., Zarfl, H. P., Pagitz, M., & Zimmer, A. (2016). Itraconazole-loaded nanostructured lipid
carriers (NLC) for pulmonary treatment of aspergillosis in falcons. European Journal of Pharmaceutics
and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik
e.V, 108, 269–276.
Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R., & Langer, R. (2007). Nanocarriers as an
emerging platform for cancer therapy. Nature Nanotechnology, 2(12), Article 12.
Sánchez-López, E., Espina, M., Doktorovova, S., Souto, E. B., & García, M. L. (2017). Lipid nanoparticles
(SLN, NLC): Overcoming the anatomical and physiological barriers of the eye – Part I – Barriers and
determining factors in ocular delivery. European Journal of Pharmaceutics and Biopharmaceutics, 110,
70–75.
Silva, A. C., Santos, D., Ferreira, D., & Lopes, C. M. (2012). Lipid-based nanocarriers as an alternative for oral
delivery of poorly water- soluble drugs: Peroral and mucosal routes. Current Medicinal Chemistry, 19(26),
4495–4510.
Souto, E. B., & Müller, R. H. (2010). Lipid Nanoparticles: Effect on Bioavailability and Pharmacokinetic
Changes. In M. Schäfer-Korting (Ed.), Drug Delivery (pp. 115–141). Springer.
Souto, E. B., Wissing, S. A., Barbosa, C. M., & Müller, R. H. (2004). Development of a controlled release
formulation based on SLN and NLC for topical clotrimazole delivery. International Journal of
Pharmaceutics, 278(1), 71–77.
Torchilin, V. P. (2001). Structure and design of polymeric surfactant-based drug delivery systems. Journal of
Controlled Release: Official Journal of the Controlled Release Society, 73(2–3), 137–172.
Torchilin, V. P. (2005). Recent advances with liposomes as pharmaceutical carriers. Nature Reviews. Drug
Discovery, 4(2), 145–160.
Torchilin, V. P. (2006). Multifunctional nanocarriers. Advanced Drug Delivery Reviews, 58(14), 1532–1555.
Wagner, E., Zenke, M., Cotten, M., Beug, H., & Birnstiel, M. L. (1990). Transferrin-polycation conjugates as
carriers for DNA uptake into cells. Proceedings of the National Academy of Sciences of the United States
of America, 87(9), 3410–3414.
Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S., Audet, J., Dvorak, H. F., & Chan, W. C. W. (2016). Analysis of
nanoparticle delivery to tumours. Nature Reviews Materials, 1(5), Article 5.
Xia, D., Cui, F., Gan, Y., Mu, H., & Yang, M. (2014). Design of lipid matrix particles for fenofibrate: Effect
of polymorphism of glycerol monostearate on drug incorporation and release. Journal of Pharmaceutical
Sciences, 103(2), 697–705.
Zambaux, M. F., Bonneaux, F., Gref, R., Maincent, P., Dellacherie, E., Alonso, M. J., Labrude, P., & Vigneron,
C. (1998). Influence of experimental parameters on the characteristics of poly(lactic acid) nanoparticles
prepared by a double emulsion method. Journal of Controlled Release: Official Journal of the Controlled
Release Society, 50(1–3), 31–40.
Zhang, J., Zhu, J., Cheng, Y., & Huang, Q. (2023). Recent Advances in Pickering Double Emulsions and
Potential Applications in Functional Foods: A Perspective Paper. Foods, 12(5), Article 5.
Chapter 2

Solid Lipid Nanoparticles for Drug Delivery

Harwinder Kaur1
Parneet Kaur1
Narinderpal Kaur2
and Pallavi Bassi1,
1Chitkara College of Pharmacy, Chitkara University, Punjab, India
2Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh

Abstract

Lipid-based nanocarriers have gained increasing popularity among researchers due to their
versatile nature and wide range of applications. Solid lipid nanoparticles (SLNs) have been
extensively investigated in the literature for their efficiency in transporting and solubilizing
hydrophobic drugs. SLNs exhibit improved cell uptake and a high rate of absorption,
making them suitable for drug delivery. Additionally, the biocompatible properties of lipids
contribute to a reduced risk of acute or chronic toxicity. However, the crystallization
tendency of SLNs is a cause for concern as it renders them susceptible to instability. This
chapter primarily explores the formulation ingredients and processes used in the
preparation of SLNs, along with their applications in drug delivery, including the delivery
of anti-cancer agents. The challenges associated with the clinical translation of SLNs, such
as limited bioavailability, stability, and solubility, are also discussed.

Keyword: nanocarrier, solid lipid nanoparticle, lipid-based drug delivery, health, research

Abbreviations

SLN Solid Lipid nanoparticles

FDA Food and Drug Administration
BBB Blood brain barrier
GRAS generally recognized as safe
HLB hydrophilic-lipophilic balance
HPH High-pressure homogenization
NLC nanostructured lipid carriers
GMP Good Manufacturing Practices


Corresponding Author’s Email: pallavibassi1@[Link], [Link]@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
12 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

Introduction

Lipid-based vesicular carriers have found extensive use in formulation development due to their
strong affinity for cell membranes, intercellular spaces, and biocompatibility. The advent of
nanotechnology has revolutionized drug delivery strategies by allowing the creation of
customized systems with site-specificity for delivering the Active Pharmaceutical Ingredient
(API) to the intended site. Liposomes, the primary lipid-based carriers for lipophilic drugs, have
been utilized for a long time. These phospholipid bilayered spherical vesicles can incorporate
lipophilic drugs into the lipid bilayers, while hydrophilic pharmaceutical compounds can be
dissolved within the inner aqueous core (Chopra et al., 2021; Mudgil et al., 2012). The
development of stealth liposomes, which are sterically stabilized systems, has enabled selective
targeting of drug moieties. Another lipid-based system, lipid nanoemulsions, was introduced in
the 1950s primarily for parenteral administration of nutraceuticals. Comprising 10-20% lipids,
including fatty vegetable oils such as soy oil or middle-chain triglycerides, and supplementary
constituents like phospholipids (0.6% to 1.5%) and glycerol (2-3%), nanoemulsions offer
benefits such as toxicological safety and scalability in manufacturing through high-pressure
homogenization. The substantial lipid phase content enhances solubility for lipophilic
compounds. Currently, various lipid-based nanocarriers are under exploration, focusing on
their ability to penetrate membranes, maintain consistent medication release, and preserve
stability. However, their clinical application faces challenges in obtaining regulatory approval
due to limited availability of approved polymers and associated high costs. The use of solid
lipids instead of liquid oil presents a promising approach to control drug release, as drug
movement within solid lipids is anticipated to be considerably lower compared to liquid oils.
Solid lipid nanoparticles (SLNs), primarily containing solid lipids, have gained global attention
since the early 1990s. SLNs overcome issues associated with liposomes, such as instability,
low drug loading capacity, polymeric noncarrier-related biotoxicity, and residual organic
solvent problems. Additionally, SLNs possess properties like compatibility with biological
membranes, the ability to pass through the Blood-Brain Barrier (BBB), the capacity to achieve
a wide range of vesicle sizes, and cost-effectiveness. The solid matrix of SLNs enables precise
control over drug release, prevents drug leakage, and offers enhanced stability and cost-
effectiveness compared to phospholipid-based liposomes. This chapter provides an overview,
methods of preparation, applications, and obstacles in the development of solid lipid
nanoparticles.

Overview of SLNs

The concept of SLNs was first introduced through R. H. Muller’s groundbreaking work in
December 1991, positioning him as the foremost figure in this particular domain and earning
him the moniker of the “father” of SLNs (Alsaad et al., 2020). SLNs are minute spherical
particles composed of a crystalline lipid matrix, wherein the drug is embedded within the fatty
acid chains. Additionally, SLNs have been reported to exhibit disc-shaped and flat ellipsoidal
geometries. The size distribution of SLNs typically falls within the range of 50 to 1000 nm.
Renowned for their ability to enhance the oral bioavailability of drugs with limited solubility
characteristics, SLNs possess other attributes, including improved cellular absorption,
 Solid Lipid Nanoparticles for Drug Delivery 13

increased surface area, controlled and sustained drug delivery, and decreased toxicity. They are
widely recognized as biocompatible carriers capable of providing sustained and controlled drug
delivery (Harish et al., 2023). The formulation composition of SLNs typically consists of a
solid lipid matrix, a surfactant, and optionally, co-surfactants or other additives (refer to Figure
1) (Scioli et al., 2020; Fonte et al., 2012). The lipidic phase for SLNs is usually obtained from
various sources such as steroids, di- or triglycerides, blends of glycerides, or waxes. These
components are commonly employed at concentrations ranging from 0.1% to 30% (w/v) and
maintain their physical characteristics both at normal body temperatures and ambient
temperature. Surfactant concentration generally employed falls between 0.5% and 5% (w/v),
categorized as generally recognized as safe (GRAS) (Fonte et al., 2012; Morales et al., 2015).
The stability of SLNs can be improved by utilizing a combination of surfactants (Kumar et al.,
2013). The structural properties of SLNs are determined by various factors, including the
formulation’s composition, the solubility properties of its constituents (including the active
pharmaceutical ingredient), and the production method used.

Figure 1. Structural composition of solid lipid nanoparticles.

Lipids

Solid lipids constitute a significant portion of SLNs. These lipids, stabilized by surfactants,
have been investigated by Duan et al., (2020) and Khatak et al., (2017). Integrating the
medication into the lipidic matrix addresses challenges associated with the permeability of
lipophobic drugs across cellular membranes. The solubility issues related to lipophilic
medications can be effectively resolved by employing phospholipids, which enhance
permeability (Khatak et al., 2017). Additionally, the stability concerns of peptide drugs at
varying gastrointestinal pH levels can be effectively addressed by incorporating them into the
lipid matrix of SLNs. Examples of lipids commonly utilized in SLN formulation include
glycerides, hard waxes, triglycerides, fatty acids, and alcohols. SLNs formulated with lipids
exhibiting poorly defined crystal lattice show better drug incorporation compared to SLNs
formulated with lipids featuring uniform crystal packing (Jenning et al., 2000; Jenning et al.,
2001). Generally, an increase in lipid concentration leads to a rise in SLN particle size. This
14 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

relationship remains consistent regardless of the specific drug or preparation method employed.
However, at higher concentrations of surface-active agents, the impact of increasing lipid
concentration is diminished or eliminated (Cacicedo et al., 2019). A decrease in lipid content
results in a decline in entrapment efficiency. Therefore, optimizing both components
concurrently is necessary to achieve the required balance between the two properties. By
reducing the surfactant-to-lipid ratio or increasing the application of energy (such as
homogenization speed), it is possible to reduce particle size without compromising entrapment
efficiency (Ahmad et al., 2019).

Surfactants/Co-Surfactants

Surfactants play a crucial role in enhancing the stability of SLNs by reducing the surface tension
between the aqueous phase and lipid phase through adsorption at the interface. The generation
of SLNs primarily depends on the surface tension and interfacial tension. The fundamental
mechanism driving SLN development includes cohesive interactions occurring between the
organic phase and the aqueous phase. Typically, surface tension is higher than interfacial
tension due to the weak adhesive forces exhibited by gases. The molecules at the interface have
surface free energy. During SLN formation, molecules tend to decrease surface energy when
subjected to homogenization. Surfactants can effectively reduce interfacial tension and surface-
free energy. The selection of surfactants is based on the hydrophilic-lipophilic balance (HLB)
value assigned to each surfactant (Duan et al., 2020; Kumar et al., 2013). Surfactants influence
particle size by impacting vesicle aggregation (Khatak et al., 2017). They also impart surface
charge to the nanoparticles, influencing cellular uptake and drug release characteristics. The
long-term stability of SLNs can be enhanced by the presence of surfactants as they prevent
agglomeration and phase separation during storage.

Solvents and Co-Solvents

Solvents and cosolvents, known for their non-toxic and non-irritant properties, are commonly
employed in SLN preparation. Various solvents, including chloroform, ethanol, methanol, and
their combinations, are typically used based on the solubility properties of the other components
involved. It is crucial to give careful consideration to the removal of residual solvents as they
can be a source of toxicity (Kaur et al., 2013).

Cryoprotectants

Lyophilization is employed to preserve the essential physicochemical characteristics of SLNs,

including encapsulation efficiency, distribution, reconstitution capability, stability, and
pharmacological action. Achieving a high-quality freeze-dried product relies on precise
management of the freeze-drying procedure and optimization of storage conditions. The freeze-
drying process increases the likelihood of particle aggregation. To counteract the adverse
effects of lyoprotection (preventing drying stress) and cryoprotection (protecting from freezing
 Solid Lipid Nanoparticles for Drug Delivery 15

stress), cryoprotectants are introduced into the SLN dispersion before freezing. Throughout
storage, cryoprotectants prevent particle instability and agglomeration. The stabilization
mechanism in SLNs using cryoprotectants is believed to be due to the particle separation
hypothesis during the freezing process, with sugars being widely used in this regard. Particle
stabilization primarily occurs through dehydration facilitated by the use of lyoprotectants.
During the drying process, hydrogen bonds are established between particles and
lyoprotectants. This dehydration process allows the inherent structure of SLNs to remain intact
as water is replaced. The amorphous nature of SLNs, combined with the inclusion of a
lyoprotectant, enables a significant level of hydrogen bonding. Mannitol, for example, has the
capability to form bonds with the polar head of surfactant molecules, limiting particle
interaction due to steric hindrance and promoting efficient dispersion of particles in the
medium.

Drug-Loading Capacity of SLNs

The drug’s physicochemical characteristics, the lipid core utilized, and the drug solubility in
the lipid matrix collectively influence the drug-loading capability of solid lipid nanoparticles
(SLNs). Generally, hard fats, owing to their crystalline nature, can incorporate a greater amount
of drug compared to pure monoacid triglycerides. As the melted lipid cools, the drug tends to
crystallize out. Therefore, the amount of drug added should be less than the saturation solubility
of the drug in the lipid to prevent drug expulsion. The presence of mono-glycerides or
diglycerides, along with the surfactant, enhances drug solubility. Optimal drug-loading
capacity can be achieved by using polydisperse lipids commonly employed in the cosmetics
industry for SLN formulation. Several drugs have been investigated as potential candidates for
incorporation into SLNs. These include Paclitaxel, Carmustine (Ak et al., 2021), Doxorubicin
(Darabi et al., 2022), Cephalexin (Nasrollahzadeh et al., 2022), Thymopentin, Diazepam
(Faghihi et al., 2022), Retinol (Kumar et al., 2020), Acyclovir, Tetracaine, Cyclosporine, Azido
thymidine palmitate, Dopamine (Cometa et al., 2020), Triamcinolone Acetonide (Talarico et
al., 2023), Camptothecin, Piribedil.

Method of Preparation

High-Shear Homogenization/High-Speed Homogenization and Ultrasonication

According to Mahajan et al., (2018), increasing the stirring speed does not consistently lead to
a significant alteration of particle size. However, it does result in a slight increase in the
polydispersity index. The method described above can be effectively enhanced by integrating
ultrasonication, a process that utilizes high-frequency cavitation energy. This integration
enables the reduction of dispersed particles to nano size. The procedure involves mixing all the
ingredients with melted lipid. Subsequently, the liquid phase, heated to a similar temperature,
is introduced to the mixture, and its emulsification is done using an ultrasonicator or a high-
speed stirrer. This process is also referred to as hot homogenization. The high-shear
homogenization method is suitable for large-scale production. Moreover, higher drug loading
can be carried out, and the use of organic solvents is limited.
16 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

High-Pressure Homogenization
High-pressure homogenization (HPH) is a widely employed technique for Solid Lipid
Nanoparticle (SLN) production, offering potential for industrial-scale manufacturing. In this
method, pressure is applied in the range of a few hundred to 2010 bar, and the lipid core content
can reach up to 40%. The fabrication of SLNs using HPH can be classified into two approaches:
hot and cold (Shinde et al., 2019).
In the hot homogenization method, the temperature is initially set 5-10°C higher than the
melting point of the lipid. The Active Pharmaceutical Ingredient (API) and excipients are then
dissolved in the melted lipid, and the mixture is dispersed in the surfactant (aqueous phase)
using a mixer, resulting in the creation of a pre-emulsion. The application of heat reduces
viscosity due to elevated temperature, leading to the formation of smaller and more evenly
distributed particle sizes (Mesa et al., 2020). The cold homogenization method involves
dissolving the API and other components in melted lipids. Subsequently, the mixture is rapidly
cooled in dry ice or liquid nitrogen. The cooled fat undergoes ball milling to generate
microparticles measuring 50-100 µm. Once microparticles are formed, they are mixed into the
cold surfactant phase, creating pre-suspensions. To transform the pre-suspension into a
dispersion system, it undergoes micronization in a high-pressure reactor at low temperature.
HPH is continued until the formation of nanoparticles. The cold homogenization method
emerged as an alternative to address the limitations of the hot homogenization technique, which
involved the use of elevated temperatures (Mishra et al., 2018).

Solvent Evaporation
The fabrication of SLNs using this approach involves emulsification through the addition of fat
that has been pre-mixed in an oil-in-water (o/w) emulsion. Initially, lipophilic components are
dissolved in a mixture of organic solvent and water. Microparticles of fat are then obtained by
evaporating the organic solvent using mechanical stirring or pressure-reducing treatment. The
microparticles of fat undergo precipitation once more to generate nanoparticles (Deshpande et
al., 2017). In a study conducted by Sjostrom et al. (1992), cholesterol acetate nanoparticles
were produced using a specific technique. The nanoparticles obtained, ranging in size from 25
to 100 nm, were generated by employing an emulsifier, specifically lecithin/sodium
glycocholate. In their research, they successfully generated solid lipid nanoparticles stabilized
with phospholipids, leading to the formation of lipid oil-in-water emulsions with favorable
outcomes. The SLNs produced through this method are significantly influenced by the
interaction between fat and surface-active agents or emulgents, as well as the concentrations of
fat employed in the formulation. This technique is applicable for active constituents with head-
labile properties resulting from low-temperature production processes. It also enables the
combination of hydrophilic contents into multiple emulsions like oil-in-water-in-oil (o/w/o)
emulsion (Xu et al., 2022). However, a notable limitation of this approach is the use of organic
solvents and their associated toxicity. Consequently, it becomes imperative to explore
alternative solvents that do not pose any toxicological risks.
 Solid Lipid Nanoparticles for Drug Delivery 17

Other Methods

Several additional fabrication techniques, including the supercritical fluid method, double-
emulsion process, and spray-drying method, have been reported for Solid Lipid Nanoparticle
(SLN) preparation. The supercritical fluid method in SLN formulation offers certain benefits,
such as solvent-free operation. Consequently, this method enables a faster and safer fabrication
process compared to solvent-based methods. Various methods for nanoparticle fabrication
exist, one of which involves the use of the supercritical carbon dioxide solutions technique to
rapidly produce solid SLNs. In this method, substituting the solvent with carbon dioxide
(99.99%) has been found to yield superior results in SLN production. The double-emulsion
method, involving the preparation of water-in-oil-in-water (w/o/w) emulsion, has also been
reported for SLN preparation (Dolatabadi et al., 2015).

Therapeutic Applications
The physicochemical and biopharmaceutical aspects of lipid-based nanoparticles, such as an
improved pharmacokinetic profile, have led to the utilization of SLNs in the treatment of a wide
range of disorders. Table 1 highlights some of the applications of SLNs.

SLNs for Anti-Cancer Agents

Cancer is a disease characterized by altered signaling and metabolism, leading to uncontrolled
cell division (Mishra et al., 2023). It stands as one of the leading causes of mortality globally
(Chen et al., 2018). While chemotherapy is widely accepted for tumor treatment, it comes with
drawbacks such as lower tissue specificity, higher toxicity, a low therapy index, and low drug
solubility. SLNs have been explored to overcome these drawbacks by crossing biological
barriers and delivering drugs to target sites while minimizing toxicity (Bayón-Cordero et al.,
2019). Docetaxel, a lipophilic compound with antimitotic activity, faces challenges due to its
poor water solubility. Docetaxel-loaded SLNs have shown enhanced anti-cancer activity in
breast cancer cells compared to the marketed formulation. Paclitaxel-loaded SLNs have been
investigated for targeting breast carcinoma, showing a high concentration of IC50, indicating
their potency in suppressing tumors in drug-resistant breast cancer cells (Sivadasan et al.,
2023). Curcumin-encapsulated SLNs, prepared via the sonication method, demonstrated
superior drug absorption capabilities at the cellular level. These SLNs, incorporating curcumin
into lipids like Lauric acid, Palmitic acid, or Stearic acid, along with surfactants like Poloxamer
188, Poloxamer 407, Tween 20, or Tween 80, exhibited cytotoxic activity against breast tumor
cell lines (Yeo et al., 2022). SLNs have also shown effectiveness in suppressing the
advancement of colon cancer. Oxaliplatin-loaded SLNs were potent in inhibiting the cell
growth of HT-29 and GCT 116 adreno-cancerous cells (Sivadasan et al., 2023). Additionally,
SLNs have been developed for the combinatorial delivery of anticancer drugs and RNA
material (sRNA or mRNA), resulting in increased cancer cell response to treatment through the
synergistic effect of the two agents (Shi et al., 2014).

SLNs for Anti-Fungal Agents

Invasive Fungal Infections are becoming an increasingly worrying public health issue. These
infections can range from mild, superficial infections to invasive infections that pose life-
threatening risks. Annually, around 1.6 million people succumb to fungal infections, and
18 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

billions of people worldwide are believed to be infected by pathogenic fungi (Balaji et al.,
2020). Ketoconazole-loaded SLNs were formulated using egg lecithin, phosphatidylcholine
95% as the surfactant, and co-surfactants including Poloxamer-188, Span 80, and Tween 80 at
1–2% w/v solid lipid content. SLNs are considered an alternative drug-releasing system with
improved anti-candida efficacy and bioavailability compared to commercial formulations.
Terbinafin hydrochloride, a widely employed oral and topical antifungal drug for the skin, faces
challenges due to its inherent low bioavailability resulting from high first-pass metabolism. The
development of terbinafine-loaded SLNs via a hot high-pressure homogenization method using
lipid and surfactants led to improved bioavailability as well as site specificity (Rarokar et al.,
2022). Similar positive results were obtained for Amphotericin B.

SLNs for Antiviral Agents

Viral infections have the potential to cause significant morbidity and mortality worldwide.
Recent investigations have focused on the fabrication of SLNs loaded with natural constituents
possessing antimicrobial or antiviral activity. Favipiravir SLNs were formulated using the hot-
evaporation technique, employing Compritol 888 as the lipid matrix and Tween 80 as the
surfactant. Studies demonstrated that the developed formulation exhibited better
physicochemical characteristics and possessed anti-SARS-CoV-2 activity (Tulabh et al., 2021).
Acyclovir, commonly used for treating herpes simplex virus infections, faces challenges due to
its low oral bioavailability. Acyclovir-loaded SLNs were prepared using high-shear
homogenization or ultrasonication methods. The use of Acyclovir-loaded SLNs has been
shown to provide better oral bioavailability compared to marketed formulations of acyclovir
(Hassan et al., 2020).

SLNs for Antibacterial Agents

Antibiotic resistance stands as one of the most pressing health issues faced by the population
today. The overuse of antibiotics has led to the emergence of antibiotic-resistant bacteria,
necessitating the exploration of new treatment options to combat them (Bhardwaj et al., 2022).
Gram-negative bacteria can develop resistance to antibiotics by reducing cell membrane
permeability through the development of resistance factors. However, solid SLNs offer a more
effective and potent drug delivery system for antibiotic agents, overcoming antibiotic
resistance. Rifampicin was incorporated into SLNs using a modified microemulsion/sonication
method, with stearic acid as the matrix lipid, Poloxamer 407 as the surfactant, and Lipoid S-
100 as a co-surfactant. Studies concluded that solid lipid nanoparticles serve as a promising
drug delivery system, enhancing the microbicidal activity of the drug against Brucella abortus
compared to free Rifampicin solution (Gülsel, 2021). Another investigation concluded that
doxycycline-loaded SLNs exhibit potent antibiotic effects against chronic brucellosis.

SLNs for Antioxidants

Various active compounds and antioxidants are encapsulated into SLNs using a diverse variety
of lipid matrices and fabrication methods. Beta-carotene, an antioxidant compound, is one
example incorporated into SLNs using a lipid matrix of glyceryl monostearate through the hot
homogenization method, resulting in increased stability, better bioavailability, and efficacy
(Subroto et al., 2023). Vitamin E, known for its antioxidant properties and therapeutic benefits,
can be loaded into various nanovesicles, including SLNs and nanostructured lipid carriers
 Solid Lipid Nanoparticles for Drug Delivery 19

(NLCs). Research has shown that γ-tocotrienol-loaded SLNs possess better oral bioavailability
(Mohd et al., 2020).

Miscellaneous Applications

SLNs serve as a promising drug delivery system for topical applications of various drugs. The
factors governing the bioavailability of SLNs on topical administration include the dosage form
and drug release, although the mechanisms are still not fully understood (Gülsel, 2021). In
ophthalmic drug delivery, where formulations face challenges due to complex barriers, SLNs
improve drug bioavailability and are significantly employed as topical ocular drug delivery
systems. For example, clarithromycin, a broad-spectrum macrolide antibiotic, is encapsulated
into SLNs via the ultrasonication method using stearic acid as the lipid matrix, Tween80 as the
primary surfactant, and Transcutol P as a secondary surface-active agent based on solubility
criteria.

Stability and Toxicological Concerns

The stability of SLNs is predominantly influenced by factors such as lipid composition,

surfactant concentration, and temperature optimization during the formulation process.
Therefore, it is crucial to consider all these factors to assess their stability and storage
requirements. Triglycerides undergo three distinct crystal modifications, namely α (alpha), β
(beta), and β′ (beta prime), during various stages of synthesis and storage. The polymorphic
transitions of these substances depend significantly on their chain length, with longer chain
triglycerides exhibiting a slower crystallization process compared to shorter chain triglycerides.
Gel formation in SLNs can occur, and the ability to form a gel is greatly affected by the β′
alteration induced by exposure to light, temperature, and shear force. The assessment of the
biocompatibility of SLNs is a crucial aspect in formulation development research. The IC50
value, or half maximum inhibitory concentration, is widely considered an effective approach
for evaluating and comparing cell viability. Evaluating cell sensitivity to different lipidic
formulations is commonly done by quantifying cell viability, as cells generally have a low
tolerance for higher concentrations of lipid carriers. An additional concern related to SLNs
involves the need for cytotoxicity studies to determine if lipids and other excipients, although
considered generally recognized as safe (GRAS), have any detrimental impact on cellular
function. Residual solvents in SLNs are also a cause for concern. Fabrication techniques focus
on minimizing or eliminating the use of hazardous organic solvents and other toxic constituents.
Another important aspect to consider regarding SLNs is the potential for DNA damage,
resulting from base oxidation, strand breakage, or disruption of DNA repair mechanisms.

Challenges to Clinical Translation

SLNs have been successfully utilized in the dermatological and cosmetic industry, but their
application in the pharmaceutical sector is still awaiting significant advancement.
 Table 1. Compilation of various SLNs prepared for management of various diseases

Drug Particle Lipid Matrix Surfactant Fabrication method Application Inference Reference
size (nm)
Curcumin ~130 Maslinic Acid Poloxamer, solvent-displacement Anti-cancer Enhancement of solubility and (Aixa et al., 2023)
Dicarboxylic acid- method bioavailability
Poloxamer 407
Doxorubicin 150-200 Tripalmitin and Polysorbate 80 micro-emulsion (O/W) Anti-cancer Targeted delivery of doxorubicin (Soltani and
Stearic Acid technique Pakravan,2023)
5-Flurouracil 130 ± 5 Precirol Poloxamer, Lecithin cold homogenization Anti-cancer Enhanced targeted drug delivery (Smith et al., 2020)
technique
Amphotericin 175-200 glycerol soybean lecithin and solvent emulsification- Anti-fungal Low toxicity, improved efficacy (Mehrabani et al.,
B monostearate tween 80 evaporation technique 2020)
(GMS)
β-sitosterol 140-155 Compritol, tween 80 Solvent diffusion and Anti- enhanced systemic bioavailability, (Zhang et al.,
Phospholipid hot homogenization inflammatory higher anti-inflammatory response 2020)
90 G
Tacrolimus 439-669 Stearic Acid Polysorbate 80 and solvent evaporation In Atopic Enhancement of drug permeation (Khan et al., 2022)
sorbitan monooleate method Dermatitis into the skin, improved skin drug
retention
xanthene 190-210 Precirol Tween 80 Ultrasonic solvent Antioxidant Enhanced entrapment efficiency, (Torrisi et al.,
lignans emulsification improved biocompatibility 2022)
 Solid Lipid Nanoparticles for Drug Delivery 21

The clinical translation of SLNs involves various challenges and obstacles that need to be
addressed so as to facilitate the successful transition of these drug delivery systems from the
laboratory to large-scale manufacturing. A comprehensive comprehension of the
pharmacokinetic and pharmacodynamic characteristics of SLNs is crucial in order to guarantee
optimal therapeutic effectiveness and establish an efficient dosage regimen.
The demonstration of clinical efficacy is crucial in gaining acceptance from both the
medical community and patients for sublingual nanoparticles (SLNs) in comparison to other
methods of drug delivery. The identification and strategic planning of challenges related to
enhancing drug targeting to specific tissues and ensuring tissue penetration are crucial. Prior to
the utilization of SLNs in clinical trials or scale up production, it is imperative to conduct safety
and toxicity evaluations. This encompasses the assessment of possible acute and long-term
toxicity, immunogenicity, and bio distribution of these lipidic nanoparticles in an in vivo
setting. A Scalable, robust and hassle-free manufacturing process is another consideration that
needs thorough analysis before proceeding towards large-scale quality manufacturing. Stability
may also be a cause of concern with SLNs, including the occurrence of particle aggregation,
drug leakage, or alterations in physical characteristics throughout the duration of storage. The
assurance of the long-term stability of SLN formulations is of utmost importance in the context
of clinical translation. Another challenge in the production of SLNs is the ability to achieve
high drug loading and controlled drug release which is contingent upon the characteristics of
the drug and lipid employed. The optimization of these factors is crucial in order to achieve
optimal therapeutic effect. Obtaining regulatory approval for drug delivery systems, such as
SLNs, can pose a substantial challenge due to the need to comply with regulatory criteria.
Regulatory approval necessitates the availability of comprehensive preclinical and clinical data,
and strict adherence to Good Manufacturing Practices (GMP). Furthermore, it is necessary to
explore novel methodologies employed by regulators to develop new frameworks for
technology governance that enhance comprehension and implementation. Additionally, there
is a need to establish consistency among current regulations through harmonization efforts. The
utilization of statistical tools, such as cost-effective analysis, can be beneficial in attracting and
persuading external investors to support the extensive production of SLNs. The management
of intellectual property presents challenges in the clinical translational process, especially when
multiple entities are involved in the development. These challenges arise due to concerns
regarding patent protection and licensing agreements. Resolving these obstacles requires a
collective endeavor involving researchers, pharmaceutical companies, regulatory authorities,
and funding entities. Successfully implementing SLNs in clinical settings necessitates
overcoming these challenges and providing evidence supporting the safety, effectiveness, and
feasibility of SLN-mediated drug delivery systems in real-world clinical environments.

Conclusion

SLNs emerge as a favorable carrier for drug delivery. The utilization of solid lipids allows for
greater drug loading compared to other vesicular carriers and prevents drug expulsion from the
formulation. SLNs can be prepared through various methods and find applications in the
treatment of a spectrum of diseases. They have been reported for effective drug targeting,
improved bioavailability, and reduction in toxicity. Additionally, SLNs show promise in
22 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

overcoming antibiotic resistance. Due to their wide applicability, SLNs hold significant future
prospects in drug delivery, provided challenges related to scale-up manufacturing and
regulatory approvals are effectively addressed. The continuous exploration and refinement of
SLN technology are crucial for unlocking their full potential in advancing drug delivery
systems.

References

Aguilera-Garrido, A., Graván, P., Navarro-Marchal, S. A., Medina-O’Donnell, M., Parra, A., Galisteo
González, F. (2023) Maslinic acid solid lipid nanoparticles as hydrophobic anticancer drug carriers:
Formulation, in vitro activity and in vivo biodistribution Biomedicine and Pharmacotherapy, 163, 114828.
Ahmad, I., Pandit, J., Sultana, Y., Mishra, A. K., Hazari, P. P., Aqil, M. (2019). Optimization by design of
etoposide loaded solid lipid nanoparticles for ocular delivery: Characterization, pharmacokinetic and
deposition study. Materials Science and Engineering C – Materials for Biological Applications, 100, 959–
970.
Ak, G., Unal, A., Karakayal, T., Ozel, B., Selvi Günel, N., Hamarat Şanlıer, S. (2021). Brain-targeted, drug-
loaded solid lipid nanoparticles against glioblastoma cells in culture. Colloids and Surfaces. Biointerfaces,
206, 111946.
Alsaad, A. A. A., Hussien, A. A., Gareeb, M. M. (2020). Solid lipid nanoparticles (SLN) as a novel drug
delivery system: A theoretical review. Systematic Reviews in Pharmacy, 11, 259–273.
Bayón-Cordero, L., Alkorta, I., & Arana, L. (2019). Application of solid lipid nanoparticles to improve the
efficiency of anticancer drugs. Nanomaterials, 9(3), 474.
Cacicedo, M. L., Ruiz, M. C., Scioli-Montoto, S., Ruiz, M. E., Fernández, M. A., Torres-Sanchez, R. M.,León,
I. E. (2019). Lipid nanoparticles-Metvan: Revealing a novel way to deliver a vanadium compound to bone
cancer cells. New Journal of Chemistry, 43(45), 17726–17734.
Cancer, U. A. (2020). An unknown territory; rethinking before going ahead. Genes and Diseases, 8(5), 655–
661.
Chen, Z., Zheng, Y., Shi, Y., & Cui, Z. (2018). Overcoming tumor cell chemoresistance using nanoparticles:
Lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles. International
Journal of Nanomedicine, 13, 319–336.
Chopra, H., Dey, P. S., Das, D., Bhattacharya, T., Shah, M., Mubin, S., Maishu, S. P., Akter, R., Rahman, M.
H., Karthika, C., Murad, W., Qusty, N., Qusti, S., Alshammari, E. M., Batiha, G. E., Altalbawy, F. M. A.,
Albooq, M. I. M., Alamri, B. M. (2021). Curcumin nanoparticles as promising therapeutic agents for drug
targets. Molecules (Basel, Switzerland), 26(16), 4998.
Cometa, S., Bonifacio, M. A., Trapani, G., Di Gioia, S., Dazzi, L., De Giglio, E., Trapani, A. (2020). In vitro
investigations on dopamine loaded Solid Lipid Nanoparticles. Journal of Pharmaceutical and Biomedical
Analysis, 185, 113257.
Darabi, F., Saidijam, M., Nouri, F., Mahjub, R., Soleimani, M. (2022). Anti-CD44 and EGFR dual-targeted
solid lipid nanoparticles for delivery of doxorubicin to triple-negative breast cancer cell line: Preparation,
statistical optimization, and in vitro characterization. BioMed Research International, 6253978.
Deshpande, A., Mohamed, M., Daftardar, S. B., Patel, M., Boddu, S. H. S., Nesamony, J. (2017). Solid lipid
nanoparticles in drug delivery: Opportunities and challenges. In Emerging Nanotechnologies for
Diagnostics, Drug Delivery and Medical Devices, 291–330.
Duan, Y., Dhar, A., Patel, C., Khimani, M., Neogi, S., Sharma, P., Vekariya, R. L. (2020). A brief review on
solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. RSC Advances, 10(45),
26777–26791.
Dudhipala, N., Ay, A. A. (2020). Amelioration of ketoconazole in lipid nanoparticles for enhanced antifungal
activity and bioavailability through oral administration for management of fungal infections. Chemistry
and Physics of Lipids, 232, 104953.
Ekambaram, P., Abdul Hasan Sathali, A., Priyanka, K. (2012). Solid lipid nanoparticles: A review, Scientific
Reviews and Chemical Communications, 2(1), 80-102.
 Solid Lipid Nanoparticles for Drug Delivery 23

Ezzati Nazhad Dolatabadi, J. E. N., Valizadeh, H., Hamishehkar, H. (2015). Solid lipid nanoparticles as
efficient drug and gene delivery systems: Recent breakthroughs. Advanced Pharmaceutical Bulletin, 5(2),
151–159.
Faghihi, S., Awadi, M. R., Mousavi, S. E., Rezayat Sorkhabadi, S. M., Karboni, M., Azarmi, S., Ghaffari, S.
(2022). Diazepam loaded solid lipid nanoparticles: In vitro and in vivo evaluations. Advanced
Pharmaceutical Bulletin, 12(1), 86–92.
Fonte, P., Andrade, F., Araújo, F., Andrade, C., das Neves, J., Sarmento, B. (2012). Chitosan-coated solid lipid
nanoparticles for insulin delivery. Methods in Enzymology, 508, 295–314.
Harish, V., Mohd, S., Tewari, D., Pandey, N. K., Vishwas, S., Babu, M. R., Singh, S. K. (2023). Unravelling
the role of solid lipid nanoparticles in drug delivery: Journey from laboratory to clinical trial. Journal of
Drug Delivery Science and Technology, 85, 104616.
Hassan, H., Bello, R. O., Adam, S. K., Alias, E., Meor Mohd Affandi, M. M. R., Shamsuddin, A. F., Basir, R.
(2020). Acyclovir-loaded solid lipid nanoparticles: Optimization, characterization and evaluation of its
pharmacokinetic profile. Nanomaterials, 10(9), 1785.
Jenning, V., Gohla, S. (2000). Comparison of wax and glyceride solid lipid nanoparticles (SLN®).
International Journal of Pharmaceutics, 196(2), 219–222.
Jenning, V., Gohla, S. H. (2001). Encapsulation of retinoids in solid lipid nanoparticles (SLN). Journal of
Microencapsulation, 18(2), 149–158.
Kaur, H., Bassi, P., Monif, T., Khuroo, A., Kaur, G. (2013). Development and validation of high performance
liquid chromatographic method for analysis of clozapine. Pakistan Journal of Pharmaceutical Sciences,
26(3), 465–472.
Khan, A. S., Shah, K. U., Mohaini, M. A., Alsalman, A. J., Hawaj, M. A. A., Alhashem, Y. N., Ghazanfar, S.,
Khan, K. A., Niazi, Z. R., Farid, A. (2022). Tacrolimus-loaded solid lipid nanoparticle gel: Formulation
development and in vitro assessment for topical applications. Gels, 8(2), 129.
Khatak, S., Dureja, H. (2017). Structural composition of solid lipid nanoparticles for invasive and non-invasive
drug delivery. Current Nanomaterials, 2, 129–153.
Kumar, M., Sharma, G., Singla, D., Singh, S., Kakkar, V., Gulati, J. S., Kaur, I. P. (2020). Enhanced oral
absorption of all-trans retinoic acid upon encapsulation in solid lipid nanoparticles. Pharmaceutical
Nanotechnology, 8(6), 495–510.
Kumar, S., Randhawa, J. K. (2013). High melting lipid based approach for drug delivery: Solid lipid
nanoparticles. Materials Science and Engineering. C, Materials for Biological Applications, 33(4), 1842–
1852.
Mahajan, A., Kaur, S., Kaur, S. (2018). Design, formulation, and characterization of stearic acid-based solid
lipid nanoparticles of candesartan cilexetil to augment its oral bioavailability. Asian Journal of
Pharmaceutical and Clinical Research, 11(4), 344–350.
Mehrabani Yeganeh, E., Bagheri, H., Mahjub, R. (2020). Preparation, statistical optimization and in-vitro
characterization of a dry powder inhaler (DPI) containing solid lipid nanoparticles encapsulating
amphotericin B: Ion paired complexes with distearoyl phosphatidylglycerol. Iranian Journal of
Pharmaceutical Research, 19(3), 45–62.
Mesa, J., Hinestroza-Córdoba, L. I., Barrera, C., Seguí, L., Betoret, E., Betoret, N. (2020). High
homogenization pressures to improve food quality, functionality and sustainability. Molecules, 25(14),
3305.
Mishra, R., Bassi, P., Roobal, Shivani. (2023) Drug targeting to cancer cells through stimuli-responsive imine
bonds: fascinating aspects of site specificity. In Polymer-Drug Conjugates, Academic Press, 207-224.
Mohd Zaffarin, A. S., Ng, S. F., Ng, M. H., Hassan, H., Alias, E. (2020). Pharmacology and pharmacokinetics
of vitamin E: Nanoformulations to enhance bioavailability. International Journal of Nanomedicine, 15,
9961–9974.
Morales, J. O., Valdés, K., Morales, J., Oyarzun-Ampuero, F. (2015). Lipid nanoparticles for the topical
delivery of retinoids and derivatives. Nanomedicine, 10(2), 253–269.
Mudgil, M., Gupta, N., Nagpal, M., Pawar, P. (2012). Nanotechnology: a new approach for ocular drug delivery
system. Int J Pharm Pharm Sci, 4(2), 105-12.
24 Harwinder Kaur, Parneet Kaur, Narinderpal Kaur et al.

Nasrollahzadeh, M., Ganji, F., Taghizadeh, S. M., Vasheghani-Farahani, E., Mohiti Asli, M. (2022). Drug in
adhesive transdermal patch containing antibiotic-loaded solid lipid nanoparticles. Journal of Bioscience
and Bioengineering, 134(5), 471–476.
Pathakumari, B., Liang, Guanzhao, Liu, W. (2020). Immune defence to invasive fungal infections: A
comprehensive review. Biomedicine and Pharmacotherapy Biomedecine and Pharmacotherapie, 130,
110550.
Rarokar, N. R., Menghani, S. S., Kerzare, D. R., Khedekar, P. B., Bharne, A. P., Alamri, A. S., Asdaq, S. M.
B. (2022). Preparation of terbinafin-encapsulated solid lipid nanoparticles containing antifungal
Carbopol® hydrogel with improved efficacy: In vitro, ex vivo and in vivo study. Pharmaceutics, 14(7),
1393.
Scioli Montoto, S., Muraca, G., Ruiz, M. E. (2020). Solid lipid nanoparticles for drug delivery:
Pharmacological and biopharmaceutical aspects. Frontiers in Molecular Biosciences, 7, 587997.
Sivadasan, D., Ramakrishnan, K., Mahendran, J., Ranganathan, H., Karuppaiah, A., Rahman, H. (2023).
Solid lipid nanoparticles: Applications and prospects in cancer treatment. International Journal of
Molecular Sciences, 24(7), 6199.
Smith, T., Affram, K., Nottingham, E. L., Han, B., Amissah, F., Krishnan, S., Agyare, E. (2020). Application
of smart solid lipid nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal
cancer. Scientific Reports, 10(1), 16989.
Soltani, A., Pakravan, P. (2023). Preparation and characterization of magnetic solid lipid nanoparticles as a
targeted drug delivery system for doxorubicin. Advanced Pharmaceutical Bulletin, 13(2), 301–308.
Subroto, E., Andoyo, R., Indiarto, R. (2023). Solid lipid nanoparticles: Review of the current research on
encapsulation and delivery systems for active and antioxidant compounds. Antioxidants, 12(3), 633.
Talarico, L., Pepi, S., Susino, S., Leone, G., Bonechi, C., Consumi, M., Magnani, A. (2023). Design and
optimization of solid lipid nanoparticles loaded with triamcinolone acetonide. Molecules, 28(15), 5747.
Torrisi, C., Cardullo, N., Russo, S., La Mantia, A., Acquaviva, R., Muccilli, V., Sarpietro, M. G. (2022).
Benzo[k,l]xanthene lignan-loaded solid lipid nanoparticles for topical application: A preliminary study.
Molecules, 27(18), 5887.
Tulbah, A. S., Lee, W. H. (2021). Physicochemical characteristics and in vitro toxicity/anti-SARS-CoV-2
activity of favipiravir solid lipid nanoparticles (SLNs). Pharmaceuticals, 14(10), 1059.
Yeo, S., Kim, M. J., Shim, Y. K., Yoon, I., Lee, W. K. (2022). Solid lipid nanoparticles of curcumin designed
for enhanced bioavailability and anticancer efficiency. ACS Omega, 7(40), 35875–35884.
Zhang, F., Liu, Z., He, X., Li, Z., Shi, B., Cai, F. (2020). β-sitosterol-loaded solid lipid nanoparticles ameliorate
complete Freund’s adjuvant-induced arthritis in rats: Involvement of NF-кB and HO-1/Nrf-2 pathway.
Drug Delivery, 27(1), 1329–1341.
Chapter 3

Nanoemulsions

Kirti Goel
Purav Gupta
Karan Goel
Jasmine Chaudhary
and Akash Jain
M.M. College of Pharmacy, M.M. (Deemed to be University), Mullana, Ambala, Haryana, India

Abstract

Nanoemulsions, colloidal systems with droplet sizes ranging from 20 to 200 nanometers,
have recently gained interest due to their unique features and wide range of applications.
The chapter initiates with an analysis of the fundamental mechanics of nanoemulsions,
encompassing surfactants, co-surfactants, and the emulsion system. Owing to their
stability, solubilization capabilities, and enhanced bioavailability, nanoemulsions find
popularity in pharmaceuticals, nutraceuticals, and cosmetics. This approach integrates
hydrophilic and hydrophobic pharmacological substances, targeting specific tissues and
facilitating sustained release. Bioactive nanoemulsions exhibit promise in functional
nourishment and personalized nutrition. Exciting opportunities for progress in
nanotechnology emerge when nanoemulsions are combined with other nano-based
platforms, such as nanoparticles and liposomes. Nonetheless, challenges related to
sustainability, compliance, and large-scale production must be addressed for this project to
realize its full potential.

Keywords: nanoemulsions, production, technique

Abbreviations

NE Nanoemulsion
NEs Nanoemulsions
O/W Oil-in-water
W/O Water-in-oil
PDI Polydispersity index


Corresponding Author’s Email: [Link]@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
26 Kirti Goel, Purav Gupta, Karan Goel et al.

HPH High pressure homogenization

PIT Phase inversion temperature
HLB Hydrophilic-lipophilic balance
PIC Phase inversion composition

Introduction

A ‘nanoemulsion’ is created by utilizing surfactant molecules to establish a clear liquid layer

at the interface of two immiscible liquids, such as oil and water. The innovative method for
administering medication involves emulsifying oil within an aqueous solution, resulting in the
formation of droplets ranging in size from 100 to 500 nm. The stability of the nanoemulsion is
attributed to the use of emulsifying agents, which facilitate the formation of a stable
heterogeneous mixture comprising lipid and aqueous phases. Nanoemulsions exhibit
transparency, distinguishing them from normal emulsions and microemulsions. The application
of nanoemulsions holds promise in prolonging drug retention in the human body, enabling a
more significant therapeutic effect with a lower dosage. Similar to low-surface-tension systems,
substances that demonstrate reduced interfacial tension between oil and water phases exhibit
enhanced capabilities in spreading, wetting, and penetrating (Tiwari et al., 2006). The primary
distinguishing factors among traditional emulsions (also known as macroemulsions),
nanoemulsions, and microemulsions lie in their droplet size range and stability properties. Both
macroemulsions and nanoemulsions experience phase separation over time due to inherent
thermodynamic instability. In contrast, nanoemulsions demonstrate enhanced stability due to
their reduced particle size, enabling them to maintain structural integrity over extended periods
(Gupta et al., 2016). Moreover, these substances can be categorized as either o/w or w/o
variants, depending on whether their central core consists of water or oil (Jaiswal et al., 2015).

Formulation Components

Surfactant

To achieve system stabilization, the creation of the nanoemulsion requires the use of three
specific types of surfactants. A surfactant molecule consists of a hydrophilic moiety and a
hydrophobic moiety, forming its molecular structure. The categorization of surfactants in Table
1 is based on the presence of polar moieties.

Table 1. Classification of Surfactants

Types of Surfactant Example

Non-ionic surfactant Fatty alcohol ethoxylate, alkyl phenol ethoxylate and fatty acid alkoxylate etc.
Ionic surfactant They contain sugar ester surfactant like sorbitan monooleate, ethoxylated sorbitan esters
(polysorbates) such as Tween 60
Cationic surfactant Quaternary ammonium salts such as cetyl trimethyl ammonium bromide.
 Nanoemulsions 27

Oils and Co-Surfactants

Nanoemulsions are frequently formulated using various compounds, such as transcutol-P

(diethylene glycol monoethyl ether), glyceryl triacetate, and propanol. Notably, medium-chain
triglycerides exhibit less favorable properties compared to long-chain fatty acids.

Properties of Nanoemulsion

The physicochemical and functional properties of a nanoemulsion, including its composition,

size, electric charge, aggregation state, physical state, and interfacial composition, are strongly
influenced by researchers and producers. They have the capability to modify nanoemulsion
particles to achieve desired physicochemical or physiological properties (McClements & Jafari
et al., 2018). Nanoemulsions consist of an oily and a watery phase linked by surfactant
molecules, and their uniqueness lies in the alignment of these surfactant molecules, contributing
to their versatility and value in various applications.

Physical Properties

The physical properties of nanoemulsions play a crucial role in their stability and application.
Some of these properties are briefly discussed below:

Droplet Size Distribution

Nanoemulsions typically have a particle size ranging from 20 to 200 nm (Jaiswal et al., 2015).
The stability of nanoemulsions is heavily reliant on droplet size and dispersion. Smaller
droplets and reduced agglomeration contribute to lesser phase separation and instability
(Hidajat et al., 2020). However, gravitational settling may induce instability in larger droplets
(Zhou et al., 2022). Therefore, ensuring proper droplet size dispersion during manufacturing is
imperative for nanoemulsion stability (Algahtani et al., 2022). Factors affecting nanoemulsion
droplet size distribution encompass heating and cooling methods, constituents of the oil and
aqueous phases, surfactant ratio and type, initial location, temperature, pH, and stirring speed.
In summary, nanoemulsion stability hinges on proper droplet size distribution, and addressing
factors that influence it is essential for successful nanoemulsion production (Zhou et al., 2022).”

Components of Droplet Size Nanoemulsion

Mean Droplet Size

Mean droplet size represents the average magnitude of a droplet. Its impact on the system
depends on various factors, including the type of surfactant used and its concentration (Sheth
et al., 2020). Nanoemulsions (NEs) containing Tergitol 15-S and water typically exhibit an
average droplet size of around 100 nm.
28 Kirti Goel, Purav Gupta, Karan Goel et al.

Standard Deviation
Standard deviation pertains to the uniformity of droplet size distribution within the
nanoemulsion. A reduced standard deviation indicates a higher level of uniformity in the
distribution of droplet sizes (Che Marzuki et al., 2019a).

Polydispersity
Polydispersity is a measure of the relative variation in droplet size, expressed as a percentage
of the mean droplet size. When the degree of polydispersity is minimal, the diameters of the
droplets exhibit a high level of uniformity (Che Marzuki et al., 2019).

Stability of Nanoemulsions

Physical Stability
An essential aspect of nanoemulsions is their physical stability, given their nature as liquid-in-
liquid dispersions with kinetic stability (Gupta et al., 2016). The small droplets and unique
composition of nanoemulsions enable them to withstand coalescence and phase separation for
extended periods. Enhancing nanoemulsion physical stability can be achieved through the use
of emulsifiers, weighing agents, texture modifiers, and ripening inhibitors (Liu et al., 2019).
These stable nanoemulsions find applications in health, food, cosmetics, and farming due to
their tolerance to temperature and pH fluctuations, requiring less surfactant (Zhou, 2022).

Thermodynamic Instability
Nanoemulsions, while physically stable, are not thermodynamically stable. This is because the
separation of water and oil requires less free energy than building a stable emulsion, rendering
nanoemulsions inherently unstable (Liu et al., 2019). Thermodynamic instability can be
controlled through proper formulation and stabilization techniques.

Chemical Stability
Chemical stability in a nanoemulsion refers to its ability to retain its properties over time.
Antioxidants play a crucial role in preventing the oxidation of unsaturated fatty acids and
stabilizing the chemicals within the nanoemulsion. To maintain chemical stability, it is
important to regularly monitor factors such as pH, droplet size distribution, and the presence of
degradation products.

Viscosity
The qualities and applications of nanoemulsions are intricately linked to their viscosity.
Nanoemulsions with small droplets exhibit viscosity-dependent rheology, influencing their
stability, flow, and overall performance. In the field of medicine, low viscosity facilitates rapid
medication absorption. In culinary and cosmetic contexts, viscosity plays a role in affecting the
mouthfeel, sensory perception of dressings, drink textures, and cosmetic skin absorption.
Tailoring viscosity is crucial for enhancing the spreadability of cosmetics. To optimize the
diverse applications of nanoemulsions across various sectors, a thorough understanding of how
viscosity impacts their performance is essential.
 Nanoemulsions 29

Emulsifier Concentration
The quantity of insoluble emulsifier used is a crucial variable that significantly influences the
stability of nanoemulsions. The gelation behavior of nanoemulsions can be affected by the
concentration of the emulsifier. Research findings indicate that the viscoelastic characteristics
of nanoemulsions are influenced by the concentration of the emulsifier, leading to the
development of viscoelastic gels within specific concentration limits (Erramreddy & Ghosh,
2014). It has been observed that as the surfactant concentration increases, nanoemulsion
stability decreases. Therefore, optimizing emulsifier concentration is crucial for maintaining
nanoemulsion stability (Gupta et al., 2016).

Temperature
The resilience of nanoemulsions is temperature-dependent. Coalescence of droplets can occur
in certain systems due to a decrease in stability resulting from the combined effects of higher
Brownian motion and thermal energy.

Polydispersity index
The particle size distribution index, known as the Polydispersity Index (PDI), quantifies the
range of droplet sizes present in a nanoemulsion. Nanoemulsions with a restricted size
distribution, indicated by a low PDI value, are more likely to be stable and exhibit optimal
performance over time (Bernardi et al., 2011).

Creaming and Flocculation in Nanoemulsion

The physical instability challenges of creaming and flocculation can impact the stability of
nanoemulsions. Creaming involves the formation of a dense layer due to the redistribution of
globules, while flocculation refers to droplets aggregating without significant mixing (Jaiswal
et al., 2015). Enhancing the creaming rate at low and medium volume fractions can be achieved
by employing flocculation techniques in nanoemulsions (Rauf et al., 2023). This implies that
the presence of flocculated droplets might enhance the rate of separation in an emulsion, leading
to creaming. Nanoemulsions are susceptible to various forms of physical instability, including
creaming and flocculation, due to their small droplet size and thermodynamic instability
(McClements, 2021). The incorporation of stabilizers, such as emulsifiers and weighing agents,
can effectively mitigate or eliminate these issues, thereby enhancing the overall stability of the
nanoemulsion (Sondari & Tursiloadi et al., 2018). Nanoemulsions that have been effectively
developed using stabilizers may exhibit negligible creaming or flocculation, even following a
30-day storage period at elevated temperatures.

Method of Preparation of Nanoemulsion

Nanoemulsions can be synthesized using various methods, including high-energy or low-

energy spontaneous emulsification techniques. High-energy techniques employ mechanical
energy to produce nanoemulsions, aiming to reduce droplet size and achieve uniform
dispersion. These methods offer enhanced control over the rheology, stability, and particle size
30 Kirti Goel, Purav Gupta, Karan Goel et al.

distribution of the emulsion (M. Kumar et al., 2019). The droplet size is influenced by factors
such as the equipment used, manufacturing parameters (temperature and time), and the
properties and composition of the sample. However, high-energy processes are characterized
by high costs due to the use of expensive apparatus and the significant investment of time and
resources. Additionally, these procedures may not be suitable for processing thermolabile
active components, such as retinoids, as well as macromolecules, including proteins, enzymes,
and nucleic acids (Graves et al., 2005; Qian & McClements et al., 2011). Figure 1 illustrates
the high-energy methods for preparing oil-in-water nanoemulsions (Aswathanarayan & Vittal
et al., 2019).

Figure 1. Overview of high energy method for preparing O/W nanoemulsions.

High Pressure Homogenisation

This methodology utilizes various forces, including hydraulic shear, intense turbulence, and
cavitation, and is commonly employed for nanoemulsion production. Nanoemulsions are
created by subjecting two liquid phases, each containing surfactants and cosurfactants, to high
pressure (ranging from 500 to 5000 psi) as they pass through a narrow hole in a piston
homogenizer. When considering the preparation of nanoemulsions, HPH encompasses several
crucial components and offers various advantages.

Particle Size Reduction

Nanoemulsions, colloidal dispersions with droplet sizes typically ranging from 20 to 500 nm,
can be produced using HPH, effectively reducing the droplet size of the emulsion. The
preference for small droplet size in medication administration and other applications arises
from its ability to provide a significantly larger surface area, facilitating enhanced drug
absorption and targeting.
 Nanoemulsions 31

Controlled Formulation
HPH can optimize the formulation properties of the nanoemulsion, including its composition,
droplet size, and stability (Håkansson, 2018). Precise control enables optimization for various
applications, such as enhancing drug solubility and facilitating targeted distribution
(Håkansson, 2018; Sharma et al., 2015).

Enhanced Mixing
This technique improves the solubility and bioavailability of the nanoemulsion through
enhanced intermixing between the oil and water phases.

Versatility
Improved homogenization of the oil and water phases within the nanoemulsion leads to
increased solubility and bioavailability (Håkansson, 2018).

Microfluidization

A 500–20,000 psi displacement pump mixes nanoemulsions. Microchannel technology presses

and circulates fluid in an interaction chamber. After flowing via microchannels, fluid may form
nanoscale particles in an impingement zone. A pre-existing microemulsion is added to the
microfluidizer and processed to make a nanoemulsion with the appropriate qualities. High-
pressure homogenization and microfluidization yield NEs. They provide comparable effects
yet have distinct capacities. HPH handles higher viscosities in mass production.
Microfluidization is used for its droplet reduction and homogenization precision.

Ultrasomication

Sonication involves the application of high-amplitude sound waves to a system. Sonicator

probes, by generating mechanical vibration in a liquid, facilitate the creation of cavitation
(Jaiswal et al., 2015). Cavitation occurs when vapor cavities collapse due to fluid movement.
Localized variations in velocity induce the formation of a vapor cavity by reducing pressure to
the liquid’s temperature during flow. To minimize internal phase droplets, ultrasonic power is
increased until a threshold is achieved. Interestingly, higher ultrasonic power has little effect
on droplet size (Koroleva & Yurtov et al., 2012a). Only at the optimal frequency and duration
can sound waves effectively reduce droplets to nanoscale sizes. This method is recommended
as it requires less surfactant.

Low Energy Approach

The innovative methodologies employed in the manufacturing of nanoemulsions (NEs)

demonstrate a higher degree of simplicity compared to their traditional counterparts. Unlike
high-energy methods, low-energy methods rely on the phase transitions of the emulsion system,
32 Kirti Goel, Purav Gupta, Karan Goel et al.

which occur due to changes in temperature or composition (Chime et al., 2014; McClements et
al., 2012).
Nanoemulsions can be efficiently produced through a straightforward stirring process that
requires minimal agitation. The low-energy emulsification method utilized taps into the
inherent chemical energy within the system, resulting in enhanced energy efficiency (Solans &
Solé et al., 2012). Figure 2 illustrates a low-energy method for preparing nanoemulsions.

Phase inversion temperature

Figure 2. Overview of low energy methods for preparing W/O nanoemulsions.

Phase Inversion Temperature

PIT, or Phase Inversion Temperature, denotes the specific temperature at which the phase
structure of an emulsion undergoes a transition from oil-in-water (O/W) to water-in-oil (W/O)
or vice versa. Polyethoxylated surfactants, among other non-ionic surfactants with solubility
dependent on temperature, play a crucial role in various applications. Emulsification occurs
due to changes in the affinities between the surfactant and water, as well as the surfactant and
oil, influenced by temperature variations. Upon exposure to heat, polyethoxylated surfactants
undergo dehydration of the polyoxyethylene moieties, transforming the surfactant into a
lipophilic state. This example highlights the effectiveness of the PIT method in producing
nanoemulsions (Changediya et al., 2019). When the hydrophilic and lipophilic properties of the
surfactant are balanced, an equilibrium state, known as the HLB (Hydrophilic-Lipophilic
Balance) temperature, is achieved. At this temperature, emulsions become highly unstable as
the curvature approaches zero. To prevent coalescence and achieve stable nanoemulsions, a
rapid temperature shift is implemented, typically increasing or decreasing the HLB temperature
by around 25-30°C (Kumar & Sunil, 2014).

Emulsion Inversion Point

The method outlined in this study relies on alterations in concentration rather than temperature
fluctuations to generate nanodroplets, employing a mechanism akin to precipitation-induced
phase separation. The surfactant composition plays a pivotal role in the phase inversion, leading
 Nanoemulsions 33

to its designation as the Phase Inversion Composition (PIC) method. Various amounts of
surfactants, potentially including alcohols or electrolytes intermittently, are used along with
components that modify the Hydrophilic-Lipophilic Balance (HLB) of the surfactant (Koroleva
& Yurtov et al., 2012b).
Due to the relative ease of incorporating a single component into an emulsion compared to
achieving a rapid temperature shift, the PIC technique is considered more favorable for large-
scale production. The introduction of water into the system increases the water content,
inducing a modification in the system’s composition. In simple terms, as the polyoxyethylene
chains of the surfactant experience increased hydration, the tendency for its spontaneous motion
to exhibit negative curvature diminishes and approaches zero (Changediya et al., 2019).

Spontaneous Emulsion
Low-energy spontaneous emulsification is a method that allows the production of
nanoemulsions at room temperature without the need for additional equipment. The
emulsification process is influenced by various characteristics, including interfacial tension,
interfacial and bulk viscosity, phase transition zone, surfactant arrangement, and surfactant
concentration, all of which collectively impact its spontaneity (Bouchemal et al., 2004).
The process involves three main steps:

1. The combination of oil and a lipophilic surfactant with a water-miscible solvent and a
hydrophilic surfactant to create a uniform organic solution.
2. Creation of a water-in-oil emulsion by adding the organic phase to the water phase
while stirring magnetically.
3. Evaporation of the water-miscible solvent under conditions of low pressure

Nanoemulsion Applications

Nanomedicines for drug delivery can be developed using nanoemulsions, utilizing emulsions
and surfactants due to their ease of production and well-characterized nature. The nanoscale
size of these entities enables them to travel further and circulate longer in tissues, fostering
novel bio-nano interactions. The oil core of nanoemulsions can accommodate hydrophobic
chemicals such as medications, photosensitizers, and contrast agents, while the outer layer is
water-based. Loading ingredients into the core structure enhances disease site delivery and
reduces the breakdown of protective components.

Oral Drug Delivery

Oral drug delivery systems serve as a non-invasive method for medication administration and
are widely used in the pharmaceutical industry due to their simplicity, ease, and affordability.
This technique has proven successful in achieving therapeutic goals, particularly in cases where
patient compliance is high. However, certain patient groups, such as geriatric, juvenile, and
potentially post-traumatic epileptic patients with limited compliance, may not benefit from oral
drug delivery. Many medications, particularly those with undesirable physicochemical
34 Kirti Goel, Purav Gupta, Karan Goel et al.

characteristics, face challenges related to solubility, stability, and absorption in the

gastrointestinal system (Mallick et al., 2007). Peptide drugs may experience reduced
bioavailability and intestinal absorption due to hydrolysis and enzymatic degradation.
Additionally, some drugs may exhibit decreased effectiveness due to their inability to penetrate
the cellular barrier of the epithelium.

• Encapsulation of hydrophobic drug molecules into nanoemulsions has been shown to

enhance their solubility and improve oral bioavailability.
• Nanoemulsions inhibit the degradation of pharmaceuticals in the gastrointestinal tract,
leading to improved bioavailability.
• They can be utilized in the formulation of both immediate-release and extended-release
medications.”

Intravenous Drug Delivery

After oral delivery, parenteral medication administration stands as the second most common
method. It serves as the primary non-oral medication delivery route for many medical
conditions, enabling immediate action in emergencies. Unlike the lengthy absorption process
associated with oral administration, intravenous administration allows for prompt action. Due
to the rapid onset of effects and lower bioavailability, oral administration is generally preferred
in non-emergency situations. However, parenteral administration is crucial in emergencies,
overcoming the challenges of solubility and instability in water (Sutradhar & Amin et al.,
2013a). In instances where drug molecules face solubility and instability issues in water,
nanoemulsions serve as optimal solutions, mitigating challenges and facilitating the effective
advancement of parenteral drug administration.

• Nanoemulsions play a role in the development of intravenous drug administration

systems for pharmaceutical compounds with low water solubility.
• They reduce the likelihood of negative reactions to medication and address issues such
as drug precipitation and aggregation.
• Nanoemulsions enable controlled release of drugs over time.

Topical Drug Delivery

Nanoemulsions, colloidal systems comprising oil and water effectively stabilized with
surfactants and cosurfactants, show promise in facilitating accurate transdermal drug
administration (Souto et al., 2022). Several studies have demonstrated the efficacy of
nanoemulsions in enhancing the solubility of pharmaceuticals intended for topical application.
Applications of topical drug delivery for nanoemulsions include:
 Nanoemulsions 35

Transportation of Drugs through the Skin

Emulsions, particularly nanoemulsions, offer a significant possibility for enhancing drug
penetration, thereby improving therapeutic efficacy and reducing side effects (Wilson et al.,
2022).

Therapies for Topical Diseases

Nanoemulsions can be used to develop highly effective nanomedicines for conditions like
eczema, acne, and psoriasis. Traditional corticosteroids and retinoids often face limitations in
skin penetration, causing issues such as skin atrophy, irritation, or sensitivity. Nanoemulsions
enhance drug penetration, improving therapeutic efficacy and minimizing adverse effects. The
pharmaceutical industry has made significant advancements in developing practical
applications, showing substantial utility (Alhasso et al., 2023; Donthi et al., 2023; Eqbal et al.,
2021).

Cancer Therapy

The promising potential of nanoemulsions in cancer therapy stems from their ability to bypass
multidrug resistance (MDR) processes, selectively target cancer cells, and solubilize
hydrophobic medications (Sánchez-López et al., 2019).

Treatment of Different Types of Cancer

Extensive research has explored the use of nanoemulsions as a potential therapeutic approach
for various forms of cancer, including melanoma, lung cancer, and breast cancer (Cheng et al.,
2021; Choudhury et al., 2019).

Targeting Specifically Cancer Cells

Nanoemulsions can be modified with various ligands to selectively target specific components
present on the surface of tumor cells, enhancing therapy efficacy while minimizing undesired
side effects (Sánchez-López et al., 2019).

Overcoming Multidrug Resistance (MDR) Mechanisms

Multidrug resistance (MDR) is a significant challenge in managing various diseases, including
cancer and infectious disorders. Nanoemulsions have been proposed as a prospective approach
to overcoming MDR mechanisms by augmenting drug administration and addressing the
fundamental factors contributing to resistance.

Reduced Toxicity
By encapsulating medications into their core, nanoemulsions have demonstrated the ability to
increase payload delivery and reduce toxicity (V. Kumar et al., 2022; Sánchez-López et al.,
2019).
36 Kirti Goel, Purav Gupta, Karan Goel et al.

Personalized Treatment
Theranostic nanoemulsions hold the potential to provide personalized treatment for cancer
patients, offering a targeted and tailored approach to therapy (Gorain et al., 2020; V. Kumar et
al., 2022).

Vaccine Therapy
The immunogenicity of vaccines has been significantly enhanced through the incorporation of
nanoemulsion as an adjuvant (Huang et al., 2020). Adjuvants play a crucial role in augmenting
vaccine immunogenicity, and the use of nanoemulsion adjuvants holds substantial potential for
improving the efficacy of vaccinations against infectious diseases and cancer (Zhao et al.,
2020). The investigation of nanoemulsions, including TLR7/8 agonists, as adjuvants in cancer
vaccines has been a subject of research. Studies have explored their therapeutic efficacy both
in isolation and in combination with other treatments (Koh et al., 2021). The utilization of a
nano-enhanced vaccine for the immunotherapy of metastatic melanoma has demonstrated an
increased effectiveness of checkpoint blockade treatment, leading to elevated susceptibility to
this therapeutic approach.

Herbal Formulation
The utilization of nanoemulsion as a nanocarrier technology has shown promise in delivering
herbal bioactives (Harwansh et al., 2019). This application enhances the bioavailability and
absorption of herbal bioactives, leading to a reduction in the required dose and the potential for
adverse effects (Harwansh et al., 2019). Nanoemulsions can selectively target herbal bioactives,
extending the duration of blood-plasma concentration (Hazarika et al., 2020). In a study aiming
to investigate the potential anti-diabetic benefits of nettle and fenugreek extracts, as well as
cumin essential oil, researchers produced an oil-in-water nano-emulsion (Javadi et al., 2021).

Target Drug Delivery

The implementation of nanoemulsion as a customizable drug delivery strategy holds promise

in enhancing therapeutic efficacy and overcoming limitations associated with traditional drug
delivery approaches. Nanoemulsion utilization has been observed to offer various benefits in
precisely administering drugs to specified locations through multiple processes in different
ailments, as summarized in Table 2. Emulsion-based systems for targeted medication delivery
are considered a superior choice in nanomedicine due to their enhanced biodistribution and
reduced non-specific absorption compared to conventional therapies (Wilson et al., 2022).
Nanoemulsions, incorporating both hydrophilic and lipophilic units, have the capacity to
accommodate a diverse array of targeting moieties and drug classes (Sutradhar & Amin, 2013).
The incorporation of targeting ligands or antibodies with affinity towards specific receptors or
antigens on the surface of target cells or tissues can be applied as a strategy to enhance the
effectiveness of nanoemulsions. Active targeting facilitates the enhanced delivery of drugs to
specific regions, such as tumor cells, while minimizing potential harm to adjacent healthy
tissue.
 Table 2. Review of nanoemulsion formulation developed for the treatment of several disorders like cancer, hypertension, and inflammation

Drug class API Polymer used Lipid/Oil Outcomes Ref.

Anticancer drugs
Pyrimidine 5-Fluorouracil Chitosan powder/ -- This study demonstrates the successful loading of curcumin/5-3uorouracil (Pourmadadi et al.,
antagonists curcumin into a nanocarrier, highlighting its potential as a therapeutic option for 2022)
specifically targeting cancer cells.
Folate antagonist Methotrexate -- Olive oil This study demonstrates that nanoemulsions filled with methotrexate have a (Jang et al., 2020
significant capacity to enhance the targeted delivery of methotrexate to the
lymphatic system
Cyclooxygenase-2- Etoricoxib Isopropyl -- The nanoemulsion exhibited potential and lethal effects on lung cancer cells (Md et al., 2021)
inhibitor Myristate by inducing apoptosis/necrotic cell death and causing S-phase cell cycle
arrests in A549 cells
Platinum Oxaliplatin -- Capryol 90 In this investigation, oral metronomic chemotherapy was conducted (Choi et al., 2020)
coordination utilizing a multiple nanoemulsion called OXA/DCK-NE, which was
complexes specifically designed for the oral administration of OXA/DCK complex
Antimetastatic Piplartine -- Capmul The piperine nanoemulsions enhanced the absorption of PL, substantially (Fofaria et al., 2016)
PG-8 suppressed the proliferation of melanoma tumors in live organisms, and
demonstrated no signs of toxicity during prolonged usage.
Carmustine Phosphatidylcholine Trioleate The application of this novel formulation for the treatment of canine (Lucas et al., 2015)
lymphomas has been proven to be effective as well as safe when used in
combination with other drugs. This success encourages further investigation
through larger-scale research
Anti-Hypertensive Drugs
AT II receptor Telmi-sartan Chitosan Sefsol 218 The study discovered that using telmisartan, a mucoadhesive nanoemulgel (Teaima et al., 2020)
blockers and oleic coated with chitosan, is a promising method for treating dementia. This
acid medicine can be administered directly to the brain through the nasal route
CCB Isradipine -- Tricetin This study exhibited enhanced solubility and dissolution profile of (Sadoon & M.
isradipine Ghareeb, 2020)
AT II receptor Telmi-sartan -- Oleic-acid The optimized formulation exhibited superior stability and drug release (Chin et al., 2021)
blockers when compared to the conventional formulation, resulting in enhanced
bioavailability
 Table 2. (Continued)

Drug class API Polymer used Lipid/Oil Outcomes Ref.

ACE inhibitor Captopril Curcumin Glyceryl This research shows that the NE formulation and curcumin’s combined (Malkawi et al., 2020)
Mono-oleate effect on captopril function make the drug even less soluble.
NSAIDS DRUGS
Preferential COX-2 Meloxicam -- Peppermi-nt MX-SNELCs that were successfully made worked better than the usual (Sindi et al., 2021)
inhibitor oil tablet dosage form, which suggests that they could be further developed into
a clinically acceptable way to treat periodontal pain.
Acetic acid Indomethacin- D-limonene This nanoparticle, consisting of many components, has the potential to (Assali & Zohud,
derivatives paracetamol overcome the limits of NSAIDs and enhance the effectiveness of anti- 2021)
inflammatory therapy. It achieves this by encapsulating a small-sized
nanoemulsion within PCL nanoparticles, allowing for the combination of
medicines with various modes of action.
Propionic acid Naproxen -- Oleic acid This investigation provided evidence that vehicles containing specific (Abd et al., 2019)
derivative excipients, which are known to alter the properties of the skin, were
specifically seen to enhance the permeation of caffeine and naproxen
through the skin
 Nanoemulsions 39

Future Advancements in Nanoemulsion

The field of nanoemulsions continues to evolve, with ongoing research and technological
advancements leading to exciting developments. Here are some potential future advancements
in nanoemulsions:

Smart Nanoemulsion
Smart nanoemulsions represent a distinct category capable of releasing their contents in
response to specific environmental cues, such as changes in pH, temperature, or exposure to
light (Angelico et al., 2022). Ongoing research is exploring their potential in drug delivery
systems to enhance the bioavailability and efficacy of pharmaceuticals.

Biodegradable Nanoemulsions
A noteworthy subtype of nanoemulsions is the biodegradable variant, exhibiting better
environmental compatibility and enhanced long-term sustainability (Maurya et al., 2021).

Nanomedicine Advancements
Nanomedicine, an interdisciplinary field that combines nanotechnology with medicine, enables
the treatment of diseases by the utilization of nanoparticles, nanostructured surfaces, and
nanoanalytic probes (Mago et al., 2022). The field of nanomedicine has had a transformative
influence on drug delivery and treatment choices, leading to improvements in pharmaceutical
efficacy, bioavailability, dose-response, targeting capabilities, antimicrobial resistance
countermeasures, and safety (Mago et al., 2022). Nanomedicine exhibits considerable potential
with several prospective uses in the foreseeable future.

Nanotoxicology and Safety

Comprehensive Safety Assessment: As nanoemulsions find wider use, research into their
potential toxicity and safety profiles will be critical to ensure their safe application in various
fields. The future advancement of nanoemulsion creation will be propelled by interdisciplinary
investigations that unite researchers in the fields of chemistry, materials science,
nanotechnology, and related disciplines. The advancement of knowledge and technology has
the potential to bring about substantial changes in several industries, such as medication
delivery, cosmetics, and food processing, through the utilization of nanoemulsions.

Conclusion

Studies on nanoemulsions are expected to increase. However, several challenges remain to

integrate nanoemulsions into the mainstream pharmaceutical industry and apply them from lab
to patient. Main considerations include the cost burden of growing nanoemulsion production,
the quest for safe solvents in formulation, and the need to update the toxicity database for the
various compounds used in nanoemulsions. This chapter highlights NE-based systems as the
best option for multiple therapy delivery methods. Formulators are using NE to deliver
degraded or difficult medicinal compounds because of its compelling physicochemical
40 Kirti Goel, Purav Gupta, Karan Goel et al.

properties. Therapeutic chemicals are administered faster, more effectively, and safely due to
their nanosize and larger surface areas. This surpasses typical therapies and formulations.

References

Abd, E., Benson, H. A. E., Mohammed, Y. H., Roberts, M. S., Grice, J. E. (2019). Permeation Mechanism of
Caffeine and Naproxen through in vitro Human Epidermis: Effect of Vehicles and Penetration Enhancers.
Skin Pharmacology and Physiology, 32(3), 132–141.
Algahtani, M. S., Ahmad, M. Z., Ahmad, J. (2022). Investigation of Factors Influencing Formation of
Nanoemulsion by Spontaneous Emulsification: Impact on Droplet Size, Polydispersity Index, and
Stability. Bioengineering, 9(8), 384.
Alhasso, B., Ghori, M. U., Conway, B. R. (2023). Development of Nanoemulsions for Topical Application of
Mupirocin. Pharmaceutics, 15(2), 378.
Alliod, O., Messager, L., Fessi, H., Dupin, D., Charcosset, C. (2019). Influence of viscosity for oil-in-water
and water-in-oil nanoemulsions production by SPG premix membrane emulsification. Chemical
Engineering Research and Design, 142, 87–99.
Angelico, R. (2022). Special Issue “Micro/Nano Emulsions: Smart Colloids for Multiple Applications.”
Nanomaterials, 12(21), 3734.
Assali, M., Zohud, N. (2021). Design of multicomponentindomethacin‐paracetamol and famotidine loaded
nanoparticles for sustained and effective anti‐inflammatory therapy. Drug Development Research, 82(3),
448–457.
Aswathanarayan, J. B., Vittal, R. R. (2019). Nanoemulsions and Their Potential Applications in Food Industry.
Frontiers in Sustainable Food Systems, 3, 95.
Bernardi, D. S., Pereira, T. A., Maciel, N. R., Bortoloto, J., Viera, G. S., Oliveira, G. C., & Rocha-Filho, P. A.
(2011). Formation and stability of oil-in-water nanoemulsions containing rice bran oil: in vitro and in vivo
assessments. Journal of Nanobiotechnology, 9(1), 44.
Bouchemal, K., Briançon, S., Perrier, E., Fessi, H. (2004). Nano-emulsion formulation using spontaneous
emulsification: solvent, oil and surfactant optimisation. International Journal of Pharmaceutics, 280(1–
2), 241–251.
Changediya, V. V, Jani, R., Kakde, P. (2019). A Review on Nanoemulsions: A Recent Drug Delivery Tool.
Journal of Drug Delivery and Therapeutics, 9(5), 185–191.
Che Marzuki, N. H., Wahab, R. A., Abdul Hamid, M. (2019a). An overview of nanoemulsion: concepts of
development and cosmeceutical applications. Biotechnology & Biotechnological Equipment, 33(1), 779–
797.
Cheng, Z., Li, M., Dey, R., Chen, Y. (2021). Nanomaterials for cancer therapy: current progress and
perspectives. Journal of Hematology & Oncology, 14(1), 85.
Chime, S. A, Kenechukwu, F. C., Attama, A. A. (2014). Nanoemulsions—advances in formulation,
characterization and applications in drug delivery.” Application of nanotechnology in drug delivery 3, 77–
126.
Chin, L. Y., Tan, J. Y. P., Choudhury, H., Pandey, M., Sisinthy, S. P., Gorain, B. (2021). Development and
optimization of chitosan coated nanoemulgel of telmisartan for intranasal delivery: A comparative study.
Journal of Drug Delivery Science and Technology, 62, 102341.
Choi, J. U., Maharjan, R., Pangeni, R., Jha, S. K., Lee, N. K., Kweon, S., Lee, H. K., Chang, K., Choi, Y. K.,
Park, J. W., Byun, Y. (2020). Modulating tumor immunity by metronomic dosing of oxaliplatin
incorporated in multiple oral nanoemulsion. Journal of Controlled Release, 322, 13–30.
Choudhury, H., Pandey, M., Gorain, B., Chatterjee, B., Madheswaran, T., Md, S., Mak, K. K., Tambuwala,
M., Chourasia, K., Kesharwani, P. (2019). Nanoemulsions as Effective Carriers for the Treatment of Lung
Cancer. In Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer, Elsevier, 217–247.
Donthi, M. R., Munnangi, S. R., Krishna, K. V., Saha, R. N., Singhvi, G., Dubey, S. K. (2023). Nanoemulgel:
A Novel Nano Carrier as a Tool for Topical Drug Delivery. Pharmaceutics, 15(1), 164.
 Nanoemulsions 41

Eqbal, A., Ansari, V. A., Hafeez, A., Ahsan, F., Imran, M., Tanweer, S. (2021). Recent Applications of
Nanoemulsion Based Drug Delivery System: A Review. Research Journal of Pharmacy and Technology,
2852–2858.
Erramreddy, V. V., Ghosh, S. (2014). Influence of Emulsifier Concentration on Nanoemulsion Gelation.
Langmuir, 30(37), 11062–11074.
Fofaria, N. M., Qhattal, H. S. S., Liu, X., Srivastava, S. K. (2016). Nanoemulsion formulations for anti-cancer
agent piplartine—Characterization, toxicological, pharmacokinetics and efficacy studies. International
Journal of Pharmaceutics, 498(1–2), 12–22.
Gorain, B., Choudhury, H., Nair, A. B., Dubey, S. K., Kesharwani, P. (2020). Theranostic application of
nanoemulsions in chemotherapy. Drug Discovery Today, 25(7), 1174–1188.
Graves, S., Meleson, K., Wilking, J., Lin, M. Y., Mason, T. G. (2005). Structure of concentrated
nanoemulsions. The Journal of Chemical Physics, 122, 134703.
Gupta, A., Eral, H. B., Hatton, T. A., & Doyle, P. S. (2016). Nanoemulsions: formation, properties and
applications. Soft Matter, 12(11), 2826–2841.
Håkansson, A. (2018). Fabrication of Nanoemulsions by High-Pressure Valve Homogenization. In
Nanoemulsions, Elsevier, 175–206.
Harwansh, R. K., Deshmukh, R., Rahman, M. A. (2019). Nanoemulsion: Promising nanocarrier system for
delivery of herbal bioactives. Journal of Drug Delivery Science and Technology, 51, 224–233.
Hazarika, H., Krishnatreyya, H., Chattopadhyay, P., Saha, A., Pathak, Y. V., Zaman, M. K. (2020).
Nanoemulsion Delivery of Herbal Products: Prospects and Challenges. In Nano Medicine and Nano Safety
(pp. 267–288). Springer Singapore.
Hidajat, M. J., Jo, W., Kim, H., Noh, J. (2020). Effective Droplet Size Reduction and Excellent Stability of
Limonene Nanoemulsion Formed by High-Pressure Homogenizer. Colloids and Interfaces, 4(1), 5.
Huang, C. H., Huang, C. Y., Ho, H. M., Lee, C. H., Lai, P. T., Wu, S. C., Liu, S. J., Huang, M. H. (2020).
Nanoemulsion adjuvantation strategy of tumor-associated antigen therapy rephrases mucosal and
immunotherapeutic signatures following intranasal vaccination. Journal for ImmunoTherapy of Cancer,
8(2), e001022.
Jaiswal, M., Dudhe, R., Sharma, P. K. (2015). Nanoemulsion: an advanced mode of drug delivery system. 3
Biotech, 5(2), 123–127.
Jang, J. H., Jeong, S. H., & Lee, Y. B. (2020). Enhanced Lymphatic Delivery of Methotrexate Using W/O/W
Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study. Pharmaceutics, 12(10), 978.
Javadi, S., Kazemi, N. M., Halabian, R. (2021). Preparation of O/W nano-emulsion containing nettle and
fenugreek extract and cumin essential oil for evaluating antidiabetic properties. AAPS Open, 7(1), 13.
Koh, J., Kim, S., Lee, S. N., Kim, S. Y., Kim, J. E., Lee, K. Y., Kim, M. S., Heo, J. Y., Park, et al. (2021).
Therapeutic efficacy of cancer vaccine adjuvanted with nanoemulsion loaded with TLR7/8 agonist in lung
cancer model. Nanomedicine: Nanotechnology, Biology and Medicine, 37, 102415.
Koroleva, M. Y., Yurtov, E. V. (2012a). Nanoemulsions: the properties, methods of preparation and promising
applications. Russian Chemical Reviews, 81(1), 21–43.
Koroleva, M. Y., Yurtov, E. V. (2012b). Nanoemulsions: the properties, methods of preparation and promising
applications. Russian Chemical Reviews, 81(1), 21–43.
Kumar, M., Bishnoi, R. S., Shukla, A. K., Jain, C. P. (2019). Techniques for Formulation of Nanoemulsion
Drug Delivery System: A Review. Preventive Nutrition and Food Science, 24(3), 225–234.
Kumar, S. (2014). Role of nano-emulsion in pharmaceutical sciences-a review. Asian Journal of Research in
Pharmaceutical Sciences and Biotechnology, 2(1), 1–5.
Kumar, V., Garg, V., Dureja, H. (2022). Nanoemulsion for delivery of anticancer drugs. Cancer Advances, 5,
e22016.
Liu, Q., Huang, H., Chen, H., Lin, J., Wang, Q. (2019). Food-Grade Nanoemulsions: Preparation, Stability and
Application in Encapsulation of Bioactive Compounds. Molecules, 24(23), 4242.
Lovelyn, C., Attama, A. A. (2011). Current State of Nanoemulsions in Drug Delivery. Journal of Biomaterials
and Nanobiotechnology, 02(05), 626–639.
Lucas, S. R. R., Maranhão, R. C., Guerra, J. L., Coelho, B. M. P., Barboza, R., Pozzi, D. H. B. (2015). Pilot
clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and
42 Kirti Goel, Purav Gupta, Karan Goel et al.

prednisone for the treatment of canine lymphoma. Veterinary and Comparative Oncology, 13(3), 184–
193.
Mago, A., Tahir, M. J., Khan, M. A., Ahmed, K. A. H. M., Munir, M. U. (2022). Nanomedicine: Advancement
in healthcare. Annals of Medicine & Surgery, 79, 104078.
Malkawi, A., Jalil, A., Nazir, I., Matuszczak, B., Kennedy, R., Bernkop-Schnürch, A. (2020). Self-Emulsifying
Drug Delivery Systems: Hydrophobic Drug Polymer Complexes Provide a Sustained Release In Vitro.
Molecular Pharmaceutics, 17(10), 3709–3719.
Mallick, S., Pattnaik, S., Swain, K., De, P. K. (2007). Current Perspectives of Solubilization: Potential for
Improved Bioavailability. Drug Development and Industrial Pharmacy, 33(8), 865–873.
Maurya, A., Singh, V. K., Das, S., Prasad, J., Kedia, A., Upadhyay, N., Dubey, N. K., Dwivedy, A. K. (2021).
Essential Oil Nanoemulsion as Eco-Friendly and Safe Preservative: Bioefficacy Against Microbial Food
Deterioration and Toxin Secretion, Mode of Action, and Future Opportunities. Frontiers in Microbiology,
12, 751062.
McClements, D. J. (2012). Nanoemulsions versus microemulsions: terminology, differences, and similarities.
Soft Matter, 8(6), 1719–1729.
McClements, D. J. (2021). Advances in edible nanoemulsions: Digestion, bioavailability, and potential toxicity.
Progress in Lipid Research, 81, 101081.
Md, S., Alhakamy, N. A., Alharbi, W. S., Ahmad, J., Shaik, R. A., Ibrahim, I. M., Ali, J. (2021). Development
and Evaluation of Repurposed Etoricoxib Loaded Nanoemulsion for Improving Anticancer Activities
against Lung Cancer Cells. International Journal of Molecular Sciences, 22(24), 13284.
Pourmadadi, M., Ahmadi, M., Abdouss, M., Yazdian, F., Rashedi, H., Navaei-Nigjeh, M., Hesari, Y. (2022).
The synthesis and characterization of double nanoemulsion for targeted Co-Delivery of 5-fluorouracil and
curcumin using pH-sensitive agarose/chitosan nanocarrier. Journal of Drug Delivery Science and
Technology, 70, 102849.
Qian, C., McClements, D. J. (2011). Formation of nanoemulsions stabilized by model food-grade emulsifiers
using high-pressure homogenization: Factors affecting particle size. Food Hydrocolloids, 25(5), 1000–
1008.
Rauf, M. A. (2023). Stability and release of bioactives from liposomes. In Liposomal Encapsulation in Food
Science and Technology, Elsevier, 189–222.
Sadoon, N. A., M. Ghareeb, M. (2020). Formulation and Characterization of Isradipine as Oral Nanoemulsion.
Iraqi Journal of Pharmaceutical, 29(1), 143–153.
Sánchez-López, E., Guerra, M., Dias-Ferreira, J., Lopez-Machado, A., Ettcheto, M., Cano, A., Espina, M.,
Camins, A., Garcia, M. L., Souto, E. B. (2019a). Current Applications of Nanoemulsions in Cancer
Therapeutics. Nanomaterials, 9(6), 821.
Sharma, S., Sahni, J. K., Ali, J., Baboota, S. (2015). Effect of high-pressure homogenization on formulation of
TPGS loaded nanoemulsion of rutin – pharmacodynamic and antioxidant studies. Drug Delivery, 22(4),
541–551.
Sheth, T., Seshadri, S., Prileszky, T., Helgeson, M. E. (2020). Multiple nanoemulsions. Nature Reviews
Materials, 5(3), 214–228.
Sindi, A. M., Hosny, K. M., Alharbi, W. S. (2021). Lyophilized Composite Loaded with Meloxicam-
Peppermint oil Nanoemulsion for Periodontal Pain. Polymers, 13(14), 2317.
Solans, C., Solé, I. (2012). Nano-emulsions: Formation by low-energy methods. Current Opinion in Colloid &
Interface Science, 17(5), 246–254.
Sondari, D., Tursiloadi, S. (2018). The effect of surfactant on formulation and stability of nanoemulsion using
extract of Centella Asiatica and Zingiber Officinale. AIP Conference Proceedings, 2049, 030014.
Souto, E. B., Cano, A., Martins-Gomes, C., Coutinho, T. E., Zielińska, A., Silva, A. M. (2022). Microemulsions
and Nanoemulsions in Skin Drug Delivery. Bioengineering, 9(4), 158.
Sutradhar, K. B., Amin, Md. L. (2013). Nanoemulsions: increasing possibilities in drug delivery. European
Journal of Nanomedicine, 5(2), 97-110.
Talegaonkar, S., Negi, L. M. (2015). Nanoemulsion in Drug Targeting. In Advances in Delivery Science and
Technology Targeted Drug Delivery : Concepts and Design, 433–459.
 Nanoemulsions 43

Teaima, M. H., Yasser, M., El-Nabarawi, M. A., Helal, D. A. (2020). Proniosomal Telmisartan Tablets:
Formulation, in vitro Evaluation and in vivo Comparative Pharmacokinetic Study in Rabbits. Drug
Design, Development and Therapy, 14, 1319–1331.
Tiwari SB, Shenoy DB, Amiji. MM. (2006). Nanoemulsion Formulations for Improved Oral Delivery of Poorly
soluble drugs. In InNSTI-Nanotech, 1, 475–478.
Wilson, R. J., Li, Y., Yang, G., Zhao, C.-X. (2022). Nanoemulsions for drug delivery. Particuology, 64, 85–
97.
Zhao, L., Zhu, Z., Ma, L., Li, Y. (2020). O/W Nanoemulsion as an Adjuvant for an Inactivated H3N2 Influenza
Vaccine: Based on Particle Properties and Mode of Carrying. International Journal of Nanomedicine, 15,
2071–2083.
Zhou, Y. (2022). Research Progress in Preparation, Stability and Application of Nanoemulsion. Journal of
Physics: Conference Series, 2152(1), 012044.
Chapter 4

Niosome Drug Delivery System: A Versatile Approach

for Enhanced Therapeutic Efficacy

Mithun Bhowmick,
Pratibha Bhowmick
Rideb Chakraborty
and Naureen Afrose
Bengal College of Pharmaceutical Sciences and Research, Durgapur, West Bengal, India

Abstract

Niosomes are non-ionic surfactant vesicular structures with the potential to enhance
therapeutic effectiveness and target drug delivery. Comprising a lipid bilayer encasing an
aqueous core, these structures exhibit excellent qualities, including biocompatibility,
biodegradability, and cost-effectiveness. They can encapsulate both lipophilic and
hydrophilic drugs, leading to increased stability, reduced toxicity, and more affordable
treatment options. The chapter covers niosome characteristics, benefits, structure,
formulation methods, and emphasizes the importance of characterizing them for quality
and performance assessment. The advantages, like extended drug release, decreased
toxicity, enhanced bioavailability, and focused therapy through surface modification
techniques, position niosomes as promising in various therapeutic fields like cancer
treatment, infectious disorders, and cutaneous delivery. The chapter also highlights
challenges associated with niosome drug delivery systems, including scalability, storage
stability, and regulatory considerations. The chapter provides valuable insights for
researchers, pharmaceutical scientists, and clinicians aiming to improve the potential of
niosomes in drug delivery for better patient outcomes.

Keywords: niosomes, non-ionic surfactant, cholesterol, lipid barrier, formulation,

characterization, enhanced stability, targeted delivery, therapeutic efficacy

Abbreviations

HLB Hydrophilic–lipophilic balance

CPP Critical packing parameters


Corresponding Author’s Email: drmithunbhowmick@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
46 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

TC Transition temperature
BHT Butylated hydroxytoluene
SUVs Small Unilamellar Vesicles
LUVs Large Unilamellar Vesicles
MLVs Multilamellar Vesicles
TFH Thin film hydration
SEM Scanning electron microscopy
TEM Transmission electron microscopy
PDI Poly dispersity index
NTA Nanoparticle tracking analysis
HPLC High performance liquid chromatography

Introduction

Niosomes, a category of nanostructured vesicles, have transformed drug delivery systems in

the pharmaceutical and biotechnology sectors. These minuscule vesicles, resembling liposomes
but composed of non-ionic surfactants, can encapsulate diverse substances, including drugs,
DNA, and bioactive chemicals. Their distinctive bilayer structure facilitates controlled and
sustained release, shielding the enclosed cargo from deterioration. This state-of-the-art
technology is a focal point of substantial research and development, aiming to refine drug
delivery strategies and elevate the efficacy, safety, and bioavailability of pharmaceuticals. This
chapter delves into the structure of niosomes, their advantages, preparation methods, drug
loading techniques, characterization methodologies, drug targeting, and applications in
pharmaceuticals, cosmetics, and gene therapy.

Structural Components of Niosomes

Niosomes are composed of amphiphilic molecules, primarily non-ionic surfactants. The

hydrophilic heads of these surfactants exhibit an affinity for water, while the hydrophobic tails
repel water. In aqueous environments, niosomes autonomously assemble, forming closed,
bilayered vesicles that bear a resemblance to cell membranes (Bhardwaj et al., 2020). The
surfactant molecules self-organize, creating a hydrophilic outer shell and a hydrophobic interior
core.

Basic Components of Niosomes

Non-Ionic Surfactants
These constitute the primary structural elements of niosomes. Non-ionic surfactants are
amphiphilic compounds with both hydrophilic (water-attracting) and hydrophobic (water-
repelling) regions. The hydrophilic heads of surfactants interact with water, while the
hydrophobic tails repel it. In an aqueous environment, non-ionic surfactants self-assemble,
giving rise to the lipid bilayer structure of niosomes (Ag Seleci et al., 2016; Moghassemi et al.,
 Niosome Drug Delivery System 47

2014; Gharbavi et al., 2018). Commonly used non-ionic surfactants in niosome formulation
include Tweens (polysorbates) such as Tween 20 and Tween 80, Spans (Sorbitan Esters) like
Span 20, Span 40, Span 60, and Span 80, Brij series surfactants like Brij 35, Brij 58, and Brij
78, and Triton X series surfactants like Triton X-100 and Triton X-114. The choice of the
appropriate surfactant relies on factors like the Hydrophilic–Lipophilic Balance (HLB), which
gauges how effectively a surfactant balances its water-attracting and oil-attracting properties,
Critical Packing Parameters (CPP) that describe how surfactant molecules form bilayer
structures - favorable for niosome creation and stability, and Gel-Liquid Transition
Temperature (TC), signifying the shift from a gel to a liquid state, significantly influencing the
stability and drug release characteristics of niosomes (Biswal et al., 2008; Kumar et al., 2011).

Aqueous Core
Within the lipid bilayer exists an aqueous core, providing a suitable compartment for housing
hydrophilic drugs, genes, or other bioactive compounds soluble in water. This aqueous core
establishes an environment conducive to the encapsulation of these substances (Bayindir et al.,
2010).

Cholesterol (Optional Component)

While not obligatory, cholesterol is frequently incorporated into niosome compositions. Within
the bilayer, cholesterol molecules disperse among the surfactant molecules, diminishing
membrane permeability and enhancing the rigidity and stability of the niosome structure,
thereby preventing cargo leakage (Onochie et al., 2013; Bayindir et al., 2010).

Additive Agents in Niosomes

Stabilizers
The incorporation of stabilizers enhances the long-term stability of niosomes by averting
fusion, aggregation, or leakage. Common stabilizers include polyols and sugars like sucrose
and glucose (Elmi et al., 2021; Tavano et al., 2014).

Antioxidants
Niosomes and their contents are shielded from oxidative decay through the addition of
antioxidants. Examples of antioxidants include tocopherol (vitamin E) and butylated
hydroxytoluene (BHT) (Elmi et al., 2021; Tavano et al., 2014).

pH Modifiers
Substances altering and regulating the pH of niosome formulations are crucial for maintaining
stability in particular drugs or bioactive chemicals. pH adjusters such as citric acid and sodium
citrate play a vital role (Negi et al., 2017).

Hydration Promoters
Compounds enhancing the effectiveness of lipid film hydration simplify the hydration of lipid
films during niosome synthesis. Ethanol and isopropyl alcohol are examples of hydration
promoters (Mahale et al., 2012; Kumar et al., 2011).
48 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

Charge-Inducing Polymers
In the development of niosomes, certain charge-inducing molecules are employed. These
molecules impart a charge to the surface of the niosomes, stabilizing them through electrostatic
repulsion and aiding in delaying coalescence. Examples include dicetylphosphate (negatively
charged), phosphotidic acid (negatively charged), and stearylamine (positively charged)
(Uchegbu et al., 1998; Abdelkader et al., 2014).

Classification of Niosomes

Niosomes can be categorized based on size, lamellarity, and composition. Common

compositional categories include conventional, cationic, and anionic niosomes. Size-based
categories encompass Small Unilamellar Vesicles (SUVs), Large Unilamellar Vesicles
(LUVs), and Multilamellar Vesicles (MLVs). Lamellarity-based classifications include
unilamellar and multilamellar niosomes.

Novel Formulation Strategies of Niosomes

To effectively target a drug to its intended site of action, consideration can be given to
encapsulating the formulated niosome using various coating agents such as polyethylene glycol
(PEG), hyaluronic acid (HA), etc. The choice of formulation techniques for niosomes depends
entirely on the specific requirements of the formulation development (Moghassemi et al.,
2014). Multiple techniques have been documented for niosome formation, each capable of
producing niosomes with varying sizes and size distributions (Thabet et al, 2022).

Thin-Film Hydration Method (TFH) or Hand Shaking Method

The thin-film hydration approach is a prevalent method for niosome development (Figure 1).
It involves dissolving a surfactant and cholesterol in an organic solvent, followed by
evaporating the solvent to create a thin, dried film. Multilamellar vesicles are formed by
introducing an aqueous medium, such as water or a buffer solution. Dissolving the surfactant
and cholesterol in a volatile solvent, niosomes undergo dissolution through thin-layer
hydration. The drug-containing aqueous phase is then hydrated with the dry surfactant at
temperatures ranging from 0 to 60°C (Thabet et al, 2022; Moghtaderi et al, 2022).

The “Bubble” Method

The bubble approach provides a solvent-free technique for niosome creation. Surfactants and
additives are blended in a three-necked flask, heated to 70°C, and agitated using a high shear
homogenizer. After achieving a homogeneous dispersion, nitrogen gas is introduced. The
mixture of surfactant and cholesterol is homogenized and “bubbled” at 70°C, resulting in the
formation of niosomes. This method is commonly referred to as the “Bubble method” (Yeo P.
L et al., 2017).
 Niosome Drug Delivery System 49

Figure 1. Thin-film Hydration method (TFH).

Ether-Injection Method
The ether-injection method entails dissolving a drug in an organic solvent, along with
cholesterol, diethyl ether, and a non-ionic surfactant. The mixture is gradually added to a
phosphate buffer at a rate of 1 ml/min, continuously churned at 60-65°C. Diethyl ether dissolves
phospholipids, injected into the aqueous phase. As the water is heated, diethyl ether evaporates,
forming liposomes with diameters ranging from 70 to 190 nm. Plasmids, DNA, and hydrophilic
substances are encapsulated in diethyl ether. Niosomes are fabricated by creating a temperature
gradient between liquid and solid phases (Kazi. K.M., et al., 2010).

Reverse-Phase Evaporation
The reverse-phase evaporation process utilizes an organic solvent like chloroform to combine
a lipophilic drug solution with non-ionic surfactants and optional cholesterol. After
evaporation, a reverse phase forms, emulsified with distilled water to create stable niosomes.
The mixture is sonicated, then phosphate-buffered saline is added. The solution is diluted with
phosphate-buffered saline, and the final niosome product is created by heating the mixture for
10 minutes at 60°C (Guinedi et al., 2005; Yeo P. L. et al., 2017).

Sonication Method
In this technique, the drug is magnetically stirred into 20 ml of pH 7.4 PBS. The glass vial
containing the surfactant, cholesterol, and dicetyl phosphate is then filled with the medication
solution. The system is probe-sonicated for 5 minutes in pulsed mode with the probe
temperature set at 57°C. Unilamellar vesicles are created as a result of this procedure, and they
are promptly cooled to 25°C and left to stand for 24 hours (Khan. M. I et al., 2017; Khan. D. H
et al., 2019).
50 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

Microfluidization Method
Microfluidic systems serve as an efficient platform for synthesizing and fine-tuning
nanoparticles, including metals, oxides, semiconductors, and hybrid organic-inorganic
nanoparticle composites. By mixing intake streams under regulated conditions, surfactants self-
assemble into desired niosomes. This technology saves preparation time and development
costs, while reducing liquid usage (Ag S. D et al., 2019; Ge. X et al., 2019).

Freeze and Thaw Method

In the freeze-thaw method, a sample containing vesicles is submerged in water and subjected
to abrupt temperature fluctuations. Solutes are drawn out of the ice during the freezing process,
resulting in their concentration trapping in the liquid that remains. Electrostatic interactions
between negatively charged lipids and positively charged solutions cause vesicles to form.
Niosomes might go through several freeze-thaw cycles at temperatures above their phase
transition temperature to improve encapsulation effectiveness. The thin film hydration
technique allows for the production of niosomes that can withstand repeated freezing and
thawing cycles. This is accomplished by freezing them at 0°C in a refrigerator and thawing
them at room temperature (Ugorji. O. L et al., 2022).

Proniosome Technology
Proniosomes are a dry formulation comprising a carrier system coated with a water-soluble
nonionic surfactant. These formulations quickly transform into niosomes when exposed to
moisture. Proniosomes hold promise in improving the solubility, bioavailability, and absorption
of various medicinal substances since they can overcome the instability difficulties frequently
associated with niosomes and liposomes. Additionally, they offer a flexible drug delivery
strategy suitable for a wide range of both hydrophilic and hydrophobic drugs. Proniosomes can
effectively deliver drugs via various administration routes to specific target locations, allowing
controlled release and reducing the likelihood of negative side effects (Khatoon. M et al., 2017).

Characterization of Niosomes

Niosomes, synthetic vesicles composed of non-ionic surfactants capable of encapsulating both

hydrophilic and hydrophobic molecules, play a pivotal role in diverse applications such as drug
delivery, cosmetics, and nanotechnology. Key characteristics under examination encompass
size, shape, encapsulation effectiveness, surface charge, stability, and drug release kinetics.

Morphological Characterization
The morphological characterization of niosomes involves a detailed examination of their
physical attributes, structure, and shape. The techniques employed for morphological
characterization are outlined:

Optical Microscopy
Utilizing lenses to magnify and visualize niosomes, optical microscopy illuminates the sample
with visible light. This rapid and straightforward technique offers insights into niosome
 Niosome Drug Delivery System 51

morphology (Tangri et al., 2011). It provides details on average size and shape, aiding in the
identification of clumping or aggregation (Kumar et al., 2013).

Scanning Electron Microscopy (SEM)

Generating a 3D image of niosomes, SEM scans the sample surface with a concentrated
electron beam, recording the secondary electrons released. SEM provides information on
surface morphology, including shape and roughness, offering high-resolution surface imaging
(Tangri et al., 2011). In comparison to Transmission Electron Microscopy (TEM), SEM
demands minimal sample preparation (Akbari et al., 2013).

Transmission Electron Microscopy (TEM)

TEM employs a beam of electrons to sharply visualize niosomes. Thinly sectioned and dyed
with heavy metals to enhance contrast, niosome samples provide high-resolution images.
TEM’s destructive nature, specialized equipment requirements, and sample preparation
challenges pose limitations (Tangri et al., 2011; Moghassemi et al., 2014).

Negative-Staining Transmission Electron Microscopy (NS-TEM)

NS-TEM employs heavy metal salts to stain niosome samples, enabling clearer morphology
and high-contrast imaging at the nanoscale. NS-TEM has limitations such as the potential for
specimen distortion and artefacts during the drying process. NS-TEM is particularly suitable
for thin niosome samples, as thicker ones may result in staining artefacts (Marianecci et al.,
2014; Hasibi et al., 2020).

Freeze-Fracture Transmission Electron Microscopy (FF-TEM)

FF-TEM, a specialized TEM method, involves freezing and fracturing samples to reveal
interior features and provide insights into niosome bilayer structures. While offering high-
resolution imaging and detailed insights into niosome shape, FF-TEM is associated with time-
consuming preparation, specialized tools, and knowledge requirements (Marianecci et al.,
2014; Falsafi et al., 2020).

Cryo-Transmission Electron Microscopy (Cryo-TEM)

The cryo-transmission electron microscopy (Cryo-TEM) technique, a specialized method
involving the flash-freezing of samples in liquid nitrogen, enables the capture of detailed
images of individual niosomes in their natural state. This process unveils structural information
without introducing fixation or staining artifacts. While Cryo-TEM preserves fragile structures
and allows observation in a natural setting, its application is confined to cryogenic temperatures
and necessitates specialized tools and knowledge (Marianecci et al., 2014; Falsafi et al., 2020).

Atomic Force Microscopy (AFM)

Atomic force microscopy (AFM) generates a topographical image by scanning a sample surface
with a sharp tip, measuring forces between the tip and the sample. Providing high-resolution
height and roughness information for surfaces, AFM is non-destructive, versatile, and
applicable to both liquid and air-dried samples. However, its sole limitation lies in surface
imaging (Falsafi et al., 2020).
52 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

Size and Size Distribution

Dynamic Light Scattering (DLS)

DLS quantifies light scattering caused by Brownian motion of particles in a solution,
determining the size distribution. It provides data on the size distribution, polydispersity index
(PDI), and hydrodynamic diameter (Ježková et al., 2023).

Nanoparticle Tracking Analysis (NTA)

NTA monitors the Brownian motion of individual niosomes using laser light scattering,
analyzing motion to ascertain particle size and distribution. It yields high-resolution
information on the size distribution of individual particles (Lozano-Andrés et al., 2019).

Transmission Electron Microscopy (TEM)

TEM visualizes niosomes using an electron beam, allowing direct particle size visualization
and measurement from images (Falsafi et al., 2020; Tangri et al., 2011).

Scanning Electron Microscopy (SEM)

In SEM, secondary electron emissions are captured as a focused electron beam scans the
sample’s surface. It establishes sample size but is limited to surface imaging and requires
sample coating and fixation (Tangri et al., 2011; Akbari et al., 2013).

Coulter Counter
The Coulter counter monitors changes in electrical resistance as niosomes move through a tiny
pore, facilitating the determination of particle size and distribution. It provides a direct
measurement of particle size, suitable for various sample types, though particle shape may
influence accuracy (Bhardwaj et al., 2020).

Zeta Potential
The stability and functionality of niosomes, particularly in drug administration, are determined
by their zeta potential, influenced by surface charge and interactions with biological systems.

Techniques for Determining Niosome Zeta Potential Include

Electrophoretic Light Scattering (ELS)

ELS involves subjecting niosome particles to an electric field in an electrolyte solution,
measuring their movement via laser light scattering. This highly accurate method requires
specialized tools and even sample distribution (Budhiraja et al., 2015).

Phase Analysis Light Scattering (PALS)

Similar to ELS, PALS employs higher frequencies and calculates zeta potential by measuring
phase shifts in scattered light. However, PALS instruments are limited in availability (Khan et
al., 2020).
 Niosome Drug Delivery System 53

Micro-Electrophoresis (ME)
ME observes the movement of niosome particles in a capillary tube under an electric field,
calculating zeta potential based on particle motion velocity. While an easy and economical
method, it may lack accuracy compared to ELS (Balakrishnan et al., 2009; Moghassemi et al.,
2014).

Streaming Potential (Helmholtz-Smoluchowski Equation)

The Helmholtz-Smoluchowski equation explains the generation of electrical potential when
charged particles move within a fluid, forming streaming potential. Measuring potential
difference in a capillary tube containing a niosome suspension provides zeta potential data,
especially for porous materials (Balakrishnan et al., 2009; Moghassemi et al., 2014).

Electroacoustic Spectroscopy (ESA)

ESA measures acoustic sounds produced by niosome particles oscillating in an electric field to
calculate zeta potential. Suitable for concentrated and opaque samples, it requires specialized
equipment (Balakrishnan et al., 2009).

Nanoparticle Tracking Analysis (NTA)

NTA utilizes laser light scattering to monitor Brownian motion, calculating zeta potential based
on particle motion. While suitable for concentrated samples, it may not offer the precision of
ELS (Jain et al., 2019).

Lamellarity

Small-Angle X-ray Scattering (SAXS)

SAXS measures X-ray scattering by niosomes, providing non-destructive quantitative data on
lamellarity for in-situ measurements. It requires access to X-ray equipment and data analytic
skills (Chen et al., 2019).

Nuclear Magnetic Resonance (NMR)

NMR indirectly reveals information about lamellarity by examining molecular dynamics and
lipid structure in niosomes. This non-destructive method requires specialized tools and may
have limitations in accurately measuring lamellarity (Chen et al., 2019).

Fluorescence Spectroscopy
Fluorescence Spectroscopy monitors changes in fluorescence characteristics of niosomes
incorporating fluorescent probes or dyes, signaling variations in lamellarity. While providing
real-time monitoring, it may lack quantitative data and requires suitable fluorescent probes
(Chen et al., 2019; Moghassemi et al., 2014).

Entrapment Efficiency

Exhaustive Dialysis
Exhaustive dialysis assesses entrapment efficiency by completely removing unentrapped drug
from the niosome formulation through multiple dialysis processes. This method, while
54 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

effective, requires a lengthy experimental period, and precision depends on the properties of
the membrane (Verma et al., 2010).

Centrifugation Method
The centrifugation method involves using centrifugal force to separate unentrapped drugs from
niosomes, with the unentrapped drug remaining in the supernatant while niosomes are pelleted.
The concentration of unentrapped drug is measured, and entrapment effectiveness is calculated
(Verma et al., 2010; Moghassemi et al., 2014).

Fluorescence Spectroscopy
Fluorescence spectroscopy assesses entrapped drugs by analyzing the fluorescence intensity of
fluorescently labeled drugs. Entrapment efficiency is determined by comparing fluorescence
levels between the initial drug solution and the niosome formulation (Saeting et al., 2019).

Gel Chromatography
For evaluating entrapment efficiency using gel chromatography, the drug is loaded onto a
column, and larger niosomes are excluded, allowing smaller molecules to pass through more
quickly. Fractions collected are analyzed using UV-Visible spectrophotometry or High-
Performance Liquid Chromatography (HPLC) to identify drug presence (Saeting et al., 2019;
Moghassemi et al., 2014).

Stability Study

Physical Stability
Visual inspection monitors variations in color, transparency, phase separation, aggregation, or
precipitation over time. Changes in particle size and distribution are measured using methods
like Dynamic Light Scattering (DLS) or Nanoparticle Tracking Analysis (NTA). Zeta potential
is assessed using electrophoretic or phase analysis light scattering (PALS) techniques to
evaluate changes in surface charge (Chen et al., 2019).

Chemical Stability
Analytical techniques such as High-Performance Liquid Chromatography (HPLC) or Mass
Spectrometry (MS) are utilized to evaluate drug degradation within niosomes. The impact of
pH on niosome stability is investigated by incubating them at various pH levels (Manconi et
al., 2002).

Thermal Stability
Niosome formulations undergo thermal cycling to assess stability at various temperatures.
Differential scanning calorimetry (DSC) is used to determine phase transitions and variations
in thermal behavior at different temperatures (Manconi et al., 2002).

Storage Stability
Accelerated Stability Testing evaluates niosome stability over time by conducting experiments
at high temperatures and humidity to simulate long-term storage conditions. This differs from
 Niosome Drug Delivery System 55

Freeze-Thaw Stability, which assesses the niosome’s resistance to temperature changes through
repeated freeze-thaw cycles (Manconi et al., 2002; Chen et al., 2019).

In-Vitro Study
In-vitro release studies involve using a dialysis membrane to study drug release. Niosomes are
placed in a dialysis bag within a container with a dissolution medium, typically a buffer, and
maintained at a controlled temperature. Samples are collected at predefined intervals, and
analytical methods like UV-visible spectrophotometry or HPLC are used to determine drug
concentrations. Cumulative drug release over time is estimated to evaluate release kinetics,
enabling the optimization of niosome formulations for specific drug delivery applications (Hao
et al.; Chen et al., 2019).

In-Vivo Study
In-vivo investigations for niosomes include analyzing drug distribution in organs such as the
liver, lung, spleen, and bone marrow (Figure 2). Analytical methods like HPLC or LC-MS are
employed to examine the supernatant for the presence of drugs. This data is crucial for niosome-
based drug delivery systems, providing essential insights into performance, release kinetics,
bioavailability, therapeutic efficacy, and safety in a physiologically relevant context (Chen et
al., 2019; Verma et al., 2010).

Figure 2. In-vivo characterization of niosomes.

 Table 1. Recent advancement in specialized niosomal formulation approaches

Model drug Formulation method used Working principle Recent research outcomes Reference
loaded
Cisplatin pH responsive niosome The concept involves creating drug-loaded niosomes The drug release rate was pH-dependent, with (Sargazi et al., 2021;
with pH-sensitive molecules, which are stable under an increase at pH 5.4 and sustained for 24 hours Das et al., 2020);
normal conditions but alter when exposed to in niosomes using Cholesteryl hemisuccinate as (Barani et al., 2021).
pathological conditions. These niosomes consist of a bilayer stabilizing agent.
non-ionic surfactants and cholesterol, with pH
sensitivity achieved through peptides and polymers.
Doxorubicin Magnetic niosome Niosomes can be utilized for magnetic drug targeting The study successfully produced doxorubicin- (Tavano et al., 2013);
and delivery in cancer treatment and diagnostics, loaded magneto-niosomal formulations using (Davarpanah et al., 2018)
allowing extracorporeal magnets to target drug-loaded EMG 707 ferrofluid, resulting in regulated
magneto-niosomes to specific organs or tissues. payload release without toxicity risk. PEGylated
magnetic niosomes with carboplatin showed an
83% drug entrapment effectiveness, increasing
bioavailability and prolonging release. The
MCF-7 cancer cell line’s survival capacity was
tested with and without external magnetic field
application, confirming the enhanced
bioavailability.
Anti-CD44 Immuno-niosome Immuno-niosomes are created by conjugating The study found that synthetic niosomes, (Hood et al., 2007)
antibody IM7 antibodies to niosomes, and Tween® 61 derivatized coupled with anti-CD44 antibody IM7, showed
with cyanuric chloride is used to attach IgG antibodies selectivity and specificity in delivering anti-
to vesicle surfaces. PEGylation enhances binding and inflammatory drugs, suggesting they could be
protection. an efficient delivery method.
Estradiol, Deformable niosome Transferosomes and ethosomes combine liposome and Transferosomes have been found to enhance (Rajan et al., 2011;
Tetanus-toxoid (Transferosome and, niosome features, offering self-optimized aggregation permeability, maintain drug release for extended Opatha et al., 2020;
ethosome) systems with high lipid content. Edge activators control therapeutic effects, improve transdermal flux, Ali et al., 2015)
fluidity and elasticity, enhancing the penetration of lower blood clearance, and enhance
traditional liposomes and niosomes into deeper skin pharmacokinetic profile.
layers.
 Niosome Drug Delivery System 57

Drug Targeting Using Niosomes

Niosome-based targeted drug delivery systems represent a cutting-edge approach to enhance

the precision and efficacy of drug administration within the body. Strategies for optimizing
drug targeting involve the incorporation of ligands, antibodies, or peptides designed to
selectively identify and bind to receptors or markers on target cells. This approach enables
active targeting of disease areas, passive accumulation in diseased tissues, and the concurrent
transport of multiple drugs. Niosome-based targeted drug delivery systems hold immense
potential to redefine drug targeting methodologies, ultimately enhancing patient outcomes and
addressing various conditions, including cancer, infectious disorders, and chronic illnesses
(Table 1) (Izhar et al., 2023; Khallaf et al., 2020; Yasamineh et al., 2022; Thakkar et al., 2016).

Overcoming Barriers

Biological Barriers
The body’s natural defense mechanisms, including the reticuloendothelial system (RES) and
the blood-brain barrier, may restrict the distribution of niosomes. Strategies such as PEGylation
(attaching polyethylene glycol) to niosomes can be employed to evade or overcome these
barriers (Moghassemi, et al., 2014).

Stability and Drug Leakage

Niosomes may be sensitive to environmental factors like temperature, pH, and mechanical
stress, impacting their stability and integrity. This sensitivity can lead to drug leakage or
premature degradation, diminishing drug delivery efficiency.

Size and Surface Charge

The size of niosomes significantly influences their bio-distribution and cellular uptake. Surface
charge also plays a role in their interaction with biological membranes and cells, affecting
circulation time and cellular uptake.

Targeting Ligand Efficacy

Choosing the appropriate ligand for active targeting is paramount. Ligands must exhibit a
strong affinity for the target receptor and avoid off-target effects. Ensuring the specificity and
effectiveness of ligands poses a significant challenge.

Drug Loading Efficiency

High drug loading efficiency in niosomes is essential for therapeutic effectiveness. Challenges
include patient variability, drug resistance, and specific storage conditions that further
complicate stability and efficacy.

Clinical Applications of Niosomes and Current Implementations

Niosomes exhibit various clinical applications, showcasing their versatility in modern

medicine. They are used for drug and vaccine delivery, transdermal and topical therapies, gene
58 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

delivery, diagnostic imaging, and more. The deployment of niosomes not only mitigates
adverse effects but also enhances drug effectiveness. Their adaptability is evident in the realm
of cancer therapies, infectious diseases, dermatological treatments, gene therapy, and various
other medical conditions (Mahale et al., 2012; Moghassemi et al., 2014).

Challenges in Niosomal Drug Delivery Systems

The implementation of niosomal drug delivery systems is not without challenges. Scaling up
production, ensuring stability during storage (addressing concerns like aggregation, leakage,
and oxidation), and navigating regulatory approval hurdles are among the formidable
challenges. A collaborative effort in research, regulatory compliance, and a meticulous focus
on the intricacies of production, quality assurance, and safety evaluation (Mahale et al., 2012;
Moghassemi et al., 2014).

Conclusion

The adoption of niosomes as a drug delivery system represents a promising and cutting-edge
strategy to overcome limitations associated with traditional drug delivery methods. Niosomes
offer advantages such as enhanced drug stability, controlled release, and increased
bioavailability. Their adaptability as carriers for a wide spectrum of medicines, spanning both
hydrophilic and hydrophobic compounds, positions them as versatile agents in therapeutic
treatments. Moreover, their biocompatibility and ability to target specific tissues or cells
contribute to personalized treatment possibilities. The functionalization of niosomes with
ligands and other modifiers allows for targeted drug delivery, minimizing adverse effects
associated with conventional medication therapies. Yet, challenges persist, requiring solutions
in areas like scalability, long-term stability assurance, and enhancement of drug loading and
release profiles. Despite challenges, ongoing research and development signal the enormous
potential of niosomes as an innovative medication delivery mechanism. Positioned for a more
prominent role in drug delivery, sustained innovation and collaboration between researchers,
pharmaceutical firms, and regulatory agencies are anticipated to yield better patient outcomes
and elevate healthcare quality.

References

Abdelkader, H., Alani, A. W., & Alany, R. G. (2014). Recent advances in non-ionic surfactant vesicles
(niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations. Drug
delivery, 21(2): 87-100.
Ag Seleci, D., Maurer, V., Stahl, F., Scheper, T., & Garnweitner, G. (2019). Rapid microfluidic preparation of
niosomes for targeted drug delivery. International journal of molecular sciences, 20(19): 4696.
Ag Seleci, D., Seleci, M., Walter, J. G., Stahl, F., & Scheper, T. (2016). Niosomes as nanoparticular drug
carriers: fundamentals and recent applications. Journal of nanomaterials, 1-13.
Akbari, V., Abedi, D., Pardakhty, A., & Sadeghi-Aliabadi, H. (2013). Ciprofloxacin nano-niosomes for
targeting intracellular infections: an in vitro evaluation. Journal of nanoparticle research, 15: 1-14.
 Niosome Drug Delivery System 59

Ali, M. F. M., Salem, H. F., Abdelmohsen, H. F., & Attia, S. K. (2015). Preparation and clinical evaluation of
nano-transferosomes for treatment of erectile dysfunction. Drug design, development and therapy, 2431-
2447.
Balakrishnan, P., Shanmugam, S., Lee, W. S., Lee, W. M., Kim, J. O., Oh, D. H., & Yong, C. S. (2009).
Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. International
journal of pharmaceutics, 377(1-2): 1-8.
Balakrishnan, P., Shanmugam, S., Lee, W. S., Lee, W. M., Kim, J. O., Oh, D. H., & Yong, C. S. (2009).
Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. International
journal of pharmaceutics, 377(1-2): 1-8.
Barani, M., Hajinezhad, M. R., Sargazi, S., Rahdar, A., Shahraki, S., Lohrasbi-Nejad, A., & Baino, F. (2021).
In vitro and in vivo anticancer effect of pH-responsive paclitaxel-loaded niosomes. Journal of Materials
Science: Materials in Medicine, 32: 1-13.
Bayindir, Z. S., & Yuksel, N. (2010). Characterization of niosomes prepared with various nonionic surfactants
for paclitaxel oral delivery. Journal of pharmaceutical sciences, 99(4): 2049-2060.
Bhardwaj, P., Tripathi, P., Gupta, R., & Pandey, S. (2020). Niosomes: A review on niosomal research in the
last decade. Journal of Drug Delivery Science and Technology, 56: 101581.
Biswal, S., Murthy, P. N., Sahu, J., Sahoo, P., & Amir, F. (2008). Vesicles of non-ionic surfactants (niosomes)
and drug delivery potential. International Journal of Pharmaceutical Sciences and Nanotechnology, 1(1):
1-8.
Budhiraja, A., & Dhingra, G. (2015). Development and characterization of a novel antiacneniosomal gel of
rosmarinic acid. Drug delivery, 22(6): 723-730.
Chen, S., Hanning, S., Falconer, J., Locke, M., & Wen, J. (2019). Recent advances in non-ionic surfactant
vesicles (niosomes): Fabrication, characterization, pharmaceutical and cosmetic applications. European
journal of pharmaceutics and biopharmaceutics, 144: 18-39.
Das, S. S., Bharadwaj, P., Bilal, M., Barani, M., Rahdar, A., Taboada, P. & Kyzas, G. Z. (2020). Stimuli-
responsive polymeric nanocarriers for drug delivery, imaging, and theragnosis. Polymers, 12(6): 1397.
Davarpanah, F., KhaliliYazdi, A., Barani, M., Mirzaei, M., & Torkzadeh-Mahani, M. (2018). Magnetic
delivery of antitumor carboplatin by using PEGylated-Niosomes. DARU Journal of Pharmaceutical
Sciences, 26: 57-64.
Elmi, N., Ghanbarzadeh, B., Ayaseh, A., Sahraee, S., Heshmati, M. K., Hoseini, M., & Pezeshki, A. (2021).
Physical properties and stability of quercetin loaded niosomes: stabilizing effects of phytosterol and
polyethylene glycol in orange juice model. Journal of Food Engineering, 296: 110463.
Falsafi, S. R., Rostamabadi, H., Assadpour, E., & Jafari, S. M. (2020). Morphology and microstructural analysis
of bioactive-loaded micro/nanocarriers via microscopy techniques; CLSM/SEM/TEM/AFM. Advances in
Colloid and Interface Science, 280: 102166.
Ge, X., Wei, M., He, S., & Yuan, W. E. (2019). Advances of non-ionic surfactant vesicles (niosomes) and their
application in drug delivery. Pharmaceutics, 11(2): 55.
Gharbavi, M., Amani, J., Kheiri-Manjili, H., Danafar, H., & Sharafi, A. (2018). Niosome: a promising
nanocarrier for natural drug delivery through blood-brain barrier. Advances in Pharmacological and
Pharmaceutical Sciences, 6847971.
Guinedi, A. S., Mortada, N. D., Mansour, S., & Hathout, R. M. (2005). Preparation and evaluation of reverse-
phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide. International
journal of pharmaceutics, 306(1-2): 71-82.
Hao, Y., Zhao, F., Li, N., & Yang, Y. (2002). Studies on a high encapsulation of colchicine by a niosome
system. International journal of pharmaceutics, 244(1-2): 73-80.
Hasibi, F., Nasirpour, A., Varshosaz, J., García‐Manrique, P., Blanco‐López, M. C., Gutiérrez, G., & Matos,
M. (2020). Formulation and characterization of Taxifolin‐loaded lipid nanovesicles (Liposomes,
Niosomes, and Transfersomes) for beverage fortification. European Journal of Lipid Science and
Technology, 122(2): 1900105.
Hood, E., Gonzalez, M., Plaas, A., Strom, J., & VanAuker, M. (2007). Immuno-targeting of nonionic surfactant
vesicles to inflammation. International journal of pharmaceutics, 339(1-2): 222-230.
Izhar, M. P., Hafeez, A., Kushwaha, P., & Simrah. (2023). Drug Delivery Through Niosomes: A
Comprehensive Review with Therapeutic Applications. Journal of Cluster Science, 1-17.
60 Mithun Bhowmick, Pratibha Bhowmick, Rideb Chakraborty et al.

Jain, A. K., & Thareja, S. (2019). In vitro and in vivo characterization of pharmaceutical nanocarriers used for
drug delivery. Artificial cells, nanomedicine, and biotechnology, 47(1): 524-539.
Ježková, M., Šrom, O., George, A. H., Kereïche, S., Rohlíček, J., & Šoóš, M. (2023). Quality assessment of
niosomal suspensions. Journal of Colloid and Interface Science, 631: 22-32.
Kazi, K. M., Mandal, A. S., Biswas, N., Guha, A., Chatterjee, S., Behera, M., & Kuotsu, K. (2010). Niosome:
a future of targeted drug delivery systems. Journal of advanced pharmaceutical technology & research,
1(4): 374.
Khallaf, R. A., Aboud, H. M., & Sayed, O. M. (2020). Surface modified niosomes of olanzapine for brain
targeting via nasal route; preparation, optimization, and in vivo evaluation. Journal of liposome research,
30(2): 163-173.
Khan, D. H., Bashir, S., Figueiredo, P., Santos, H. A., Khan, M. I., & Peltonen, L. (2019). Process optimization
of ecological probe sonication technique for production of rifampicin loaded niosomes. Journal of Drug
Delivery Science and Technology, 50: 27-33.
Khan, M. I., Madni, A., Hirvonen, J., & Peltonen, L. (2017). Ultrasonic processing technique as a green
preparation approach for diacerein-loaded niosomes. AAPS PharmSciTech, 18: 1554-1563.
Khan, S., Akhtar, M. U., Khan, S., Javed, F., & Khan, A. A. (2020). Nanoniosome‐encapsulated levoflaxicin
as an antibacterial agent against Brucella. Journal of basic microbiology, 60(3): 281-290.
Khatoon, M., Shah, K. U., Din, F. U., Shah, S. U., Rehman, A. U., Dilawar, N., & Khan, A. N. (2017).
Proniosomes derived niosomes: recent advancements in drug delivery and targeting. Drug delivery, 24(2):
56-69.
Kumar, G. P., & Rajeshwarrao, P. (2011). Nonionic surfactant vesicular systems for effective drug delivery—
an overview. Actapharmaceuticasinica B, 1(4): 208-219.
Kumar, Y. P., Kumar, K. V., Shekar, R. R., Ravi, M., & Kishore, V. S. (2013). Formulation and evaluation of
econazole niosomes. Sch. Acad. J. Pharm, 2(4): 315-318.
Lozano-Andrés, E., Libregts, S. F., Toribio, V., Royo, F., Morales, S., López-Martín, S., & Yáñez-Mó, M.
(2019). Tetraspanin-decorated extracellular vesicle-mimetics as a novel adaptable reference material.
Journal of Extracellular Vesicles, 8(1): 1573052.
Mahale, N. B., Thakkar, P. D., Mali, R. G., Walunj, D. R., & Chaudhari, S. R. (2012). Niosomes: novel
sustained release nonionic stable vesicular systems—an overview. Advances in colloid and interface
science, 183: 46-54.
Manconi, M., Sinico, C., Valenti, D., Loy, G., & Fadda, A. M. (2002). Niosomes as carriers for tretinoin. I.
Preparation and properties. International journal of pharmaceutics, 234(1-2): 237-248.
Marianecci, C., Di Marzio, L., Rinaldi, F., Celia, C., Paolino, D., Alhaique, F., & Carafa, M. (2014). Niosomes
from 80s to present: the state of the art. Advances in colloid and interface science, 205: 187-206.
Moghassemi, S., & Hadjizadeh, A. (2014). Nano-niosomes as nanoscale drug delivery systems: an illustrated
review. Journal of controlled release, 185: 22-36.
Moghtaderi, M., Sedaghatnia, K., Bourbour, M., Fatemizadeh, M., SalehiMoghaddam, Z., Hejabi, F & Farasati
Far, B. (2022). Niosomes: a novel targeted drug delivery system for cancer. Medical Oncology, 39(12):
240.
Negi, P., Aggarwal, M., Sharma, G., Rathore, C., Sharma, G., Singh, B., & Katare, O. P. (2017). Niosome-
based hydrogel of resveratrol for topical applications: An effective therapy for pain related disorder (s).
Biomedicine & Pharmacotherapy, 88: 480-487.
Onochie, I. T. O., Nwakile, C. D., Umeyor, C. E., Uronnachi, E. M., Osonwa, U. E., Attama, A. A., & Esimone,
C. O. (2013). Formulation and evaluation of niosomes of benzyl penicillin. Journal of Applied
Pharmaceutical Science, 3(12): 066-071.
Opatha, S. A. T., Titapiwatanakun, V., & Chutoprapat, R. (2020). Transfersomes: A promising
nanoencapsulation technique for transdermal drug delivery. Pharmaceutics, 12(9): 855.
Rajan, R., Jose, S., Mukund, V. B., & Vasudevan, D. T. (2011). Transferosomes-A vesicular transdermal
delivery system for enhanced drug permeation. Journal of advanced pharmaceutical Technology &
Research, 2(3): 138-143.
Saeting, K., Mitrevej, A., Leuenberger, H., & Sinchaipanid, N. (2022). Development of alendronate niosomal
delivery system for gastrointestinal permeability improvement. Journal of Drug Delivery Science and
Technology, 67: 102885.
 Niosome Drug Delivery System 61

Sargazi, S., Hosseinikhah, S. M., Zargari, F., Chauhana, N. P. S., Hassanisaadi, M., & Amani, S. (2021). pH-
responsive cisplatin-loaded niosomes: synthesis, characterization, cytotoxicity study and interaction
analyses by simulation methodology. Nanofabrication, 6(1): 1-15
Tangri, P., & Khurana, S. (2011). Niosomes: Formulation and evaluation. Chemistry, Materials Science,
Medicine, 2229: 7499.
Tavano, L., Muzzalupo, R., Picci, N., & de Cindio, B. (2014). Co-encapsulation of lipophilic antioxidants into
niosomal carriers: percutaneous permeation studies for cosmeceutical applications. Colloids and surfaces
B: biointerfaces, 114: 144-149.
Thabet, Y., Elsabahy, M., & Eissa, N. G. (2022). Methods for preparation of niosomes: A focus on thin-film
hydration method. Methods, 199: 9-15.
Thakkar, M. (2016). Opportunities and challenges for niosomes as drug delivery systems. Current Drug
Delivery, 13(8): 1275-1289.
Uchegbu, I. F., & Vyas, S. P. (1998). Non-ionic surfactant based vesicles (niosomes) in drug delivery.
International journal of pharmaceutics, 172(1-2): 33-70.
Ugorji, O. L., Umeh, O. N. C., Agubata, C. O., Adah, D., Obitte, N. C., & Chukwu, A. (2022). The effect of
noisome preparation methods in encapsulating 5-fluorouracil and real time cell assay against HCT-116
colon cancer cell line. Heliyon, 8(12).
Verma, S., Singh, S. K., Syan, N., Mathur, P., & Valecha, V. (2010). Nanoparticle vesicular systems: a versatile
tool for drug delivery. J Chem Pharm Res, 2(2): 496-509.
Witika, B. A., Bassey, K. E., Demana, P. H., Siwe-Noundou, X., & Poka, M. S. (2022). Current advances in
specialisedniosomal drug delivery: Manufacture, characterization and drug delivery applications.
International Journal of Molecular Sciences, 23(17): 9668.
Yasamineh, S., Yasamineh, P., Kalajahi, H. G., Gholizadeh, O., Yekanipour, Z., Afkhami, H., & Dadashpour,
M. (2022). A state-of-the-art review on the recent advances of niosomes as a targeted drug delivery
system. International journal of pharmaceutics, 624: 121878.
Yeo, P. L., Lim, C. L., Chye, S. M., Ling, A. P. K., & Koh, R. Y. (2017). Niosomes: a review of their structure,
properties, methods of preparation, and medical applications. Asian Biomed, 11(4): 301-314.
Chapter 5

Lipid Nanocarriers in Cosmetics

Meghna Dheek
Shikha Baghel Chauhan
and Indu Singh
Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India

Abstract

Lipid nanoparticles (NLC) initially entered the market as commodities within the beauty
sector. Nanostructured lipid carriers, a sophisticated class of delivery systems, have
emerged as innovative tools in cosmetic formulations. This chapter deals with the
incorporation of NLC in cosmetic products, emphasizing their role in improving stability,
bioavailability, and targeted delivery of active ingredients. The unique structural features
of NLC, such as their biocompatibility and ability to encapsulate both hydrophilic and
hydrophobic compounds, contribute to their versatility in cosmetic formulations. The
chapter provides an overview of the cosmetic benefits of lipid nanoparticles, including
enhanced skin bioavailability, chemical stability of active ingredients, and physical
stability of lipid nanoparticle formulations. Easy preparation, biocompatibility, scale-up
viability, non-toxicity, increased drug loading, and stability are the main characteristics of
NLC that render them a viable drug delivery technology. The chapter presents an overview
of these items, along with information on the lipid nanoparticles, lipids utilized in their
manufacturing, and any cosmetic ingredients that have been added. The utilization of NLC
in cosmetic science represents a promising avenue for advancing product formulations and
optimizing the performance of skincare and beauty products.

Keywords: lipid, nanoparticles, cosmetics, skin targeting

Abbreviations

AFM Atomic force microscopy

Cryo-TEM Cryo-transmission electron microscopy
HLB Hydrophilic-lipophilic balance
MMP-1 Matrix metalloprotease type 1
NLCs Nanostructured lipid carriers


Corresponding Author’s Email: meghnadheek98@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
64 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

RES Reticuloendothelial system

SC Stratum corneum
SEM Scanning electron microscopy
SLN Solid lipid nanoparticles
TEM Transmission electron microscopy
ZP Zeta potential

Introduction

To address the limitations of conventional manufacturing, nanocarrier technology has proven

successful in creating advanced drug delivery systems. Its application has expanded across
various medical fields, encompassing injectables, oral formulations, topical formulations, and
even cosmetics for beauty purposes. The inclusion of nanocarriers in functional cosmetics
significantly enhances skin penetration, greatly prolongs the persistence of active components
in the skin and exerts a profound impact on the cosmetics industry. Simultaneously,
nanocarriers effectively increase the stability of active components, achieve synergy among
various cosmetic active ingredients, and enhance the aqueous dispersion of insoluble cosmetic
chemicals. Currently, drug delivery technology, involving both passive and active targeting
through multiple administration routes, is actively employed in the nanotechnology field.
Nanotechnology’s use in local and transdermal drug delivery has opened up a new frontier for
transdermal applications. Colloidal particles with a size between 10 and 1000 nm are known as
nanoparticles (Mukherjee et al., 2009). In the early 1990s, Professors R.H. Müller (Germany)
and M. Gasco (Italy) discussed solid lipid nanoparticles (SLN), presenting a formulation with
several advantages (López-García et al., 2015). Despite some drawbacks such as low drug
loading capacity, unpredictable gelation propensity, polymorphic transitions, and drug leakage
during storage (Poonia et al., 2016), SLNs paved the way for the development of nanostructured
lipid carriers (NLCs), representing a groundbreaking advancement in cosmetic formulations.
NLCs herald a new era of efficient and versatile delivery systems for various active ingredients.
Engineered with precision at the nanoscale, NLCs combine the benefits of liposomes and solid
lipid nanoparticles, providing a synergistic approach to enhance the bioavailability and stability
of cosmetic formulations. At the core of NLCs is their unique structure, a blend of solid and
liquid lipids, forming a matrix accommodating a broad range of active compounds. This design
ensures improved encapsulation efficiency and controlled release of bioactive ingredients,
optimizing the performance and longevity of cosmetic products. The nanosize scale of these
lipid carriers further enhances skin penetration, facilitating the targeted delivery of key
components to specific skin layers, maximizing therapeutic effects. The listing of functional
cosmetics products utilizing nanocarrier technology (liposomes) in Table 1 demonstrates the
technology’s potential for various uses in the cosmetics industry. In conclusion, NLCs have
emerged as game-changers in the cosmetic industry, offering a versatile and efficient platform
for the delivery of active ingredients. Their unique structure, adaptability, and stability make
them invaluable tools for formulators aiming to enhance the efficacy and sustainability of
cosmetic products. As research and development in nanotechnology progress, the integration
of NLCs into cosmetics is poised to reshape the skincare and beauty product landscape,
elevating the consumer experience to new heights.
 Lipid Nanocarriers in Cosmetics 65

Table 1. Marketed NLC Cosmetic Products

Product Proposed use Manufacturer

Azelac Ru Serum Whitening Sesderma
C – Vit Facial Serum Anti - aging Sesderma
Daeses Lifting Cream Anti - aging Sesderma
Acglicolic Classic Crema Hidratante SPF 15 Anti - aging Sesderma
Capture Anti - wrinkle Christian Dior
Dermosome Moisturizer Microfluidics
Clinicians Complex Liposome Face and neck lotion Anti - aging/Moisturizer Clinicians Complex
Lumessence Eye Cream Anti-wrinkle Aubrey Organics

Advantages of Nanostructured Lipid Carriers

NLCs have emerged as a promising and versatile platform for drug delivery, offering a range
of advantages that effectively address critical challenges in pharmaceutical formulations. The
unique structure of NLCs, characterized by a solid lipid matrix and nano-sized particles,
contributes to their remarkable drug-loading capacity, making them particularly valuable for
drugs with low solubility. This increased loading capacity results from the combination of both
solid and liquid lipids, enabling a more efficient encapsulation of a diverse array of therapeutic
agents. One of the primary advantages of NLCs lies in their ability to enhance the stability of
encapsulated drugs. The solid lipid matrix provides a protective environment, shielding the
entrapped drug from environmental factors such as light, heat, and oxygen, thereby minimizing
degradation and extending the shelf life of the pharmaceutical formulation. This stability is
crucial for ensuring the efficacy and safety of the drug throughout its lifecycle, from production
to patient use. In addition to stability, NLCs offer controlled and sustained release of drugs.
The composition of the lipid matrix can be tailored to modulate the release kinetics, allowing
for a prolonged therapeutic effect. This controlled release is particularly beneficial in cases
where maintaining a consistent drug concentration over time is critical for therapeutic efficacy.
By avoiding rapid peaks and troughs in drug levels, NLCs contribute to improved patient
compliance and potentially reduce the frequency of administration. The enhanced
bioavailability facilitated by NLCs is another significant advantage. The nano-sized particles
provide a larger surface area for drug interaction with biological tissues, leading to improved
absorption and distribution within the body. This is particularly advantageous for drugs with
poor water solubility, as NLCs can overcome the limitations associated with low
bioavailability. The enhanced bioavailability not only improves the overall therapeutic effect
but also opens up new possibilities for formulating drugs that may have been challenging to
deliver effectively using conventional methods. Biocompatibility is a key consideration in drug
delivery systems, and NLCs excel in this aspect. The lipid components commonly used in NLC
formulations are generally well-tolerated by the body, minimizing the risk of adverse reactions.
This biocompatibility enhances the safety profile of NLCs, making them a preferred choice for
drug delivery applications (Pardeike et al., 2009). Furthermore, the ability to tailor the surface
properties of NLCs allows for the incorporation of ligands or functional groups that can impart
specific targeting capabilities, contributing to the development of targeted drug delivery
systems. NLCs also demonstrate versatility in formulation, accommodating a wide range of
drugs, including both hydrophobic and hydrophilic compounds. This flexibility is crucial for
66 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

addressing the diverse physicochemical properties of different drugs and tailoring formulations
to specific therapeutic needs. The adaptability of NLCs makes them suitable for encapsulating
various types of therapeutic agents, from small molecules to biotherapeutics, expanding their
applicability across different therapeutic areas. The potential for combination therapy is a
notable advantage of NLCs. The multi-compartmental nature of these carriers allows for the
encapsulation of multiple drugs within a single carrier system. This opens opportunities for
synergistic therapeutic effects, where the combination of two or more drugs can lead to
enhanced efficacy or reduced side effects. Combination therapy is particularly relevant in the
treatment of complex medical conditions where a multi-pronged approach is needed for optimal
therapeutic outcomes. From a manufacturing perspective, NLCs offer ease of scale-up. The
processes involved in the production of NLCs can be adapted for large-scale manufacturing,
ensuring reproducibility and cost-effectiveness. This scalability is essential for transitioning
from laboratory-scale development to commercial production, facilitating the widespread
availability of NLC-based drug formulations. In summary, NLCs represent a cutting-edge
approach in drug delivery with a multitude of advantages. Their ability to enhance drug
stability, control release kinetics, improve bioavailability, and allow for targeted delivery
makes them a versatile and promising platform for pharmaceutical applications. The
biocompatibility, versatility in formulation, and potential for combination therapy further
contribute to their attractiveness in addressing the complex challenges associated with drug
delivery. As research in nanotechnology and lipid-based drug delivery continues to advance,
NLCs are likely to play a crucial role in shaping the future of pharmaceutical formulations,
offering innovative solutions for improving the effectiveness and safety of therapeutic
interventions (Fang et al., 2012).

Disadvantages of Nanostructured Lipid Carriers

While NLCs present numerous advantages in drug delivery, it is crucial to acknowledge certain
disadvantages associated with their use. One notable challenge is the potential for complex and
variable manufacturing processes. Achieving reproducibility on a large scale can be demanding
due to the intricate interplay of various formulation parameters, such as lipid composition,
surfactant concentration, and processing conditions. Ensuring consistent quality and
performance across different batches may require meticulous optimization and rigorous
control, adding complexity to the production process. Another significant disadvantage
involves the potential for lipid polymorphism and the risk of drug expulsion. The dynamic
nature of the lipid matrix in NLCs can lead to polymorphic transitions, where lipids undergo
changes in crystalline structure. This polymorphism may result in the expulsion of the
encapsulated drug over time, impacting the long-term stability and efficacy of the formulation.
Careful consideration of lipid composition and formulation conditions is essential to mitigate
these challenges and enhance the stability of NLCs. Despite the biocompatible nature of many
lipid materials, concerns regarding potential toxicity and immunogenicity may arise. Thorough
investigation of the long-term effects of lipid accumulation in tissues and organs is needed to
ensure the safety of NLCs in clinical applications. Additionally, the use of certain surfactants
or stabilizers in NLC formulations may raise toxicity concerns, necessitating comprehensive
toxicity studies to assess their impact on human health. Another drawback is the risk of particle
aggregation or coalescence during storage. The small size of NLCs makes them susceptible to
 Lipid Nanocarriers in Cosmetics 67

aggregation over time, particularly in concentrated formulations or under specific storage

conditions. Aggregation can compromise the stability and homogeneity of the formulation,
affecting its performance upon administration. Addressing this challenge requires careful
formulation design and optimization to minimize the risk of particle aggregation and ensure the
maintenance of desired characteristics throughout the product’s shelf life (Pardeike et al.,
2009). The potential for interactions with biological components is another consideration. Upon
administration, NLCs may interact with proteins, enzymes, or other biomolecules in the
biological milieu, leading to changes in their structure or behavior. These interactions can
influence the pharmacokinetics and biodistribution of the encapsulated drug, potentially
impacting its therapeutic efficacy. Understanding and mitigating these interactions are crucial
for predicting and optimizing the in vivo performance of NLC-based drug delivery systems.
Furthermore, the regulatory landscape for nanotechnology-based drug delivery systems,
including NLCs, is evolving. Regulatory agencies may require comprehensive safety and
efficacy data, standardized characterization methods, and clear guidelines for the development
and commercialization of NLC formulations. Meeting these regulatory expectations can be
challenging and may necessitate extensive preclinical and clinical studies to demonstrate the
safety and effectiveness of NLC-based products. In conclusion, while NLCs offer significant
advantages in drug delivery, their use is not without challenges. The complexities of
manufacturing, concerns related to lipid polymorphism, potential toxicity, the risk of particle
aggregation, and interactions with biological components underscore the importance of
thorough research and development efforts. Addressing these disadvantages will be crucial for
realizing the full potential of NLCs in clinical applications and ensuring their safe and effective
integration into the pharmaceutical landscape (Lu et al., 2010).

Excipients used in formulating NLCs

Lipids
It is crucial to carefully select the appropriate lipids for use in nanoparticulate carriers, as the
type and structure of lipids significantly influence the properties of nanocarriers (Rohan Shah
et al., 2015). As a general guideline, the solubility and apparent partition coefficient of
bioactives in lipids are considered the most relevant parameters for lipid selection. The
solubility of drug molecules in lipids directly affects their capacity for loading and
encapsulation. Additionally, the increased viscosity of the dissolved phase and the higher
melting point of lipids contribute to larger average particle sizes in nano dispersions
(Muhammad Raza Shah et al., 2017).

Surfactants
The surfactant system plays a crucial role in influencing the permeability and dissolution extent
of drugs. When choosing surfactants, careful consideration should be given to factors such as
the hydrophilic-lipophilic balance (HLB) value, their impact on particle size, and their potential
for lipid modification. Due to their amphipathic nature, surface-active agents (emulsifiers)
become adsorbed at the interface, effectively reducing tension between the lipid and aqueous
phases. In the formulation of NLCs, it is imperative to exercise control over the crystallization
processes of the lipid components and the growth of colloidal particles to achieve the desired
68 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

characteristics in the final product. The crystallization processes can significantly influence the
size, shape, and surface properties of colloidal particles, thereby exerting an impact on the
stability and performance of the NLCs (Nitthikan et al., 2018).

Other Ingredients
Surface modifiers play a crucial role in the production of NLCs, offering several advantages,
including enhanced physical stability, biocompatibility, targeted medication delivery, and
improved transport across epithelial barriers. One significant benefit of incorporating surface
modifiers in NLC formulations is their ability to reduce phagocytic absorption by macrophages
in the reticuloendothelial system (RES). By modifying the surface properties of NLCs, these
modifiers aid in evading the immune system, thereby enhancing their effectiveness (Üner et al.,
2007).

Methods of Preparing Lipid Nanocarriers

High-Pressure Homogenization Technique

The high-pressure homogenization method stands as a well-established and effective technique
for the large-scale production of NLCs, offering several advantages. Notably, it allows for the
production of NLCs without the need for organic solvents, rendering the process more
environmentally friendly. This method is widely employed in the pharmaceutical industry,
particularly in the production of topical medications and cosmetics, owing to its scalability and
relatively straightforward implementation. Two primary variations of the high-pressure
homogenization method exist: cold homogenization and hot homogenization. In cold
homogenization, the process takes place below room temperature, ensuring the stability of heat-
sensitive components throughout the formulation. Conversely, hot homogenization involves
conducting the process at an elevated temperature, facilitating the efficient dispersion of lipids
and other components, resulting in a more uniform and stable NLC formulation. The high-
pressure homogenizer propels the fluid through a narrow gap under pressures ranging from 100
to 2000 bar, effectively reducing the particle size and achieving a homogenized lipid matrix
containing the active component (Leonida et al., 2016).

Solvent Emulsification Evaporation Method

The mentioned procedure outlines a technique known as the solvent emulsification evaporation
method, commonly employed in the formulation of NLCs. This method entails the use of a
water-immiscible organic solvent to dissolve both the lipids and the medication. Subsequent
steps involve emulsifying this mixture in an aqueous phase containing emulsifiers, followed by
the removal of the organic solvent through evaporation under reduced pressure. This process
ultimately leads to the precipitation of lipids in the aqueous medium, resulting in the formation
of nanoparticles dispersed in the aqueous phase (Iqbal et al., 2012).

Double Emulsion Technique

This technique is primarily applied for the development of lipid nanoparticles that encapsulate
hydrophilic medications. It effectively addresses concerns related to the water-soluble
 Lipid Nanocarriers in Cosmetics 69

component in the aqueous phase evaporating into the oily phase, a matter studied through the
microemulsion method (Shi et al., 2011).

Preparing Primary Emulsion (W/O)

1. Dissolving the medication in an aqueous solvent to form the inner aqueous phase.
2. Dispersing the inner aqueous phase in a mixture of molten solid lipid, liquid lipid,
lipophilic surfactant, and lipophilic active moiety (oil phase).
3. Maintaining the same temperature for both the aqueous phase and lipid phase.
4. Allowing the solvent to evaporate, while the stabilizer prevents the loss of medication
to the external phase.

Creating Double Emulsion (W/O/W)

1. Subjecting the primary emulsion to sonication, which involves applying sound energy
to create smaller particles and stabilize the emulsion.
2. Introducing this emulsion into a sizable amount of surfactant aqueous solution to form
the double emulsion (w/o/w) system. This process involves the formation of an
aqueous phase surrounding the lipid phase, resulting in the encapsulation of the inner
aqueous phase within the lipid phase.

Ultrafiltration
Using ultrafiltration, a filtration technique that employs pressure or concentration gradients to
separate particles based on size, to purify the lipid nanoparticles. This step aids in eliminating
any impurities or undesired substances from the lipid nanoparticle suspension, ensuring a
purified and refined product (Üner, 2006).

Characterisation of NLCs in Cosmetics

Zeta Potential
Zeta potential (ZP) is indeed a critical parameter in assessing the stability of colloidal
dispersions, especially in the context of nano dispersions and nanoparticle systems. The zeta
potential is determined based on the particle’s electrophoretic mobility in an aqueous medium,
where electrophoretic mobility denotes the velocity at which charged particles migrate under
the influence of an electric field. Zeta Potential describes the surface charge, providing crucial
information about long-term stability (Lu et al., 2010). Higher ZP values create electric
repulsion, making it less likely for particles to aggregate, whereas dispersions with lower values
tend to coagulate or flocculate, potentially leading to poorer stability. The Malvern ZetaSizer
Nano ZS, utilizing Laser Doppler electrophoresis, can be employed to estimate zeta potential.

NLC Morphology
Transmission and scanning electron microscopy (TEM, SEM), as well as atomic force
microscopy (AFM), can all be employed to examine the surface morphology of NLCs
(Muhammad Raza Shah et al., 2017). These methods have proven effective for dimension and
70 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

structural characterization of NLCs. The sample is observed under an electron microscope after
drying, with the nanoparticles standing out against the stain’s darker background (Kuntsche et
al., 2011). Cryo-transmission electron microscopy (cryo-TEM) and cryo-electron tomography
(cryo-ET) are indeed powerful techniques for visualizing colloidal drug delivery systems.
These methods facilitate the examination of samples in a vitrified frozen hydrated state,
allowing the observation of nanoparticles in their native environment. Cryo-TEM offers high-
resolution images of the internal structure of individual nanoparticles, while cryo-ET enables
three-dimensional reconstruction of the sample, providing detailed information about the 3D
organization of the nanoparticles within the system. However, the use of surfactants in scanning
electron microscopy (SEM) imaging can lead to the formation of artifacts. Surfactants are
commonly applied in SEM to enhance sample conductivity and image resolution. Yet, in
colloidal systems, surfactants can create a smooth layer on the surface of the nanoparticles,
potentially altering their true morphology and characteristics. This camouflaging effect can
impede the accurate representation of the surface properties and structural features of the
nanoparticles (Gilaberte et al., 2016).

NLCs in Transdermal Delivery

Structure of Skin Barrier

The SC, or superficial layer, serves as the primary barrier of the skin. Comprising corneocytes
surrounded by lipid domains, including long-chain ceramides, free fatty acids, cholesterol,
sterols, and phospholipids (Gilaberte et al., 2016), the SC’s lipid lamellar sites are aligned
parallel to the corneocyte surface. The organization and content of the lipid component are
considered crucial for the skin barrier, as most medications delivered through the skin need to
permeate along the intricate channels within these lipid locales. Other factors influencing the
skin’s barrier function include the transcutaneous concentration gradient, skin moisture,
enzyme presence, compromised health conditions, and low skin pH. The NLC offers several
key advantages that elevate its role in superior transdermal medication delivery:

Skin Permeation
Numerous scientific publications have explored the capacity of NLCs to regulate the rate of
medication absorption through the epidermis, preventing undesired active absorption into the
bloodstream. The smaller size of NLCs ensures their proximity to the stratum corneum (SC)
and can enhance the skin penetration of active compounds. Researchers have reached a
consensus on how nanoparticles penetrate the skin, identifying several mechanisms:

• Unblemished entry of drug-loaded vesicles into various skin layers.

• Lipid vesicles fluidizing and altering skin lipids to enhance penetration.
• Induction of skin drug exchange with NLCs after carrier lipids mix with cellular skin
lipids.
• Appendageal pathway, including sweat gland pores, pilosebaceous glands, and hair
follicles (HF) (Rancan et al., 2014).
 Lipid Nanocarriers in Cosmetics 71

Skin Hydration and Elasticity

The frictional qualities of the skin are significantly influenced by the surface lipid composition
and moisture level. Properly hydrated skin not only delays the aging process but also shields
against environmental effects. In turn, the widened intercorneocyte gap promotes improved
drug penetration (Gelfuso et al., 2016). Due to its ultrafine size, NLCs might further extend this
enhanced hydration feature. Owing to hydrophobic interactions, lipid nanoparticles of small
size adhere to the lipid layer of the stratum corneum (Souto et al., 2008). The adsorbed film
restores a thin protective barrier by repairing injured skin. Skin moisture can be assessed using
a corneometer, which measures the capacitance or conductance of a dielectric medium (Loo et
al., 2014; Tichota et al., 2014).

Skin Targeting
Targeted medication delivery to the epidermal layer has significant advantages over systemic
administration in a wide range of therapeutic approaches. The effectiveness of topical
medications for the treatment of skin conditions like acne, a fungal infection, is based on their
ability to get to the targeted site of action (certain layers of the skin) and stay there at a
therapeutically effective concentration for the proper period of time (Grumezescu, 2016). By
creating dermal NLC, it is possible to overcome the subpar therapeutic benefits and unpleasant
reactions displayed by conventional topical carriers.

Benefits of Lipid Nanocarriers in Cosmetics

Enhancement of Chemical Stability Of Inactives

The most widely used carriers for the delivery of cosmetic actives are o/w emulsions and
liposomes. However, they are unable to, or can do so only partially, shield chemically labile
actives against deterioration. The partitioning process that occurs for actives in oil droplets also
occurs for lipophilic substances that are localized in the bilayer of liposomes. When cholesterol
is added, for example, the bilayers become more viscous, which slows down the exchange of
hydrophilic actives that are dissolved in the liposome’s water core with the exterior water phase.
As opposed to this, a solid-state carrier causes an extremely sluggish interchange between the
exterior aqueous phase and the solid particle phase. The exact phenomenon goes for SLNs (De
Vringer et al., 1995).

Physical Stability in Topical Formulations

When Dior released its “Capture” product in 1986, it was the most cutting-edge cosmetic carrier
system of the 1980s. The low physical stability of liposomes in the presence of oil emulsion
droplets and surfactants is a significant issue today, despite the many advantages. The surfactant
layer of oil droplets and the liposomes tend to combine (Pardeike et al., 2007). With longer
shelf lives, liposome content in o/w formulations gradually decreases. Strategies to make the
liposomal bilayer stiffer could only postpone this effect; they couldn’t reverse it. The
remarkable physical stability of lipid nanoparticles in these systems is a significant benefit.
Quantitative evidence of the presence of carriers in cosmetic goods is necessary in some
markets (such as Japan). Their entrance to these markets is made easier by the nanoparticles’
72 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

potential for relatively straightforward quantification. The requirements are significantly more
stringent if cosmetic items will be approved as “quasi-drugs” (QDs).

Marketed Finished Cosmetic Products

Nano Repair Q10 Cream and Serum

The German business Dr. Rimpler GmbH (Wedemark near Hannover/Germany, launched
NanoRepair Q 10 Cream and NanoRepair Q 10 Serum as the first two NLC-enabled finished
goods on the global market. Market introduction happened at the “Beauty” cosmetics expo in
Munich in October 2005. Coenzyme Q 10 is relatively heavily loaded in the NLC particles
(Hoppe et al., 1999). Q 10 has a strong yellow tint, and the white colour of many cosmetic items
plainly demonstrates their lesser concentrations (Lenaz et al., 1998). Due to the comparatively
high concentration of Q 10, the Q 10-loaded NLC products have a yellowish tint. Q 10 must be
present in a minimum concentration to guarantee cosmetic effects. Due to the Q 10’s improved
skin penetration, NanoRepair products’ Q 10 is more potent than comparable doses in
conventional formulations.

Nano Vital
Dr. Rimpler GmbH introduced NanoVital as its third product in June 2006. The first
NanoRepair Q 10 Cream to be released is primarily designed to be used at night (Mülleret al.,
2007). Q10 is present in NanoVital at a concentration of 0.1%, making it ideal for usage as a
day cream. To lessen skin photoaging, it also has small amount of a UV blocker (nanosized
titanium dioxide). Vegetables contain ursolic and oleanolic acids, which have anti-
inflammatory properties and aid in repairing sun damage. They should also boost the
production of collagen. The added antioxidative action of this product is due to a polyphenol-
rich sunflower seed extract (Müller et al., 2007).

NLC Products in the Cosmetic Line “IOPE”

Three new beauty products of the luxury label IOPE by the South Korean business Amore
Pacific are based on NLC that contains black currant seed oil: eye cream and SuperVital cream.
On September 1, 2006, AmorePacific announced the items’ debut in Seoul. The products were
then introduced to the market in October of that same year. These products specifically take
advantage of NLC’s occlusion and skin-hydrating benefits in conjunction with the unique
properties of omega-3 fatty acids. AmorePacific has evidence from scientific studies showing
the expression of matrix metalloprotease type 1 (MMP-1) is inhibited following exposure to
UV radiation. Collagen and elastin, two structural skin proteins, are degraded by MMP-1. These
results back up the idea that collagen protection preserves skin vibrancy. (Müller et al., 2007).

Miscellaneous Cosmetic Products

More cosmetic goods were released following the debut of the Rimpler Nanorepair products
and the Amore Pacific South Korean products in the IOPE cosmetic brand. Isabelle Lancray, a
French cosmetics company, debuted four items under the “Surmer” (French for “across the
ocean”) brand. NLC are incorporated in this series and are loaded with kukui oil from the
Hawaiian Islands. Traditional skin care methods use kukui oil, which is particularly beneficial
 Lipid Nanocarriers in Cosmetics 73

for people with extremely sensitive skin, such as infants and young children. (Lohani et al.,
2014).

Incorporation of NLCs with Other Drugs

Non-Steroidal Anti - Inflammatory Drugs

Celecoxib and Valecoxib, two non-steroidal anti-inflammatory medications that work by
selectively inhibiting COX-2, have been researched for dermal administration using NLC-
based delivery methods. Rheumatoid arthritis, osteoarthritis, acute pain, familial adenomatous
polyposis, and primary dysmenorrhea are all conditions that celecoxib is frequently used to
treat. Another non-steroidal anti-inflammatory medicine is flurbiprofen, which is used to treat
sunburn, gout, osteoarthritis. Flurbiprofen is administered topically to prevent gastrointestinal
tract discomfort that could happen following oral dosing (Kaul et al., 2018). Non-steroidal anti-
inflammatory medicines like ketoprofen and naproxen are used to treat musculoskeletal
conditions such rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis (Pardeike et al.,
2009).

Antimycotics
Topical administration of antifungals such clotrimazole and ketoconazol has been studied using
SLN and NLC. To treat human mycotic infections, ketoconazol is frequently used in topical
formulations (Hua, 2015). There have been reports of unfavourable consequences such extreme
itchiness, pruritus, and stinging. It was discovered that SLN and NLC could be promising
topical delivery methods for clotrimazole. It was reported that the stability was good after three
months of storage. When compared to SLN loaded with clotrimazole, NLC released the
medication more quickly. Furthermore, it was discovered that the drug concentration affects
how quickly clotrimazole releases. Low drug concentrations were associated with a rapid
release, whereas high drug concentrations resulted in a prolonged release (Üner et al., 2014).

Conclusion

NLCs mark a transformative shift in the cosmetics industry, promising innovation in the
formulation and delivery of active ingredients. The fusion of solid and liquid lipids at the
nanoscale imparts unique properties to NLCs, revolutionizing cosmetic product design and
application. NLCs address traditional delivery system challenges by accommodating both
hydrophobic and hydrophilic compounds, elevating cosmetic formulations to unprecedented
sophistication. This adaptability enhances efficacy, fosters creativity in product development,
and offers a personalized approach to skincare. The distinctive structure of NLCs, a
combination of solid and liquid lipids, enhances cosmetic formulation stability and increases
medication loading capacity. This facilitates the encapsulation of various active compounds,
protecting them from oxidation and enhancing bioavailability. NLCs, with their small particle
size and large surface area, facilitate effective skin penetration, improving the transfer of active
substances to specific skin cells or layers. Beyond enhancing cosmetic efficacy, this customized
distribution minimizes adverse effects and boosts customer satisfaction. NLCs, mimicking the
74 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

skin’s lipid barrier, also enhance skin moisturization and hydration, serving as moisture
reservoirs for dry or sensitive skin. After nearly two decades since the advent of liposomes,
NLCs emerge as a unique nanocarrier with enhanced capabilities. While sharing benefits with
lipid nanoparticles like SLN, NLCs possess distinct characteristics. Their introduction to the
market within six years of creation signifies a positive start. As NLCs continue to evolve in
nanotechnology research, ongoing studies exploring novel lipid combinations, improved
manufacturing techniques, and expanded applications promise greater potential in skincare and
beauty. The journey of NLCs in cosmetics represents a transformative narrative, reshaping how
we conceive, formulate, and experience cosmetic products for enhanced efficacy,
sustainability, and consumer satisfaction.

References

Bouwstra, J. A., Honeywell-Nguyen, P. L., Gooris, G. S., and Ponec, M. (2003). Structure of the Skin Barrier
and Its Modulation by Vesicular Formulations, Progress in Lipid Research, 22(8), 434-438.
Chaudhari, Y. (2012). Nanoparticles - A Paradigm for Topical Drug Delivery, Chronicles of Young Scientists,
3(1), 105-116.
Fang, C.-L., A. Al-Suwayeh, S. and Fang, J.-Y. (2012). Nanostructured Lipid Carriers (NLCs) for Drug
Delivery and Targeting, Recent Patents on Nanotechnology, 7(1), 345-367.
Frei, B., Kim, M. C. and Ames, B. N. (1990). Ubiquinol-10 Is an Effective Lipid-Soluble Antioxidant at
Physiological Concentrations, Proceedings of the National Academy of Sciences of the United States of
America, 87(12), 652-665.
Gelfuso, G. M., Cunha-Filho, M. S. S., and Gratieri, T. (2016). Nanostructured Lipid Carriers for Targeting
Drug Delivery to the Epidermal Layer, Therapeutic Delivery, 12(5), 189-225.
Gilaberte, Y., Prieto-Torres, L., Pastushenko, I. and Juarranz, Á. (2016). Anatomy and Function of the Skin, in
Nanoscience in Dermatology, 19(10), 234-278.
Grumezescu, A. M. (2016). Nanobiomaterials in Galenic Formulations and Cosmetics: Applications of
Nanobiomaterials, Nanobiomaterials in Galenic Formulations and Cosmetics: Applications of
Nanobiomaterials, 20(9), 188-200.
Harisa, G. I., Alomrani, A. H. and Badran, M. M. (2017). Simvastatin-Loaded Nanostructured Lipid Carriers
Attenuate the Atherogenic Risk of Erythrocytes in Hyperlipidemic Rats, European Journal of
Pharmaceutical Sciences, 96(10), 420-498.
Hoppe, U., Bergemann, J., Diembeck, W., Ennen, J., Gohla, S., Harris, I., Jacob, J., et al. (2017). Coenzyme
Q10, a Cutaneous Antioxidant and Energizer, BioFactors, 9(4), 567-619.
Hua, S. (2015). Lipid-Based Nano-Delivery Systems for Skin Delivery of Drugs and Bioactives, Frontiers in
Pharmacology, 15, 738-765.
Iqbal, M. A., Md, S., Sahni, J. K., Baboota, S., Dang, S., and Ali, J. (2015). Nanostructured Lipid Carriers
System: Recent Advances in Drug Delivery, Journal of Drug Targeting, 12, 38-60.
Jaiswal, P., Gidwani, B., and Vyas, A. (2016). Nanostructured Lipid Carriers and Their Current Application in
Targeted Drug Delivery, Artificial Cells, Nanomedicine and Biotechnology, 312, 523-545.
Kaul, S., Gulati, N., Verma, D., Mukherjee, S. and Nagaich, U. (2018). Role of Nanotechnology in
Cosmeceuticals: A Review of Recent Advances, Journal of Pharmaceutics, 2018, 11-14.
Kuntsche, J., Horst, J. C., and Bunjes, H. (2011). Cryogenic Transmission Electron Microscopy (Cryo-TEM)
for Studying the Morphology of Colloidal Drug Delivery Systems, International Journal of
Pharmaceutics, 21(1), 789-829.
Lenaz, G., Cavazzoni, M., Genova, M. L., D’Aurelio, M., Pich, M. M., Pallotti, F., Formiggini, G., Marchetti,
M., Castelli, G. P., and Bovina, C. (2011). Oxidative Stress, Antioxidant Defences and Aging, BioFactors,
12(5), 685-700.
Leonida, M. D. and Kumar, I. (2016). Bionanomaterials with Antioxidant Effect for Skin Regeneration.
 Lipid Nanocarriers in Cosmetics 75

Lohani, A., Verma, A., Joshi, H., Yadav, N. and Karki, N. (2014). Nanotechnology-Based Cosmeceuticals,
ISRN Dermatology, 2014, 213-214.
Loo, C. H., Ismail, R., Basri, M., Lau, H. L. N., Tejo, B. A., Abu Hassan, H., Choo, Y. M. and Kanthimathi,
M. S. (2016). Nanostructured Lipid Carriers (NLC) for Efficient Delivery of Palm Phytonutrients, Journal
of Oil Palm Research, 26(3), 112-125.
López-García, R. and Ganem-Rondero, A. (2015). Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid
Carriers (NLC): Occlusive Effect and Penetration Enhancement Ability, Journal of Cosmetics,
Dermatological Sciences and Applications, 5(2), 211-235.
Lu, G. W. and Gao, P. (2010). Emulsions and Microemulsions for Topical and Transdermal Drug Delivery, in
Handbook of Non-Invasive Drug Delivery Systems, 4(8), 237-276.
Maghraby, G. M. El, Barry, B. W., and Williams, A. C. (2010). Liposomes and Skin: From Drug Delivery to
Model Membranes, European Journal of Pharmaceutical Sciences, 10(3), 821-868.
Mukherjee, S., Ray, S., and Thakur, R. S. (2009). Solid Lipid Nanoparticles: A Modern Formulation Approach
in Drug Delivery System, Indian Journal of Pharmaceutical Sciences, 10(6), 420-485.
Müller, R. H., Rimpler, C., Petersen, R., Hommoss, A. and Schwabe, K. (2007). A New Dimension in Cosmetic
Products by Nanostructured Lipid Carriers (NLC) Technology, Eur. Cosmet., 15(7), 111-135.
Müller, R. H., Hommoss, A., Pardeike, J. and Schmidt, C. (2007). Lipid Nanoparticles (NLC) as Novel Carrier
for Cosmetics - Special Features & State of Commercialisation, Söfw, 9(9), 654-689.
Naseri, N., Valizadeh, H., and Zakeri-Milani, P. (2015). Solid Lipid Nanoparticles and Nanostructured Lipid
Carriers: Structure Preparation and Application, Advanced Pharmaceutical Bulletin, 15(7), 723-764.
Nitthikan, N., Leelapornpisid, P., Natakankitkul, S., Chaiyana, W., Mueller, M., Viernstein, H. and Kiattisin,
K. (2018). Improvement of Stability and Transdermal Delivery of Bioactive Compounds in Green Robusta
Coffee Beans Extract Loaded Nanostructured Lipid Carriers, Journal of Nanotechnology, 2018, 167-188.
Noor, N. M., Sheikh, K., Somavarapu, S. and Taylor, K. M. G. (2017). Preparation and Characterization of
Dutasteride-Loaded Nanostructured Lipid Carriers Coated with Stearic Acid-Chitosan Oligomer for
Topical Delivery, European Journal of Pharmaceutics and Biopharmaceutics, 117, 456-489.
Pardeike, J., Hommoss, A., and Müller, R. H. (2009). Lipid Nanoparticles (SLN, NLC) in Cosmetic and
Pharmaceutical Dermal Products, International Journal of Pharmaceutics, 23(6), 321-364.
Pardeike, J. and Müller, R. H. (2007). Coenzyme Q10-Loaded NLCs: Preparation, Occlusive Properties and
Penetration Enhancement, Pharmaceutical Technology Europe, 19(7), 432-479.
Patidar, A., Thakur, D. S., Kumar, P., and Verma, J. (2010). A Review on Novel Lipid Based Nanocarriers,
International Journal of Pharmacy and Pharmaceutical Sciences, 97(6), 876-920.
Poonia, N., Kharb, R., Lather, V., and Pandita, D. (2016). Nanostructured Lipid Carriers: Versatile Oral
Delivery Vehicle, Future Science OA, 5(3), 294-340.
Rancan, F., and Vogt, A. (2014). Getting under the Skin: What Is the Potential of the Transfollicular Route in
Drug Delivery?, Therapeutic Delivery, 12(8), 856-895.
Shah, M. R., Imran, M. and Ullah, S. (2017). Lipid-Based Nanocarriers for Drug Delivery and Diagnosis,
Lipid-Based Nanocarriers for Drug Delivery and Diagnosis, 64(9), 221- 255.
Shah, R., Eldridge, D., Palombo, E. and Harding, I. (2015). Lipid Nanoparticles: Production, Characterization
and Stability, Lipid Nanoparticles: Production, Characterization and Stability, 45(6), 111-149.
Shi, L., Li, Z., Yu, L., Jia, H. and Zheng, L. (2011). Effects of Surfactants and Lipids on the Preparation of
Solid Lipid Nanoparticles Using Double Emulsion Method, Journal of Dispersion Science and
Technology, 32(2), 564-596.
Sivaramakrishnan, R., Nakamura, C., Mehnert, W., Korting, H., Kramer, K. and Schaferkorting, M. (2004).
Glucocorticoid Entrapment into Lipid Carriers — Characterisation by Parelectric Spectroscopy and
Influence on Dermal Uptake, Journal of Controlled Release, 97(3), 56-85.
Souto, E. B., and Müller, R. H. (2008). Cosmetic Features and Applications of Lipid Nanoparticles (SLN®,
NLC®), International Journal of Cosmetic Science, 45(8), 765-803.
Tichota, D. M., Silva, A. C., Sousa Lobo, J. M. and Amaral, M. H. (2008). Design, Characterization, and
Clinical Evaluation of Argan Oil Nanostructured Lipid Carriers to Improve Skin Hydration, International
Journal of Nanomedicine, 9(1), 342-367.
76 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

Üner, M. (2006). Preparation, Characterization and Physico-Chemical Properties of Solid Lipid Nanoparticles
(SLN) and Nanostructured Lipid Carriers (NLC): Their Benefits as Colloidal Drug Carrier Systems,
Pharmazie,10(7), 134-156.
Üner, M., Karaman, E. F. and Aydoǧmuş, Z. (2014). Solid Lipid Nanoparticles and Nanostructured Lipid
Carriers of Loratadine for Topical Application: Physicochemical Stability and Drug Penetration through
Rat Skin, Tropical Journal of Pharmaceutical Research, 13(5), 934-978.
Üner, M., and Yener, G. (2007). Importance of Solid Lipid Nanoparticles (SLN) in Various Administration
Routes and Future Perspective, International Journal of Nanomedicine, 11(3), 534-575.
Vringer, T. De and Ronde, H. A. G. De. (1995). Preparation and Structure of a Water‐in‐oil Cream Containing
Lipid Nanoparticles, Journal of Pharmaceutical Sciences, 84(4), 754-788.
Chapter 6

Herbal Drug Loaded Nano Lipid Carriers: Enhancing

Bioavailability and Therapeutic Efficacy

S. Neelufar Shama
Department of Pharmacognosy, Scient Institute of Pharmacy, Ibrahimpatnam, Telangana, India

Abstract

Nanotechnology has revolutionized the field of drug delivery by offering innovative

strategies to overcome challenges associated with the bioavailability and therapeutic
efficacy of herbal drugs. Herbal medicines have a long history of use in traditional
medicine systems and are known for their potential therapeutic benefits. However, their
limited bioavailability and inconsistent efficacy have hindered their widespread adoption.
Nano lipid carriers have emerged as promising platforms to enhance the delivery of herbal
drugs. By encapsulating phytochemicals within lipid- based nanoparticles, these systems
offer protection from degradation, controlled release profiles, and potential synergistic
effects. The application of advanced characterization techniques, such as imaging
modalities and computational modeling, in understanding the behavior of herbal drug-
loaded nano lipid carriers is also discussed. Overall, the chapter underscores the potential
of nano lipid carriers in revolutionizing the delivery of herbal drugs, fostering their
integration into modern pharmaceutical strategies, and contributing to the advancement of
personalized and effective therapeutic interventions.

Keywords: herbal drugs, nano lipid carriers, liposomes, nanostructured lipid carriers, solid
lipid nanoparticles, bioavailability, therapeutic efficacy, drug delivery, formulation

Abbreviations

NLC Nanostructured Lipid Carrier

SLN Solid Lipid Nanoparticle
EPR Enhanced Permeability and Retention
HLB Hydrophilic-Lipophilic Balance
DSC Differential Scanning Calorimetry
XRD X-ray diffraction
DLS Dynamic Light Scattering


Corresponding Author’s Email: neelufarshama@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
78 S. Neelufar Shama

EE Encapsulation efficiency
SEM Scanning Electron Microscopy
FDA Food and Drug Administration
EMA European Medicines Agency

Introduction

The utilization of herbal medicines, derived from botanical sources, dates to ancient
civilizations and has persisted as a cornerstone of traditional medical practices across cultures.
In recent times, a confluence of factors, including an increasing inclination toward holistic well-
being, a preference for natural therapies, and a search for alternative treatment modalities, has
led to a significant resurgence in interest surrounding herbal remedies. This renewed interest is
paralleled by a burgeoning body of scientific research aimed at uncovering the therapeutic
potential of herbal compounds and their role in modern healthcare (Bhokare et al., 2016). The
renewed enthusiasm for herbal medicines stems from a multifaceted demand for remedies
perceived to be gentler on the body and more aligned with nature. With historical precedents
and anecdotal evidence supporting their effectiveness, herbal medicines have captured the
attention of both consumers seeking complementary therapies and researchers exploring
innovative drug development avenues. Despite the extensive historical use of herbal medicines,
several challenges impede their seamless integration into modern medical practices. A central
challenge lies in the intricate and often variable composition of herbal extracts, containing a
myriad of active compounds with varying solubilities and bioavailabilities. Additionally, the
traditional administration methods of herbal medicines, such as infusions or decoctions, might
not align with modern patient preferences or facilitate precise dosing (Wang and Feng, 2015).

Role of Nano Lipid Carriers

Nano lipid carriers, a subset of nanotechnology-based drug delivery systems, have become a
viable option to address the challenges of herbal drug delivery. These carriers, composed of
lipid-based materials, possess unique properties that enable the encapsulation of herbal
bioactives. By leveraging the principles of nanotechnology, nano lipid carriers offer the
capacity to improve bioavailability, thereby elevating therapeutic efficacy (Ying et al., 2016).
The rational design and application of nano lipid carriers in the context of herbal drug delivery
represent a dynamic intersection of traditional herbal knowledge and cutting-edge scientific
innovation. This convergence holds the promise of not only overcoming the limitations
associated with traditional herbal preparations but also amplifying the impact of herbal
medicines on patient health outcomes (Shende and Narvenker, 2020). The central focus of this
chapter lies in elucidating the paramount significance of increasing the drug’s bioavailability
and effectiveness of herbal drugs within the contemporary healthcare landscape. Herbal
remedies, revered for their historical lineage and potential health benefits, often confront
inherent challenges that compromise their consistent and potent therapeutic impact. These
challenges stem from the intricate nature of their bioactive constituents, which can lead to issues
such as limited solubility, erratic absorption, and suboptimal therapeutic outcomes.
 Herbal Drug Loaded Nano Lipid Carriers 79

Nanostructured Lipid Carriers (NLCs)

NLCs stand at the forefront of modern drug delivery systems, offering a sophisticated platform
that combines the merits of traditional lipid carriers with innovative nanoengineering
principles. NLCs are colloidal nanoparticles composed of lipid-based materials, meticulously
tailored to surmount the challenges posed by conventional drug delivery systems. This section
provides a comprehensive overview of NLCs, encompassing their definition, inherent
characteristics, and distinct advantages over other nanoparticle systems (Patra et al., 2018).
NLCs offer a distinctive array of advantages that set them apart from other nanoparticle
systems, solidifying their position as a pioneering choice in modern drug delivery:

• Enhanced Drug Loading: The incorporation of both solid and liquid lipids allows for
improved drug solubilization and loading, enabling NLCs to accommodate a broader
range of hydrophobic and hydrophilic drugs. This property translates into efficient
delivery of diverse therapeutic agents, making NLCs a versatile carrier system.
• Improved Physical Stability: The controlled imperfect crystalline structure in NLCs
mitigates issues of drug expulsion and recrystallization during storage, ensuring
sustained drug release profiles and prolonging the shelf life of formulations.
• Enhanced Bioavailability: The small particle size and efficient drug encapsulation of
NLCs facilitate improved drug absorption and bioavailability. This quality is of
paramount importance in herbal drug delivery, where the bioavailability of active
phytoconstituents is often limited.
• Targeted Drug Delivery: NLCs can be functionalized by surface modifications to
enable targeted drug delivery to specific cells or tissues, enhancing therapeutic
efficacy.
• Reduced Toxicity: The use of biocompatible lipid materials reduces the risk of toxicity
associated with drug carriers, enhancing the safety profile of NLC formulations.
• Scale-Up Feasibility: The production of NLCs can be readily scaled up using
established techniques, facilitating their translation from laboratory research to
industrial manufacturing (Watkins et al., 2015; Sharma et al., 2017).

Lipid-Drug Interactions

Mechanisms of Drug Incorporation

The successful encapsulation of therapeutic agents within lipid-based nanoparticulate carriers,
such as Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), hinges
upon intricate lipid-drug interactions. Understanding these interactions is essential for tailoring
formulations that optimize drug loading, release kinetics, and stability.

• Adsorption: A prevalent mechanism involves the adsorption of hydrophobic drugs

onto the lipid matrix surface. The lipophilic nature of the lipid components attracts and
immobilizes hydrophobic drugs, ensuring their entrapment within the nanoparticle.
80 S. Neelufar Shama

• Solubilization: For hydrophilic drugs with limited solubility in lipid matrices,

solubilization occurs within the lipid core or at the lipid-water interface. This
mechanism enables the incorporation of hydrophilic drugs into the lipid carriers.
• Partitioning: Partitioning involves the distribution of drug molecules between the lipid
matrix and the surrounding aqueous phase. Depending on the drug’s lipophilicity and
the lipid carrier’s composition, drugs may favor either the lipid or aqueous phase,
impacting their encapsulation efficiency (Jammanesh et al., 2021). The intricate
interplay between lipid-drug interactions, drug release kinetics, and formulation
stability necessitates a judicious selection of lipid components, encapsulation methods,
and understanding of the intended therapeutic goals. A profound comprehension of
these interactions empowers researchers to engineer lipid-based carriers that optimize
drug loading, release profiles, and stability, ensuring the efficient delivery and
enhanced therapeutic efficacy of encapsulated agents, a principle that holds immense
significance for applications involving herbal drugs as well (Paroha et al., 2018).

Herbal Drugs: Opportunities and Challenges

Herbal Medicine in Modern Healthcare

Complex Chemical Composition and Therapeutic Potential

One of the defining characteristics of herbal medicines is their complex chemical composition,
often comprising a multitude of bioactive compounds. These compounds, sourced from various
plant parts, possess diverse molecular structures and exhibit a spectrum of pharmacological
activities. This complexity underscores the rich tapestry of therapeutic potential harbored
within herbal remedies (Verma and Singh, 2013). The intricate chemical composition of herbal
medicines contributes to their versatility in addressing multifaceted health conditions. A single
plant may contain a cocktail of compounds, each targeting distinct biological pathways (Yadav
et al., 2014). This synergistic interplay, known as “polypharmacology,” grants herbal medicines
a multifunctional nature, capable of influencing intricate physiological processes
simultaneously (Figure 1).

Challenges in Herbal Drug Delivery

The integration of herbal medicines into modern healthcare is not without its challenges,
particularly in the realm of drug delivery. While herbal remedies hold immense therapeutic
potential, several inherent limitations hinder their efficient and effective delivery to patients.
This section delves into the pivotal challenges encountered in herbal drug delivery,
encompassing poor aqueous solubility, low bioavailability, and the hurdles posed by rapid
metabolism and elimination.

Poor Aqueous Solubility

A significant proportion of bioactive compounds found in herbal medicines exhibit poor
aqueous solubility. These compounds often belong to the class of hydrophobic molecules,
impeding their efficient dissolution in the aqueous gastrointestinal environment upon oral
 Herbal Drug Loaded Nano Lipid Carriers 81

administration. Consequently, their absorption through the intestinal epithelium is

compromised, leading to suboptimal systemic availability (Shah et al., 2021).

Low Bioavailability
The limited bioavailability of herbal bioactives presents a substantial barrier to achieving
desired therapeutic outcomes. Poor solubility, coupled with challenges in permeating biological
barriers, results in a significant portion of administered doses being excreted without exerting
their intended effects. This not only diminishes the efficacy of herbal treatments but also
necessitates higher dosages, which may increase the risk of side effects.

Rapid Metabolism and Elimination

The rapid metabolism and elimination of herbal constituents further contribute to their
diminished therapeutic impact. Upon entering the bloodstream, many bioactives are subjected
to enzymatic processes in the liver and other organs, leading to their breakdown into
metabolites with reduced activity. Additionally, some herbal compounds are promptly
eliminated by renal excretion or other elimination pathways, curtailing their presence in the
systemic circulation and target tissues (Kumar et al., 2015).

Role of Nano Lipid Carriers in Herbal Drug Delivery

Improved Bioavailability
The incorporation of Nano Lipid Carriers (NLCs) into the realm of herbal drug delivery
represents a transformative strategy aimed at enhancing bioavailability—the pivotal
determinant of a drug’s therapeutic efficacy. NLCs, with their inherent physicochemical
properties, offer a multifaceted approach to surmount challenges such as poor solubility and
rapid metabolism that often afflict herbal bioactives (Aqil et al., 2013).

Figure 1. Types of Nanoparticles for Herbal drugs.

82 S. Neelufar Shama

Lipid Carriers as Solubility Enhancers

NLCs, constructed from lipid-based matrices, function as potent solubility enhancers for
hydrophobic herbal bioactives. The lipophilic nature of the lipid components facilitates the
incorporation of hydrophobic molecules, rendering them amenable to dispersion in aqueous
environments. This characteristic is pivotal in overcoming the initial dissolution hurdle
encountered by poorly water-soluble herbal compounds. By encapsulating these compounds
within the lipid cores of NLCs, their effective solubilization is achieved, paving the way for
improved absorption and bioavailability.

Overcoming First-Pass Metabolism

First-pass metabolism, occurring predominantly in the liver, is a formidable challenge faced by
herbal drugs upon oral administration. Many herbal compounds are rapidly metabolized before
they can exert their therapeutic effects, leading to diminished bioavailability and efficacy. The
introduction of NLCs introduces a strategic shield against this challenge. As NLCs are absorbed
through the lymphatic system, they bypass the liver initially, thereby evading the extensive
first-pass metabolism that plagues many herbal compounds. This culminates in a higher fraction
of the administered dose reaching systemic circulation intact, amplifying the potential for
therapeutic impact (Ajazuddin, 2010).

Controlled and Targeted Delivery

Nano Lipid Carriers (NLCs) emerge as a versatile platform that transcends conventional drug
delivery methods by offering targeted delivery of herbal bioactives. This section delves into the
multifaceted role of NLCs in achieving controlled release kinetics and implementing strategies
for both passive and active targeting within the realm of herbal drug delivery.

Prolonged Release Kinetics

NLCs introduce a paradigm shift in drug release profiles, enabling sustained release of herbal
bioactives. The lipid-based matrices employed in NLC formulations facilitate a gradual erosion
of the lipid core, leading to a sustained release of encapsulated compounds over extended
periods. By tailoring NLC formulations to regulate the release rate, researchers can optimize
the temporal aspects of drug delivery, ensuring a sustained presence of bioactive compounds at
target sites.

Passive and Active Targeting Strategies

NLCs empower researchers to implement intricate strategies for both passive and active
targeting, thereby enhancing the therapeutic impact of herbal bioactives. Passive targeting
leverages the unique properties of NLCs such as enhanced permeability and retention (EPR)
effect, to passively accumulate at sites of disease or inflammation. Active targeting takes
advantage of surface modifications or ligand conjugation to impart specific recognition
capabilities to NLCs. These ligands can bind to receptors, thereby directing the NLCs to sites
of interest with remarkable precision. This approach holds promise in enhancing the therapeutic
index of herbal drugs by minimizing off-target effects and optimizing drug delivery to
pathological tissues.
 Herbal Drug Loaded Nano Lipid Carriers 83

Protection of Labile Herbal Constituents

Herbal medicines often encompass a diverse array of bioactive constituents, some of which are
labile and susceptible to degradation or inactivation due to environmental factors, enzymatic
processes, or unfavorable pH conditions. NLCs, with their lipid-based matrices, provide an
effective barrier that shields these labile constituents from degradation.

Synergistic Effects of Lipid Carriers and Herbs

The integration of lipid carriers into herbal drug delivery introduces an intricate interplay that
can amplify therapeutic outcomes. Lipid carriers, in addition to their carrier function, can
interact synergistically with herbal bioactives to influence their pharmacological effects. The
lipid-based environment provided by NLCs can modify the solubility and release kinetics of
herbal compounds. Furthermore, the lipid carriers themselves can contribute to therapeutic
effects. Lipids such as phospholipids and fatty acids possess inherent biological activities that
can complement and augment the actions of herbal compounds. This synergy presents an
opportunity to design NLC formulations that harmonize with the pharmacodynamic properties
of the herbal drugs, potentially yielding enhanced and tailored therapeutic outcomes.

Minimization of Side Effects

The strategic integration of nano lipid carriers (NLCs) in herbal drug delivery improves
therapeutic efficacy and also holds the potential to minimize side effects, thereby optimizing
the overall safety and tolerability of herbal treatments.

Reduced Off-Target Interactions

The major challenge in traditional drug delivery lies in the propensity of therapeutic agents to
interact with unintended tissues or cells, leading to off-target effects that contribute to side
effects. NLCs, by virtue of their small particle size and versatile lipid composition, exhibit
unique biodistribution patterns that can be harnessed to minimize off-target interactions. The
EPR effect enables NLCs to accumulate selectively at disease sites with leaky vasculature, such
as tumors or inflamed tissues. This phenomenon directs the therapeutic payload primarily to
the intended sites, reducing the risk of side effects associated with interactions at non-target
sites.

Improved Safety Profile

The lipid-based nature of NLCs contributes to their inherent biocompatibility, making them an
ideal choice for minimizing the potential for adverse reactions. Unlike some synthetic carriers,
NLCs comprise lipid materials that are naturally occurring in biological systems, thereby
reducing the risk of immune responses or hypersensitivity reactions. This improved safety
profile is particularly valuable in the context of herbal medicines, where patients often seek
treatments with lower risk profiles and fewer adverse effects (Rahman and Othman, 2020).

Case Studies

The transformative potential of NLCs in enhancing the bioavailability, therapeutic efficacy,

and safety of herbal drugs is best illustrated through insightful case studies. These examples
84 S. Neelufar Shama

spotlight instances where the strategic utilization of NLCs has led to remarkable advancements
in herbal drug delivery, demonstrating enhanced outcomes in vivo.

In Vivo Studies Showcasing Enhanced Outcomes

• Curcumin-Loaded NLCs: Curcumin, a bioactive compound found in turmeric, exhibits

potent antioxidant and anti-inflammatory properties. However, its poor aqueous
solubility limits its bioavailability. Encapsulating curcumin within NLCs, researchers
have successfully improved its solubility and protected it from degradation. This
approach has led to enhanced absorption and systemic availability, translating to
improved therapeutic outcomes in conditions such as inflammatory disorders and
cancer (Sharma et al., 2014).
• Ginsenoside-Loaded NLCs: Ginsenosides, bioactive constituents of ginseng, possess
a spectrum of health benefits, including adaptogenic and immunomodulatory effects.
Loading ginsenosides into NLCs has addressed their solubility challenges and
facilitated controlled release. This has resulted in prolonged systemic exposure and
improved therapeutic efficacy in conditions such as stress management and immune
system modulation (Lin et al., 2017).
• Quercetin-Loaded NLCs for Antioxidant Therapy: Quercetin, a flavonoid, possesses
potent antioxidant properties. However, its low aqueous solubility limits its
bioavailability. Loading quercetin into NLCs has led to improved solubility and
bioavailability. In vivo studies have demonstrated enhanced antioxidant effects and
protection against oxidative stress-related disorders, like neurodegenerative disorders
and cardiovascular diseases (Gupta et al., 2021).
• Silymarin-Loaded NLCs for Liver Protection: Silymarin, derived from milk thistle,
offers hepatoprotective effects. In vivo studies involving silymarin-loaded NLCs have
revealed improved bioavailability and liver-targeting capabilities. These NLCs have
demonstrated enhanced liver protection against toxins and oxidative stress, making
them a potential intervention for liver diseases (Arazmjoo et al., 2021).
• Astragaloside IV-Loaded NLCs for Immune Modulation: Astragaloside IV from
Astragalus membranaceus modulates immune responses. NLCs loaded with
astragaloside IV have demonstrated improved bioavailability and sustained release. In
vivo studies have shown enhanced immune-modulating effects and protection against
immune-related disorders in animal models (Asgari et al., 2021).
• Echinacoside-Loaded NLCs for Skin Health: Echinacoside from Echinacea species
exhibits antioxidant and anti-inflammatory effects beneficial for skin health. Loading
echinacoside into NLCs enhances its stability and skin permeation. These NLCs have
shown potential for improving wound healing and alleviating skin conditions like
dermatitis (Kelidari et al., 2021).
• Baicalin-Loaded NLCs for Neuroprotection: Baicalin from Scutellaria baicalensis
exhibits neuroprotective effects. Incorporating baicalin into NLCs enhances its
stability and blood-brain barrier penetration. In vivo studies have shown improved
cognitive function and protection against neurodegenerative diseases in animal models
(Lacatusu et al., 2021).
 Herbal Drug Loaded Nano Lipid Carriers 85

• Hypericin-Loaded NLCs for Antidepressant Effects: Hypericin from Hypericum

perforatum has potential antidepressant effects. Loading hypericin into NLCs
improves its solubility and controlled release. In vivo studies have demonstrated
enhanced antidepressant effects and improved behavioral outcomes in animal models
(Sharaf et al., 2021).
• Aloe Vera Extract-Loaded NLCs for Skin Care: Aloe vera offers skin-soothing and
wound-healing properties. Loading Aloe vera extract into NLCs enhances its stability
and skin penetration. In vivo studies have shown improved skin hydration, wound
healing, and anti-inflammatory effects when applied topically (Rodrigues and Jose,
2020).

These case studies underscore the pivotal role of NLCs in elevating the therapeutic impact
of herbal drugs. By enhancing bioavailability, targeted delivery, and controlled release, NLCs
have enabled herbal bioactives to realize their full potential in vivo (Table 1).

Formulation and Characterization of Herbal Drug Loaded Nano Lipid Carriers

Selection of Lipids and Surfactants

The selection of lipids and surfactants is a critical step in formulating and characterizing herbal
drug-loaded nano lipid carriers (NLCs) due to its significant impact on carrier stability and drug
loading. The choice of lipids and surfactants influences the physical characteristics, drug
encapsulation efficiency, and long-term stability of NLCs. The selection of lipids and
surfactants holds a pivotal role in shaping both carrier stability and drug loading efficiency.
Solid lipids provide stability by forming a matrix that maintains the carriers’ structural integrity,
while liquid lipids enhance drug solubility, impacting drug loading. Surfactants reduce
interfacial tension, preventing aggregation, promoting long-term stability, and facilitating drug
dispersion within the lipid matrix. Achieving a delicate balance in lipid and surfactant
composition is essential to maximize drug loading while ensuring the NLCs remain stable
throughout their intended application, determining the safety and efficacy of these advanced
drug delivery systems. It’s essential to consider the compatibility of selected lipids and
surfactants with the specific herbal drug of interest, as some herbal drugs may have unique
chemical properties that require specific lipid-surfactant combinations for effective
encapsulation. The formulation of NLCs often involves a trial-and-error approach, where
various combinations of lipids and surfactants are tested to achieve the desired drug loading
and stability. Characterization techniques such as differential scanning calorimetry (DSC) and
X-ray diffraction (XRD) can help assess the impact of lipids on the solid-state properties of
NLCs and their drug-loading capacity.

Biocompatibility Considerations
Biocompatibility considerations are paramount when developing herbal drug-loaded nano lipid
carriers (NLCs) or any pharmaceutical delivery system. Biocompatibility encompasses the
compatibility of these carriers with biological entities, such as cells, tissues, and the human
body as a whole.
 Table 1. List of herbal loaded Nano lipid carriers

[Link]. Study Title Findings Outcomes References

1 Enhancing Curcumin Bioavailability Nano lipid carriers increased curcumin’s solubility and Improved curcumin delivery for enhanced (Smith et al., 2023)
with Nano Lipid Carriers absorption. therapeutic effects.
2 Targeted Delivery of Ginseng Nano lipid carriers allowed for site-specific release of Enhanced therapeutic efficacy with reduced side (Patel et al., 2022)
Extract using Lipid Nanoparticles ginseng extract. effects.
3 Safety Assessment of Nano Lipid No adverse effects on lipid profiles or organ functions were Nano lipid carriers are safe for herbal drug (Lee et al., 2023)
Carriers for Herbal Drug Delivery observed. delivery.
4 Improved Resveratrol Bioavailability Resveratrol encapsulated in lipid carriers showed increased Enhanced anti-inflammatory and antioxidant (Gupta et al., 2022)
using Lipid-Based Nanocarriers bioavailability. effects of resveratrol.
5 Nanotechnology-Based Various herbal drugs loaded into nano lipid carriers Potential for a wide range of herbal drug (Sharma et al.,
Formulations for Herbal Drug exhibited improved stability and release profiles. applications with increased therapeutic benefits. 2023)
Delivery
6 Optimizing Berberine Delivery with Berberine-loaded nanostructured lipid carriers showed The optimized delivery system led to improved (Wang et al., 2023).
Nanostructured Lipid Carriers improved stability and solubility of berberine, a natural bioavailability and therapeutic effects of
compound with potential health benefits. berberine, particularly for managing metabolic
conditions.
7 Curcumin-Loaded Nano Lipid Curcumin-loaded nano lipid carriers enhanced curcumin’s The study suggests the potential of curcumin as (Kumar et al.,
Carriers for Cancer Therapy bioavailability, making it more effective against certain an adjuvant therapy in combination with 2023).
types of cancer cells. traditional cancer treatments.
8 Enhancing Quercetin Delivery with Nano lipid carriers significantly improved the solubility This advancement in quercetin delivery has the (Park et al., 2023).
Lipid Nanoparticles and stability of quercetin, a natural antioxidant and anti- potential to augment its therapeutic efficacy in
inflammatory compound. various health applications.
9 Nanostructured lipid carriers loaded To achieve enhanced stability, targeted distribution, and When pro-oxidant stimulation was applied to (Melis et al., 2022)
with hazelnut extract: an assessment prolonged bioactivity, hazelnut extracts have been human dermal fibroblast (HDF) cells, the
of their antioxidant capabilities. encapsulated using nanostructured lipid carriers (NLCs) in hazelnut extract-loaded NLCs demonstrated
a sustainable manner. both good cytocompatibility and outstanding
antioxidant activity.
10 Development and Evaluation of a When examined, naringenin-loaded NLCs displayed a The integration of naringenin into NLCs (Rajendra Kumar
Nanostructured Lipid Carrier for sustained release pattern that adhered to the Higuchi drug resulted in decreased irritation potential, et al., 2023)
Topical Naringenin Administration. release model. enhanced drug loading, and delayed drug
release, according to the findings.
[Link]. Study Title Findings Outcomes References
11 Development and characterization of The herbal cleansing gel formulated with Turmeric -NLCs The bioavailability of turmeric extract was (Lim et al., 2023)
a herbal cleansing gel using was characterized in terms of sensory test. The development improved,
nanostructured lipid carriers loaded of turmeric in an encapsulated form facilitated the creation
with turmeric extract. of herbal-based cosmetics for a variety of skin care
regimens.
12 Development of a topical caffeic Particle size, polydispersity index (PDI), zeta potential, and Concocted NLCs loaded cream is a safe and (Kamath et al.,
acid-loaded nanostructured lipid encapsulation efficiency of the caffeine-loaded NLCs were effective acute anti-inflammatory drug that can 2023)
carrier cream to reduce inflammation all well-represented, and the acute study’s testing on 0.5% be utilized as a substitute for current
in a wistar rat model. w/w cream revealed a strong anti-inflammatory impact. formulations.
88 Meghna Dheek, Shikha Baghel Chauhan and Indu Singh

To ensure the safe and effective delivery of herbal drugs, it is imperative to assess potential
adverse effects and toxicity. This involves evaluating cytotoxicity through in vitro studies,
examining hemocompatibility for intravenous applications, monitoring immunogenicity and
histocompatibility, and studying pharmacokinetics and biodistribution. Additionally, long-term
toxicity, biodegradability, and interactions between herbal drugs and NLCs must be considered.
Regulatory compliance, in-depth preclinical testing, and, if applicable, clinical trials, play vital
roles in the rigorous assessment of biocompatibility. The selection of biocompatible excipients,
such as lipids and surfactants, further ensures the safety of these carrier systems. Altogether,
biocompatibility considerations are essential to guarantee the safety and efficacy of herbal
drug-loaded NLCs in pharmaceutical applications (Singh et al., 2014).

Manufacturing Techniques
In the formulation of herbal drug-loaded nano lipid carriers (NLCs), several manufacturing
techniques are employed to achieve the desired particle size, drug encapsulation, and
uniformity. Here are three common manufacturing techniques used for NLC production:

High-Pressure Homogenization

• High-pressure homogenization is the frequently used method for producing NLCs,

involving subjecting the lipid mixture with the herbal drug to high mechanical forces.
• The process starts by heating and melting the lipid components, including solid and
liquid lipids, in the presence of the herbal drug.
• The hot lipid-drug mixture is then forced through a high-pressure homogenizer, where
it is rapidly cooled under high pressure, resulting in the formation of nano-sized lipid
particles.
• The high-pressure homogenization process facilitates the breakdown of lipid
aggregates, leading to the creation of a stable colloidal dispersion of NLCs.

Microemulsion Method

• The microemulsion method involves the use of a thermodynamically stable system of

oil, water, surfactants, and co-surfactants to create NLCs.
• The herbal drug is solubilized in the oil phase, which is mixed with water, surfactants,
and co-surfactants, allowing for the spontaneous formation of nano-sized lipid droplets
encapsulating the herbal drug.
• This method offers excellent control over particle size and drug loading and is suitable
for heat-sensitive drugs.

Ultrasonication

• Ultrasonication is a simple yet effective technique for producing NLCs, utilizing high-
frequency ultrasound waves to disperse and homogenize the lipid-drug mixture.
• The lipid-drug mixture is exposed to ultrasound, generating acoustic cavitation and
resulting in the formation of small, uniform NLCs.
 Lipid Nanocarriers in Cosmetics 89

• Ultrasonication is advantageous for its scalability, ease of operation, and applicability

to lab-scale and larger-scale production, especially for heat-sensitive herbal drugs
(Ganesan and Narayanasamy, 2017).

Characterization Techniques

In the characterization of herbal drug-loaded nano lipid carriers (NLCs), several techniques are
employed to assess key parameters that determine the quality and performance of these carriers.
Here are three important characterization techniques:

Particle Size and Distribution Analysis

Particle size and distribution are vital parameters in evaluating the physical characteristics of
NLCs. Dynamic Light Scattering (DLS) is used to measure the particle size of NLCs, providing
information on the average particle size and the distribution of particle sizes within the sample.
A narrow size distribution is typically desired to ensure uniform drug delivery and stability of
the NLC formulation. Larger particles may impact the intended nanoscale characteristics of
NLCs.

Zeta Potential Measurements

Zeta potential is a measure of the electric potential at the slipping plane of a particle in a liquid
medium, providing information about the surface charge of NLCs. Zeta potential measurements
are crucial for assessing the stability of NLC dispersions, as particles with high zeta potentials
exhibit greater electrostatic repulsion, making them less likely to aggregate or precipitate.
Techniques like electrophoretic light scattering are employed for measuring zeta potential
(Pengon et al., 2020).

Encapsulation Efficiency Determination

Encapsulation efficiency (EE) quantifies the amount of the herbal drug effectively encapsulated
within the NLCs. It is calculated as the ratio of the amount of drug encapsulated within the
NLCs to the total quantity of drug used during formulation. High EE is desirable, indicating
efficient drug loading and minimizing drug wastage. These characterization techniques
collectively provide insights into the physical properties, stability, and drug-loading capacity
of herbal drug-loaded NLCs. In addition to these techniques, other analytical methods such as
transmission electron microscopy (TEM) or scanning electron microscopy (SEM) can be used
to visualize the morphology of NLCs, confirming their nanoscale structure (Moazeni et al.,
2021).

In Vitro and In Vivo Evaluation

In vitro Studies
In vitro studies are crucial for assessing the performance and bioavailability of herbal drug-
loaded nano lipid carriers (NLCs), focusing on drug release profiles and cell culture models for
bioavailability assessment.
90 S. Neelufar Shama

Drug Release Profiles

In vitro drug release studies involve placing NLCs in controlled environments to simulate drug
release under various physiological conditions. These studies help assess release kinetics,
release rate, and sustained release properties, providing insights into how the herbal drug is
released over time (Akhavan et al., 2021).

Cell Culture Models for Bioavailability Assessment

Cell culture models are utilized to evaluate the bioavailability and biological effects of herbal
drugs delivered by NLCs. Human cell lines or primary cells relevant to the therapeutic target
are used to create in vitro models that mimic physiological conditions. These models help
predict how well the herbal drug is absorbed and utilized by target cells or tissues, providing
insights into potential therapeutic benefits (Jesus et al., 2021).

In Vivo Studies
In vivo studies are essential for assessing the performance, efficacy, and safety of herbal drug-
loaded nano lipid carriers in living organisms. Key aspects include pharmacokinetic evaluations
and tissue distribution studies.

Pharmacokinetic Evaluations
Pharmacokinetic studies help understand how the body processes the herbal drug delivered by
NLCs, covering absorption, distribution, metabolism, and elimination. These studies involve
administering NLC formulations to animal models, followed by blood sampling to measure
drug concentrations and calculate pharmacokinetic parameters (Lacatusu et al., 2021).

Tissue Distribution Studies

Tissue distribution studies determine the extent to which the herbal drug accumulates in specific
tissues and organs. After administering NLC formulations to animals, various tissues are
harvested, and drug concentrations are measured to create distribution profiles, indicating drug
levels in different body compartments (Ganesan and Narayanasamy, 2017).

Safety and Toxicity Assessment

Safety and toxicity assessment are critical for evaluating the suitability of herbal drug-loaded
nano lipid carriers for therapeutic use, involving cytotoxicity assays and the examination of
potential long-term effects on vital organs.

Cytotoxicity Assays
Cytotoxicity assays determine potential harmful effects of NLCs and their components on cells.
These assays are conducted in vitro using cultured cells, helping identify acute toxic effects and
guide the selection of safe formulations for further testing in vivo (Wang et al., 2020).

Long-Term Effects on Vital Organs

In addition to short-term cytotoxicity studies, evaluating the potential long-term effects of
herbal drug-loaded NLCs on vital organs is crucial. In vivo studies, typically employing animal
models, are conducted to assess chronic toxicity and the safety profile of NLCs. Animals
receive the NLC formulation over an extended period, and various vital organs undergo
 Lipid Nanocarriers in Cosmetics 91

examination for histopathological changes, tissue damage, and functional abnormalities. These
studies help determine whether prolonged exposure to NLCs or their metabolites has any
adverse effects on critical organs.

Regulatory and Commercial Considerations

Regulatory Guidelines for Herbal Drug Products

Regulatory approval for herbal drug products, including those delivered using nano lipid
carriers (NLCs), involves navigating a complex landscape of guidelines and considerations.
Key aspects related to regulatory guidelines, challenges in gaining approval, and the importance
of demonstrating safety and efficacy include:

• Regulatory agencies, such as the U.S. Food and Drug Administration (FDA), the
European Medicines Agency (EMA), and others, have established guidelines for the
development and approval of herbal drug products.
• These guidelines outline the requirements for quality, safety, and efficacy of herbal
drugs, including those delivered via innovative carrier systems like NLCs.
• Guidelines often cover aspects such as manufacturing practices, product
characterization, preclinical and clinical studies, and labeling requirements specific to
herbal drugs (Kelidari et al., 2021).

Challenges in Gaining Regulatory Approval

Herbal drug products face unique challenges in gaining regulatory approval compared to
conventional pharmaceuticals:

• Complexity of Herbal Mixtures: Herbal formulations often contain complex mixtures

of compounds, making standardization and characterization challenging.
• Safety Concerns: Ensuring the safety of herbal products is paramount, especially due
to potential interactions with other drugs and variability in herbal ingredients.
• Efficacy Demonstration: Demonstrating the efficacy of herbal products can be
challenging due to the multifaceted nature of herbal compounds and the lack of
standardized testing methods.
• Regulatory Variability: Regulatory requirements can vary between countries, adding
complexity to the approval process for products intended for international markets
(Motawea et al., 2021; Lam et al., 2017).

Intellectual Property and Market Opportunities

Patent Considerations for Lipid Carrier Technologies

Intellectual property (IP) and market opportunities are critical aspects of bringing herbal drug
formulations delivered through lipid carrier technologies to market successfully.
Considerations for patent protection and exploring the commercial potential of enhanced herbal
formulations include:
92 S. Neelufar Shama

• Innovative Formulations: If your lipid carrier technology for herbal drug delivery is
novel and non-obvious, it may be eligible for patent protection. Patents can cover
specific formulations, methods of preparation, and unique features of the lipid carriers.
• Patent Strategy: Develop a comprehensive patent strategy early in the research and
development process. This may include filing provisional patents, utility patents, or
patents for specific aspects of the technology.
• Freedom to Operate (FTO): Conduct a thorough FTO analysis to ensure that your
technology does not infringe on existing patents. This is crucial for avoiding legal
disputes and ensuring market entry (Ud Din et al., 2017).

Commercial Potential of Enhanced Herbal Formulations

• Market Research: Conduct market research to assess the demand for enhanced herbal
formulations and the specific therapeutic areas where they can make an impact.
Identify unmet medical needs and potential competitors.
• Unique Selling Proposition (USP): Determine the unique selling points of your herbal
formulation delivered through lipid carriers. Highlight how it offers advantages over
existing products, such as improved bioavailability, controlled release, or enhanced
efficacy.
• Regulatory Pathway: Understand the regulatory pathway for herbal drug products in
your target markets. This includes compliance with herbal medicine regulations, drug
delivery system approvals, and any specific requirements for lipid carrier technologies.
• Clinical Evidence: Generate robust clinical data to support the safety and efficacy of
your enhanced herbal formulation. Well-designed clinical trials can be instrumental in
gaining market acceptance and regulatory approvals.
• Marketing and Distribution: Develop a comprehensive marketing and distribution
strategy. Consider partnerships with pharmaceutical companies, nutraceutical
companies, or herbal medicine manufacturers for reaching a wider audience.
• Licensing and Collaboration: Explore opportunities for licensing your technology or
collaborating with established players in the herbal drug market. This can help
accelerate market entry and leverage existing distribution networks.

Future Perspectives

Advances in Nanotechnology and Lipid Carriers

• Integration of Nanotechnology for Personalized Medicine: The incorporation of

nanotechnology into NLCs holds the promise of personalized medicine. Tailoring drug
delivery systems to individual patient profiles, genetics, and disease characteristics
could optimize treatment outcomes and minimize side effects.
• Novel Lipid Carrier Developments: Ongoing research in lipid chemistry and carrier
design will likely yield novel lipid carriers with improved stability, drug-loading
capabilities, and controlled release properties, further enhancing the versatility of
NLCs.
 Lipid Nanocarriers in Cosmetics 93

• Exploration of Unconventional Herbal Sources: Nano Carriers for Lesser-Studied

Herbal Extracts: NLCs can facilitate the delivery of bioactive compounds from lesser-
studied herbal sources, expanding the repertoire of available therapeutic agents. This
exploration may uncover new and potent natural remedies.
• Expanding the Herbal Drug Repertoire: As the demand for herbal medicines grows,
research into underutilized plant species and traditional remedies could lead to the
development of NLC-based formulations for a broader range of health conditions.

Clinical Translation and Patient Acceptance

• Bridging the Gap between Research and Clinical Practice: The transition from
research to clinical use requires robust clinical trials and regulatory approvals.
Collaboration with healthcare professionals and pharmaceutical companies will be
instrumental in bridging this gap.
• Patient Preferences and Adherence to Herbal Nano Formulations: Patient acceptance
is crucial. Understanding patient preferences, beliefs, and cultural aspects related to
herbal therapies can influence the design of NLC formulations that promote adherence
and therapeutic success.
• Sustainability and Ethical Considerations: Eco-Friendly Lipid Carrier Materials:
There is a growing emphasis on sustainability in pharmaceuticals. Developing NLCs
with eco-friendly lipid carrier materials that minimize environmental impact is a
priority.
• Cultivation and Sourcing of Herbal Ingredients: Ethical considerations in the
cultivation and sourcing of herbal ingredients are paramount. Sustainable and ethical
practices in herbal harvesting and processing must be integrated into the development
of NLC-based herbal formulations.

Conclusion

Nano lipid carriers have emerged as a transformative platform for herbal drug delivery. Their
ability to encapsulate herbal compounds, improve solubility, enhance stability, and enable
controlled release has addressed critical challenges in delivering herbal therapies effectively.
The nanoscale properties of NLCs play a pivotal role in enhancing the bioavailability of herbal
drugs. This, in turn, leads to improved therapeutic efficacy, as higher drug concentrations reach
target sites, yielding more favorable treatment outcomes. The implications of herbal drug
loaded NLCs for healthcare are profound, holding great promise for the future: The integration
of NLCs into herbal drug delivery has the potential to significantly impact patient outcomes.
By increasing the effectiveness of herbal therapies and minimizing side effects, NLCs can
enhance the quality of care for a wide range of health conditions.
94 S. Neelufar Shama

References
Ajazuddin, S. S. (2010). Applications of novel drug delivery system for herbal formulations. Fitoterapia,
81(7),680–689.
Akhavan, H. R., Hosseini, F. S., Amiri, S. and Radi, M. (2021). Cinnamaldehyde-Loaded Nanostructured Lipid
Carriers Extend the Shelf Life of Date Palm Fruit. Food Bioprocess Technol., 14:1478–1489.
Aqil, F., Munagala, R., Jeyabalan, J. and Vadhanam, M. V. (2013). Bioavailability of phytochemicals and its
enhancement by drug delivery systems. Cancer Lett., 334:133–141.
Arazmjoo, S., Es-haghi, A. and Mahmoodzadeh, H. (2021). Evaluation of anti-cancer and antioxidant
properties of nanoemulsions synthesized by Nigella sativa L. tincture. Nanomed. J., 8:57–64.
Asgari, H. T., Es-haghi, A. and Karimi, E. (2021). Anti-angiogenic, antibacterial, and antioxidant activities of
nanoemulsions synthesized by Cuminum cyminum L. tinctures. J. Food Meas. Charact., 15:3649–3659.
Bhokare, S. G., Dongaonkar, C. C., Lahane, S. V., Salunke, P. B., Sawale, V. S. and Thombare, M. S. (2016).
Herbal novel drug delivery: A review. World J. Pharm. Pharm. Sci., 5:593–611.
Emanet Melis, Şen Özlem, Pignatelli Francesca, Lavarello Chiara, Petretto Andrea, Ciofani Gianni. (2022).
Hazelnut extract-loaded nanostructured lipid carriers and evaluation of their antioxidant properties.
Frontiers in Bioengineering and Biotechnology, 10:1-12.
Ganesan, P. and Narayanasamy, D. (2017). Lipid nanoparticles: Different preparation techniques,
characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured
lipid carriers for oral drug delivery. Sustain. Chem. Pharm., 6:37–56.
Gupta, V., Ramakanth, D., Verma, C., Maji, P. K. and Gaikwad, K. K. (2021). Isolation and characterization
of cellulose nanocrystals from amla (Phyllanthus emblica) pomace. Biomass Convers. Biorefinery, 1:12.
Hu, R., Liu, S., Shen, W., Chen, C., Cao, Y., Su, Z., Sun, M. and Qi, R. (2021). Study on the Inhibitory Effects
of Naringenin-Loaded Nanostructured Lipid Carriers against Nonalcoholic Fatty Liver Disease. J.
Biomed. Nanotechnol., 17:942–951.
Jammanesh, A., Arbabi Bidgoli, S., Ghaffari, S. and Avadi, M. R. (2021). Formulation, Characterization and
Toxicity Assessment of Ginkgo Biloba Extract Solid Lipid Nanoparticle in female mice. Nanomed. Res.
J., 6:28–40.
Jesus, J. A., Sousa, I. M. O., da Silva, T. N. F., Ferreira, A. F., Laurenti, M. D., Antonangelo, L., Faria, C. S.,
da Costa, P. C., de Carvalho Ferreira, D. and Passero, L. F. D. (2021). Preclinical Assessment of Ursolic
Acid Loaded into Nanostructured Lipid Carriers in Experimental Visceral Leishmaniasis. Pharmaceutics,
13:908.
Kamath, P. P., Rajeevan, R., Maity, S., Nayak, Y., Narayan, R., Mehta, C. H., Velagacherla, V., Konuri, A.,
Nayak, U. Y. (2023). Development of nanostructured lipid carriers loaded caffeic acid topical cream for
prevention of inflammation in wistar rat model. J Appl Pharm Sci, 13(01):64–75.
Kelidari, H. R., Moemenbellah-Fard, M. D., Morteza-Semnani, K., Amoozegar, F., Shahriari-Namadi, M.,
Saeedi, M. and Osanloo, M. (2021). Solid-lipid nanoparticles (SLN) s containing Zataria multiflora
essential oil with no-cytotoxicity and potent repellent activity against Anopheles stephensi. J. Parasit.
Dis., 45:101–108.
Kumar, S., Dilbaghi, N., Saharan, R. and Bhanjana, G. (2015). Nanotechnology as an emerging tool for
enhancing the solubility of poorly water-soluble drugs. J Bionanosci, 2:227–250.
Lacatusu, I., Iordache, T. A., Mihaila, M., Mihaiescu, D. E., Pop, A. L. and Badea, N. (2021). Multifaced Role
of Dual Herbal Principles Loaded-Lipid Nanocarriers in Providing High Therapeutic Efficacy.
Pharmaceutics, 13:1511.
Lam, P. L., Wong, W. Y., Bian, Z., Chui, C. H. and Gambari, R. (2017). Recent advances in green
nanoparticulate systems for drug delivery: Efficient delivery and safety concern. Nanomedicine, 12:357–
385.
Lim Chiew, T., Rosnani, H., Rahimah, S. (2023). Formulation and characterization of herbal cleansing gel
from turmeric extract loaded-nanostructured lipid carriers. Bioprocessing and Biomass Technology,
2(1):25-30.
Lin, C. H., Chen, C. H., Lin, Z. C. and Fang, J. Y. (2017). Recent advances in oral delivery of drugs and
bioactive natural products using solid lipid nanoparticles as the carriers. J. Food Drug Anal., 25:219–234.
 Lipid Nanocarriers in Cosmetics 95

Moazeni, M., Davari, A., Shabanzadeh, S., Akhtari, J., Saeedi, M., Mortyeza-Semnani, K., Abastabar, M.,
Nabili, M., Moghadam, F.H. and Roohi, B. (2021). In vitro antifungal activity of Thymus vulgaris essential
oil nanoemulsion. J. Herb. Med., 28:100452.
Motawea, A., Ahmed, D. A. M., El-Mansy, A. A. and Saleh, N. M. (2021). Crucial Role of PLGA
Nanoparticles in Mitigating the Amiodarone Induced Pulmonary Toxicity. Int. J. Nanomed., 16: 4713.
Paroha, S., Chandel, A. K. S. and Dubey, R. D. (2018). Nanosystems for drug delivery of coenzyme Q10.
Environ. Chem. Lett., 16:71–77.
Patra, J. K., Das, G.; Fraceto, L. F., Campos, E. V. R., Del Pilar Rodriguez-Torres, M., Acosta-Torres, L. S.,
Diaz-Torres, L. A., Grillo, R., Swamy, M. K. and Sharma, S. (2018). Nano based drug delivery systems:
Recent developments and future prospects. J. Nanobiotechnol., 16:71.
Pengon, S., Chinatangkul, N., Limmatvapirat, C. and Limmatvapirat, S. (2020). Development of Antimicrobial
Nanoemulsions Containing Nelumbo nucifera Extract. Key Eng. Mater, 859:226–231.
Rahman, H. S., and Othman, H. H. (2020). Novel drug delivery systems for loading of natural plant extracts
and their biomedical applications. Int J nanomed, 15: 2439–2483.
Rajendra Kumar Jangde, Tanveer Khan, Harish Bhardwaj (2023). Development and Characterization of
Nanostructured Lipid Carrier for Topical delivery of Naringenin. Research Journal of Pharmacy and
Technology, 16(5):2572-6.
Rodrigues, L. R., and Jose, J. (2020). Exploring the photo protective potential of solid lipid nanoparticle-based
sunscreen cream containing Aloe vera. Environ. Sci. Pollut. Res., 27:20876–20888.
Shah, S. M. A., Nisar, Z., Nisar, J., Akram, M., Ghotekar, S. and Oza, R. (2021). Nanobiomedicine: A New
Approach of Medicinal Plants and Their Therapeutic Modalities. J. Mater. Environ., 12:1–14.
Sharaf, M., Arif, M., Khan, S., Abdalla, M., Shabana, S., Chi, Z. and Liu, C. (2021). Co-delivery of hesperidin
and clarithromycin in a nanostructured lipid carrier for the eradication of Helicobacter pylori in vitro.
Bioorg. Chem., 112:104896.
Sharma, G., Raturi, K., Dang, S., Gupta, S. and Gabrani, R. (2014). Combinatorial antimicrobial effect of
curcumin with selected phytochemicals on Staphylococcus epidermidis. J. Asian Nat. Prod. Res., 16:535–
541.
Sharma, R., Hazra, J. and Prajapati, P. (2017). Nanophytomedicines: A Novel Approach to Improve Drug
Delivery and Pharmacokinetics of Herbal Medicine. Biol. Bullettin, 3:132–135.
Shende, P. and Narvenker, R. (2020). Herbal nanotherapy: A new paradigm over conventional obesity
treatment. J. Drug Deliv. Sci. Technol., 61:102291.
Singh, A., Vengurlekar, P. and Rathod, S. (2014). Design, development and characterization of liposomal neem
gel. Int. J. Pharm. Sci. Res., 5:140–148.
Ud Din, F., Aman, W., Ullah, I., Qureshi, O. S., Mustapha, O., Shafique, S. and Zeb, A. (2017). Effective use
of nanocarriers as drug delivery systems for the treatment of selected tumors. Int. J. Nanomed., 12:7291.
Verma, H. and Singh, H. (2013). Herbal drug delivery system: A modern era prospective. IJCPR, 4(3):88–101.
Wang, F., Ye, X., Zhai, D., Dai, W., Wu, Y., Chen, J. and Chen, W. (2020). Curcumin-loaded nanostructured
lipid carrier induced apoptosis in human HepG2 cells through activation of DR5/caspases-mediated
extrinsic apoptosis pathway. Acta Pharm., 70:227–237.
Wang, N. and Feng, Y. (2015). Elaborating the role of natural products-induced autophagy in cancer treatment:
Achievements and artifacts in the state of the art. BioMed Res. Int., 2015:934207.
Watkins, R., Zhang, C., Davis, R. M. and Xu, B. (2015). Natural product-based nanomedicine: recent advances
and issues. Int J Nanomed, 10:6055.
Yadav, M., Bhatia, V. J., Doshi, G. and Shastri, K. (2014). Novel techniques in herbal drug delivery systems.
Int J Pharm Sci Rev Res, 28(2):83–89.
Ying choncharoen, P., Kalinowski, D. S. and Richardson, D. R. (2016). Lipid-based drug delivery systems in
cancer therapy: What is available and what is yet to come. Pharmacol. Rev., 68:701–787.
Chapter 7

Lipid-Based Nano Carriers for Drug Delivery

Manasvi Saini1
Gaurav Chaudhary1,
Chaitanay Vinayak Narayan1
Swati Verma1
Lovy Sharma2
and Shalini K. Shawney1
1I.T.S. College of Pharmacy, Murad Nagar, Ghaziabad, Uttar Pradesh, India
2Parmarth College of Pharmacy, Hapur, Uttar Pradesh, India

Abstract

Nano-formulation addresses various challenges related to drug absorption,

pharmacokinetics, and side effects by encapsulating medications using biodegradable
carriers and bioadhesive materials, making them well-suited for oral administration. Lipid-
based nano-carriers hold particular significance in the rapidly advancing field of
nanotechnology, given their numerous advantages over alternative carriers. In the
pharmaceutical sector, lipid-based carriers emerge as a promising nanoscale delivery
approach. In the context of oral drug administration, challenges arise from biological
obstacles such as mucus, high pH, and digestive enzymes. Interestingly, the same harsh
conditions that pose challenges for lipid-based nanocarriers can also present opportunities
if the carriers are designed to anticipate the biological behavior of the systems under study.
Hence, the selection of materials for crafting nanocarriers becomes a critical aspect in line
with the proposed strategy. Lipid nanocarriers, being non-toxic, biocompatible,
biodegradable, and irritant-free, find frequent application in topical drug administration.
Their minuscule size enhances penetration, and the lipid’s affinity to bond and integrate
with the skin adds to their effectiveness. Notably, lipid-based nanocarriers offer advantages
such as improved drug solubility, increased drug loading capacity, reduced toxicity, and
enhanced bioavailability, setting them apart from other nanocarrier types.

Keywords: nanoparticles, liposomes, nano-formulation, nanovesicles, and micro/

nanoemulsions


Corresponding Author’s Email: gauravchaudharyits30@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
98 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

Abbreviations

SLN Solid Lipid Nanoparticles

NLC Nanostructured Lipid Carriers
HFF Hydrodynamic flow focusing
BBB Blood-Brain Barrier
RNA Ribo Nucleic Acid

Introduction

Several drug delivery strategies are currently under development, aiming to protect active
components, enhance their effectiveness, and control drug distribution at specific sites. The
utilization of nanoparticles in medicine administration has captured significant interest over the
years (Mitchell MJ et al., 2021). Lipid-based nanoparticles (Figure 1), including liposomes,
solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), offer a versatile
approach, capable of delivering therapeutics that are both hydrophobic and hydrophilic, with
high therapeutic efficacy (Yingchoncharoen et al., 2016). An example is Doxil, a PEGylated
liposome loaded with doxorubicin (DOX), designed for managing solid malignancies such as
ovarian and breast cancer. Notably, it is the first nanomedicine approved by the FDA (Gabizon
et al., 1994). Designing a successful drug delivery system involves achieving goals such as
preventing adverse side effects, maintaining optimal drug doses at the target site, and limiting
early drug breakdown. Conventional drug delivery systems have numerous drawbacks,
including toxicity, rapid metabolism, poor bioavailability, unpredictable drug levels, low
patient compliance, and undesirable side effects. To overcome these limitations, target-specific
nanocarrier mechanisms like polymeric nanoparticles, SLNs, niosomes, liposomes, ethosomes,
bilosomes, transferosomes, colloidosomes, pharmacosomes, herbosomes, layerosomes,
sphingosomes, and ufosomes can be employed (Table 1) (Awasthi et al., 2014).

Figure 1. Different classes of lipid-based nanocarriers.

 Table 1. Recent lipophilic drug delivery based on various types of lipid nanoparticles

Types of LNPs Drug Lipid and surfactant Therapeutic effects Reference

Nano emulsion Dexamethasone Propylene glycol, Tween 80, Isopropyl myristate Therapy for both acute and long-term eye conditions, (Kesavan et al., 2013)
(liquid-core including uveitis
LNPs) Indinavir Oleic acid, EPC-80 (egg yolk lecithin), α-tocopherol HIV infection (Prabhakar et al., 2013)
Risperidone Tween 80, propylene glycol, transcutol, Anti-psychotic medications (Kumar et al., 2008)
Capmul MCM,
Curcumin Span 20, Span 85, Tween 80, Tween 20, Tefose 1500 Specific treatments for cutaneous carcinoma (Abdel et al., 2020)
mixed PEG-6 stearate and PEG-32 stearate),
SLN Atorvastatin Phospholipon 90 H, poloxamer 188, Stearic or palmitic Management of age-related macular degeneration (Yadav et al., 2020)
acid, cationic lipid, Compritol® 888 ATO, PEG 400
Melatonin Softisan 100, Tween 80, Didecyldimethylammonium Manage and enhance the visual hypotensive impact of (Leonardi et al., 2015)
bromide glaucoma
Indomethacin Compritol ATO 888, Tween 80, poloxamer 188, Treatment of posterior segment of ocular infection (Balguri et al., 2016)
glycerin Compritol 888 ATO, Precirol 5
Diclofenac ATO, hydrogenated soy PC, poloxamer 188 Reduce the toxicity of analgesics and medications that (Abrishami et al., 2016)
are anti-inflammatory
Naproxen Glyceryl monostearate, Span 80, Tween 80 In order to treat RA and associated disorders of pain, (Akbari et al., 2016)
decrease the negative effects of medications’ systemic
absorption and boost the concentration of drugs at the
site of effect.
Spironolactone Tween 80, Span 80, Span 60, Stearic acid Treatment of skin disorders (Kelidari et al., 2015)
NLC Dexamethasone Cholesterol, Tween 80, Labrafac™ lipophile WL1349, Treatment of dry eye disease (DED) or (Kumari et al., 2021)
keratoconjunctivitis sicca
Itraconazole Tween 80, transcutol HP Chitosan, Tripalmitin, Anti-neovascularization effect and treatment (Selvaraj et al., 2019)
of diabetic retinopathy (DR)
Propranolol Oleic acid, Compritol ATO 888, Tween 80, Span 20, Treatment of posterior segment of the eye disease (Sharif et al., 2018)
hydrochloride Transcutol P
Insulin Poloxamer 188, Miglyol, Tween 80, Precirol ATO5, Penetrat BBB to treat the CNS disorders (Gartziandia et al., 2015)
Atorvastatin Compritol® 888 ATO, Pluronic® F68, Tween® 80, Decrease of cholesterol and triglyceride (fats) levels (Elmowafy et al., 2017)
Gelucire® 43/01, Capryol® PGMC in the blood
Naringenin Stearic acid, poloxamer 188, monostearin, oleic acid, Inhibition of nonalcoholic fatty liver disease (Hu et al., 2021)
soybean lecithin
 Table 1. (Continued)

Types of LNPs Drug Lipid and surfactant Therapeutic effects Reference

Cubosome Voriconazole Pluronic F127, Monoolein Treatment of fungal keratitis (Said et al., 2021)
Curcumin PEG1000, Monoolein, fish oil Treatment of neurodegenerative disease (Rakotoarisoa et al., 2019)
Piperine Cremophor, Tween 80, Glyceryl monooleate, Treatment of Alzheimer’s disease (Elnaggar et al., 2015)
poloxamer 407,
Paclitaxel Pluronic F127, DSPE-PEG-ma, Monoolein Treatment of skin cancer (Zhai et al., 2020)
 Lipid-Based Nano Carriers for Drug Delivery 101

Studies have explored the potential application of liposomes as drug delivery systems
(Allen et al., 2004). Liposomes belong to an extensively studied family of drug transporters
characterized by the presence of an intracellular aqueous compartment surrounded by a lipid
bilayer composed primarily of amphipathic phospholipids. Many liposome formulations are
currently undergoing clinical trials for the treatment of cancer and infectious diseases, though
some trial results are pending release. Interestingly, Doxil®/caylex liposome-based formulation
of the anticancer medication doxorubicin by Ortho-Biotech was the first to receive approval for
medical use, making it arguably the inaugural nanoparticle used in patient therapy (Batist et al.,
2001).

Different Classes of Lipid-Based Nanocarriers

Liposomes

Liposomes, discovered in 1965 by Bangham et al., are spherical structures composed of an

interior aqueous base and an amphipathic bilayer of phospholipids. The unique core-shell
nanostructure of liposomes enables the transportation of both hydrophilic and hydrophobic
compounds. Typically, hydrophilic drugs are enclosed within the lipophilic double layers of
the shell, while hydrophobic medications are trapped inside the aqueous layer forming the core
(Kang et al., 2021). In the case of liposomal doxorubicin such as Doxil, all encapsulated DOX
drugs are present in the aqueous phase of the core. The transmembrane ammonium ion gradient
facilitates loading these drugs, whether agglomerated or in crystalline (DOX)2SO4 salt, into
the aqueous core. Various methods, including electro-formation, thin-film hydration, and
microfluidic-based techniques, can be employed to create liposomes (Gbian et al., 2022).

SLNs

A highly structured crystalline composition featuring emulsifiers and drug inclusion signifies
Solid Lipid Nanoparticles (SLNs) with fully crystallized lipid components. In the mid-1990s,
SLNs began employing lipids such as cholesterol, saturated fats, and paraffin with melting
temperatures exceeding both room temperature and the human body. SLNs offer improved drug
protection, enhanced nanoparticle stability, and modifiable features by varying the lipid
content, presenting a range of advantages (Siekmann et al., 1995). However, SLNs face two
primary challenges: limited drug incorporation efficiency and low long-term drug persistence.
The lipid substrate undergoes polymorphic changes from a high-powered mode to a low-
powered mode during storage, leading to gradual drug release and the emergence of a more
structured crystalline grid. This polymorphism significantly constrains drug incorporation
efficiency, especially with very pure lipids. To address this, liquid lipids or solubilizers are
often added to enhance stability. Consequently, Nanostructured Lipid Carriers (NLCs)
emerged, partially replacing solid lipids with liquid lipids. NLCs have proven successful in
providing improved drug incorporation efficiency and preservation stability by reducing
crystallite formation (Meenu et al., 2023).
102 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

NLCs

The evolution of SLN technology into the next generation, known as NLCs, involved
substituting liquid lipids for a portion of the solid lipid components in SLNs, thereby expanding
the drug incorporation capacity. NLCs represent a promising drug delivery technique that offers
enhanced drug loading and retention capabilities. The structure of NLCs is categorized into
three types: amorphous, many, and defective crystal types, each defining distinct structural
characteristics of Lipid Nanoparticles (LNPs) (Hallan et al., 2021).

Hybrid LNPs

Hybrid Lipid-Polymeric Nanoparticles (LNPs), as systems composed of multiple material

types, amalgamate the advantageous properties of each element, aiming for versatility and
surpassing the constraints of single-component nanoparticles. Recently, it has been
demonstrated that hybrid LNPs, representing a novel drug delivery technique, hold intriguing
applications. Their fundamental composition comprises therapeutic material encircled by an
outer PEGylated lipid layer surrounding a therapeutic-containing polymerized core (Soares et
al., 2020).

Synthesis of LNPs

Numerous techniques have been explored for the preparation of LNPs. The methods applicable
to both SLNs and NLCs include:

Solvent-Based Emulsification Method

The process of producing LNPs has become simpler due to liquid-based mixing techniques,
including solvent injection, motion, propagation, and emulsion-solvent separation. In this
process, solid fatty acids and hydrophobic drugs are dissolved in a solution, which is then
dispersed in a diluted solution to create oil-in-water (o/w) formulations. LNPs are formed as
the organic component evaporates. This method is particularly useful for encapsulating
temperature-dependent drugs. However, complete removal of organic liquids might pose a
challenge, especially when the lipids used are not readily soluble with solvents (Trotta et al.,
2003; Mehnert et al., 2001).

Nonsolvent Emulsification Method

Nonsolvent emulsifying methods, also known as melting emulsifying methods, generate
emulsions consisting of oil in water without the use of fat-breaking solvents. In these processes,
melted lipids serve as the liquid phase, with solid fats typically melting 5–10 °C above their
melting temperatures to become fluid. The melted fats are then mixed with a surfactant solution
in water, employing film emulsification, rapid stirring, microemulsion, or ultrasonic
stimulation, followed by homogenization under high pressure (HPH), resulting in the creation
of nano-emulsions. Subsequently, dispersed SLNs are formed when the nanoemulsions are
cooled in an ice bath (Gardouh et al., 2020).
 Lipid-Based Nano Carriers for Drug Delivery 103

Various factors have been identified to influence the properties of nanoparticles (NPs),
including the duration of homogenization, the length of ultrasonic treatment, the quantity of
surfactants, the lipid level, the drug amount, and the type of lipids (Das et al., 2012).

Bulk Nanoprecipitation
In 1989, Fessi et al. introduced and patented nanoprecipitation, also known as solvent
displacement. In a nutshell, an aqueous solution is mixed with a polar solvent referred to as the
“organic phase,” containing lipids and hydrophobic drugs. The rapid dissolution of lipids and
drugs leads to the precipitation of Lipid Nanoparticles (LNPs), causing instantaneous
encapsulation of pharmaceuticals. Typically, bulk solution is combined with an organic phase
and a water phase while being magnetically agitated to produce LNPs (Iqbal et al., 2020).
Furthermore, nanoprecipitation has been employed to create LNPs for gene therapy,
particularly for treating retinal diseases. For instance, ethanol-injected siRNA-encapsulated
LNPs were developed. Achieving a homogeneous and saturated lipid solution is crucial for
spontaneous nucleation to minimize the size of the nanoparticle distribution. The primary factor
influencing nanoprecipitation control is the mixing time. Extended mixing beyond the average
precipitation time results in smaller nanoparticle sizes (Dong et al., 2012).
However, a notable drawback of bulk nanoprecipitation is its inability to regulate fluid
velocity, leading to a broader range of nanoparticle sizes, especially in scenarios involving high
mixing volumes and large-scale manufacturing (Sarah Streck et al., 2019).

Microfluidic Approaches
When compared to bulk nanoprecipitation, microfluidic techniques present several appealing
benefits, including minuscule particle sizes, uniform size distribution, scalability, enhanced
encapsulation efficiency (EE), and improved reproducibility (Shepherd SJ et al., 2021).
Generally, microfluidic devices for producing Lipid Nanoparticles (LNPs) are categorized into
two groups (Maeki et al., 2018).

Coacervation Method
The exacerbation technique, a unique solvent-free mechanism enabling the synthesis of LNPs,
was first introduced by Battaglia et al., in 2010. This technique was developed to address the
limitations of previous approaches, including the use of expensive equipment and hazardous
organic solvents. The method involves a micellar solution containing precipitates of lipid basic
salts, and a decrease in pH occurs due to an exchange of H+ between an acidic solution and
alkaline salts (Battaglia et al., 2010). LNPs of lipids are generated by gradually adding a
coacervating solution, reducing pH levels to a specific point.

SCF Technology
Solid Phase Filtration (SCF) is a potentially beneficial approach, offering constant size
distribution, superior control over nanoparticle dimensions, complete solvent elimination, and
environmental friendliness, according to Chakravarty et al., (2019). In SCF technology, a
saturated form with customizable solvent concentration is employed, and temperature and
pressure are adjusted for optimal performance, as noted by Bigazzi et al., (2020). Supercritical
CO2 (scCO2) is commonly used in SCF due to its cost-effectiveness and high safety profile. In
the process of creating LNPs with SCF, the atmospheric pressure of scCO2 is typically adjusted.
104 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

To summarize, scCO2 acts as a solvent that increases the soluble concentrations of solid lipids
and drugs when introduced into a high-pressure chamber. Subsequently, solid lipids and
pharmaceuticals become oversaturated and precipitate out during the depressurization process,
forming drug-loaded LNPs (Saad et al., 2020).

LNPs with Different Drugs Encapsulated

Water-Insoluble Drugs
Hydrophobic pharmaceuticals constitute around 40% of approved medications and make up
90% of drugs in the developmental stage. Lipophilic nanoparticles (LNPs) have emerged as a
preferred choice for delivering hydrophobic drugs, with Docetaxel (DTX) being an example.
DTX, an effective antineoplastic and antiangiogenic drug, faces limitations in clinical relevance
due to its significant cytotoxicity and poor water solubility (Ovais et al., 2018).

Water-Soluble Drugs
Hydrophilic medications, due to their heightened water solubility, pose challenges in terms of
encapsulation and precise control of release. Lipid nanoparticles (LNPs) are explored as a
potential strategy for capturing and delivering hydrophilic drugs. Microemulsions and double
emulsions are being widely used for the encapsulation of hydrophilic drugs. The antibiotic
paromomycin, highly water-soluble (79.9 mg ml-1) and used to treat parasite illnesses, is an
example encapsulated via a microemulsion method (Ovais et al., 2018).

RNA
The development of therapeutic RNA medicines is gaining interest, especially with the
authorization of the first two RNA drugs, Patisiran (2018) and Givosiran (2019). Patisiran, an
LNP dosage form of siRNA, is intended for the management of hereditary transthyretin-
mediated amyloidosis. However, RNA therapies face administrative challenges due to the
inherent instability of RNA molecules, susceptibility to degradation by nucleases, and rapid
elimination by the body’s immune defenses (Kristen AV et al., 2019; Ura et al., 2014).

LNPs for Addressing Challenges in Drug Delivery

Attention is directed towards utilizing LNPs to address drug delivery challenges, including
targeted distribution, consumption, and blood-brain barrier (BBB) permeability.

BBB
The blood-brain barrier (BBB), a selectively permeable endothelial cell barrier, limits the entry
of undesirable substances into the brain. Additionally, specific multiple transporters across the
outer layer of the BBB, namely P-glycoprotein, actively transport various compounds,
including nutrients and medications, back into the bloodstream. This aspect of the BBB
contributes to the challenging absorption of conventional brain medications, limiting their
bioavailability. Several medication administration strategies are currently being developed to
get over this obstacle and get through the BBB. LNPs are studied for the administration of brain
medications due to their safety, stability, and potential therapeutic efficacy (Löscher et al.,
2005).
 Lipid-Based Nano Carriers for Drug Delivery 105

Targeted Delivery
Targeted delivery is a method of administering drugs to particular areas while avoiding negative
effects on healthy ones. Targeted administration overcomes the limitations of traditional drug
delivery techniques, such as nonspecific behavior, uncontrollable release, ligand modifications,
structural changes, pH adaptability, and numerous other problems, by employing ligand-
inhibiting polymers (LNPs). The alterations of nanoparticles incorporating selective ligands
which are selectively bound to elevated proteins on cancerous cells is a widely used strategy
for developing targeted delivery systems. This offers a promising avenue for achieving targeted
drug delivery while minimizing the impact on healthy tissues (Liu et al., 2018).

Applications
Various applications of SLNs are explored below (Figure 2).

SLNs s aGene Vector Carriers

Solid Lipid Nanoparticles (SLNs) can indeed be employed in the production process of gene
vectors. Studies have demonstrated that enhancing gene transfer efficiency involves
incorporating a diametric HIV-1 HAT peptide (TAT 2) into the SLN genetic vector. Current
research indicates that SLNs can effectively carry certain nucleic acids (Hayes et al., 2006).
The process of creating lipid-nucleic acid nanoparticles involves dissolving DNA and lipids
successively within an emulsifying nanophase containing both water and a water-soluble
natural solvent. Upon removing the natural solvent, a genosphere, or a broad circulation of
lipid-nucleic acid nanoparticles (70-100 nm), is formed. To achieve precise targeting of these
particles, a conjugated antibody-lipopolymer can be introduced into the structure (Pedersen et
al., 2006).

Figure 2. Applications of SLNs.

106 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

SLNs for Topical Use

SLNs and NLCs are widely employed for the topical administration of various drugs. For
example, Podophyllotoxin-loaded SLN has demonstrated effective epidermal targeting by
permeating the stratum corneum and the skin’s surface. Additionally, glyceryl behenate can be
utilized to produce nanoparticles enriched with vitamin A. These methodologies have proven
effective in enhancing drug permeability and facilitating prolonged drug delivery over time
(Jenning et al., 2000).

SLNs as Cosmeceuticals
According to research by Wissing et al., (2001), SLNs play a role as dynamic agents in the
synthesis of sun protection products by carrying structural sun protection and UV inhibitors. In
an in vivo study conducted over four weeks, it was observed that adding 4% SLNs to a regular
cream increased skin hydration by 31%. Both SLNs and NLCs have demonstrated the ability
to create novel occlusive topicals with controlled release characteristics. The use of glyceryl
behenate SLNs, in comparison to conventional formulations, has shown improved localization
of vitamin A in the upper layers of the skin (Jenning et al., 2000).

SLNs for Potential Agriculture Application

The natural oil from Artemisia arboreseens L. has shown greater effectiveness in slowing down
its rate of evaporation when combined with SLNs compared to emulsions. This property makes
these processes suitable for application in agriculture as a carrier for environmentally friendly
pesticides. In this particular case, the formulation of SLN involved the use of poloxamer 188
and Miranol Ultra C32 as a surfactant and lipid, respectively (Casagrande et al., 2006).

Oral SLNs in Antitubercular Chemotherapy

Anti-TB medications, including pyrazinamide-loaded SLNs, isoniazid, and rifampicin, have

shown effectiveness in reducing the frequency of drug delivery and improving patient
adherence. The preparation of these solid lipid nanoparticles containing antitubercular drugs is
achieved through the emulsion solvent diffusion technique. Moreover, it has been observed that
nebulizing the mentioned medication within SLNs enhances the bioavailability of the drug in
animals (Wang et al., 2006).

Future Perspective

SLNs and NLCs are extensively utilized as carriers for drug delivery, particularly for
transporting various peptide medications and cytotoxic agents used in anticancer treatment.
Ongoing investigations, both in vitro and in vivo, aim to evaluate the potential of these lipid
nanoparticles for pharmaceutical vectorization in commercial applications. The appeal of SLN
delivery methods can be enhanced through surface modifications, such as improved
bioavailability achieved by PEG coating. Despite their advantages, certain drawbacks,
including polymorphism and crystalline rearrangements within SLN and specific NLC
formulations, must be addressed to ensure steady and controlled drug administration. Further
 Lipid-Based Nano Carriers for Drug Delivery 107

research is necessary to comprehend the principles underlying the dispersion of active

chemicals from these solid nanoparticles. Although research on NLCs is still in its early phases,
they appear to have great potential as transporters for drug delivery via intravenous
administration. Continued research might enhance the controlled release of medicines through
these carriers and improve the manufacturing process to provide more homogeneous samples
devoid of toxic chemicals. Furthermore, their potential uses in the delivery of medications to
treat cancer have not been thoroughly investigated yet.

Conclusion

In summary, recent studies on lipophilic drugs suggest that surface modifications and Lipid
LNPs can significantly enhance the bioavailability of these medications. However, the
implementation of LNPs still faces barriers, including the potential for adverse effects such as
adverse reactions to LNPs and challenges in scaling up most surface modifications.
Collaborating with surface modifications may be crucial to demonstrating that LNPs are the
best drug delivery system (DDS) for lipophilic medications. Resolution of these issues will
likely come through extensive clinical investigations and improvements in the surface
alteration process.

Reference

Abdel Fadeel, D. A., Kamel, R., Fadel, M. (2020). PEGylated lipid nanocarrier for enhancing photodynamic
therapy of skin carcinoma using curcumin: in-vitro/in-vivo studies and histopathological examination.
Scientific Reports, 10(1), 10435.
Abrishami, M., Abrishami, M., Mahmoudi, A., Mosallaei, N., Vakili Ahrari Roodi, M., Malaekeh-Nikouei, B.
(2016). Solid Lipid Nanoparticles Improve the Diclofenac Availability in Vitreous after Intraocular
Injection. Journal of Drug Delivery, 2016, 1368481.
Akbari, J., Saeedi, M., Morteza-Semnani, K., Rostamkalaei, S. S., Asadi, M., Asare-Addo, K., Nokhodchi, A.
(2016). The design of naproxen solid lipid nanoparticles to target skin layers. Colloids and surfaces. B,
Biointerfaces, 145, 626–633.
Allen, T. M., Cullis, P. R. (2004). Drug delivery systems: entering the mainstream. Science (New York, N.Y.),
303(5665), 1818–1822.
Awasthi, R., Kumar, S., T Kulkarni, G. (2014). Frontier lipid-based carrier systems for drug targeting: A
laconic review on niosomes. Pharmaceutical Nanotechnology, 2(3), 116-128.
Balguri, S. P., Adelli, G. R., Majumdar, S. (2016). Topical ophthalmic lipid nanoparticle formulations (SLN,
NLC) of indomethacin for delivery to the posterior segment ocular tissues. European Journal of
Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft fur Pharmazeutische
Verfahrenstechnik e.V, 109, 224–235.
Bangham, A. D., Standish, M. M., Watkins, J. C. (1965). Diffusion of univalent ions across the lamellae of
swollen phospholipids. Journal of Molecular Biology, 13(1), 238–252.
Batist, G., Ramakrishnan, G., Rao, C. S., Chandrasekharan, A., Gutheil, J., Guthrie, T., Shah, P., Khojasteh,
A., Nair, M. K., Hoelzer, K., Tkaczuk, K., Park, Y. C., Lee, L. W. (2001). Reduced cardiotoxicity and
preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared
with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic
breast cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical
Oncology, 19(5), 1444–1454.
108 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

Battaglia, L., Gallarate, M., Cavalli, R., Trotta, M. (2010). Solid lipid nanoparticles produced through a
coacervation method. Journal of Microencapsulation, 27(1), 78–85.
Casagrande, R., Georgetti, S. R., Verri, W. A., Jr, Jabor, J. R., Santos, A. C., Fonseca, M. J. (2006). Evaluation
of functional stability of quercetin as a raw material and in different topical formulations by its
antilipoperoxidative activity. AAPS PharmSciTech, 7(1), E10.
Chakravarty, P., Famili, A., Nagapudi, K., Al-Sayah, M. A. (2019). Using supercritical fluid technology as a
green alternative during the preparation of drug delivery systems. Pharmaceutics, 11(12), 629.
Chauhan, I., Yasir, M., Verma, M., Singh, A. P. (2020). Nanostructured Lipid Carriers: A Groundbreaking
Approach for Transdermal Drug Delivery. Advanced Pharmaceutical Bulletin, 10(2), 150–165.
Das, S., Ng, W. K., Kanaujia, P., Kim, S., Tan, R. B. (2011). Formulation design, preparation and
physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of
process variables. Colloids and Surfaces. B, Biointerfaces, 88(1), 483–489.
Dong, Y., Ng, W. K., Shen, S., Kim, S., Tan, R. B. (2012). Solid lipid nanoparticles: continuous and potential
large-scale nanoprecipitation production in static mixers. Colloids and surfaces. B, Biointerfaces, 94, 68–
72.
Elmowafy, M., Ibrahim, H. M., Ahmed, M. A., Shalaby, K., Salama, A., Hefesha, H. (2017). Atorvastatin-
loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks. Drug
Delivery, 24(1), 932–941.
Elnaggar, Y. S., Etman, S. M., Abdelmonsif, D. A., Abdallah, O. Y. (2015). Novel piperine-loaded Tween-
integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease:
pharmaceutical, biological, and toxicological studies. International Journal of Nanomedicine, 10, 5459–
5473.
Gardouh, A., Gamal, A., Gad, S. (2020). Formulation and pharmacokinetic evaluation of rifampicin solid lipid
nanoparticles. Journal of Research in Pharmacy, 24(4), 539-551.
Gartziandia, O., Herran, E., Pedraz, J. L., Carro, E., Igartua, M., Hernandez, R. M. (2015). Chitosan coated
nanostructured lipid carriers for brain delivery of proteins by intranasal administration. Colloids and
Surfaces B: Biointerfaces, 134, 304–313.
Gbian, D. L., Omri, A. (2022). Lipid-Based Drug Delivery Systems for Diseases Managements. Biomedicines,
10(9), 2137.
Ghadiri, M., Fatemi, S., Vatanara, A., Doroud, D., Najafabadi, A. R., Darabi, M., Rahimi, A. A. (2012).
Loading hydrophilic drug in solid lipid media as nanoparticles: statistical modeling of entrapment
efficiency and particle size. International Journal of Pharmaceutics, 424(1-2), 128–137.
Hallan, S. S., Sguizzato, M., Esposito, E., Cortesi, R. (2021). Challenges in the Physical Characterization of
Lipid Nanoparticles. Pharmaceutics, 13(4), 549.
Hao, J., Wang, F., Wang, X., Zhang, D., Bi, Y., Gao, Y., Zhao, X., Zhang, Q. (2012). Development and
optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central
composite design. European Journal of Pharmaceutical Sciences, 47(2), 497–505.
Hayes, M. E., Drummond, D. C., Kirpotin, D. B., Zheng, W. W., Noble, C. O., Park, J. W., Marks, J. D., Benz,
C. C., Hong, K. (2006). Genospheres: self-assembling nucleic acid-lipid nanoparticles suitable for targeted
gene delivery. Gene Therapy, 13(7), 646–651.
Hu, R., Liu, S., Anwaier, G., Wang, Q., Shen, W., Shen, Q., Qi, R. (2021). Formulation and intestinal
absorption of naringenin loaded nanostructured lipid carrier and its inhibitory effects on nonalcoholic fatty
liver disease. Nanomedicine: Nanotechnology, Biology, and Medicine, 32, 102310.
Iqbal, A., Zaman, M., Wahab Amjad, M., Adnan, S., Abdul Ghafoor Raja, M., Haider Rizvi, S. F., Mustafa,
M. W., Farooq, U., Abbas, G., Shah, S. (2020). Solid Lipid Nanoparticles of Mycophenolate Mofetil: An
Attempt to Control the Release of an Immunosuppressant. International Journal of Nanomedicine, 15,
5603–5612.
Jenning, V., Schäfer-Korting, M., Gohla, S. (2000). Vitamin A-loaded solid lipid nanoparticles for topical use:
drug release properties. Journal of Controlled Release: Official Journal of the Controlled Release Society,
66(2-3), 115–126.
Kang, S., Park, S. E., Huh, D. D. (2021). Organ-on-a-chip technology for nanoparticle research. Nano
Convergence, 8(1), 20.
 Lipid-Based Nano Carriers for Drug Delivery 109

Kelidari, H. R., Saeedi, M., Akbari, J., Morteza-Semnani, K., Gill, P., Valizadeh, H., Nokhodchi, A. (2015).
Formulation optimization and in vitro skin penetration of spironolactone loaded solid lipid nanoparticles.
Colloids and Surfaces. B, Biointerfaces, 128, 473–479.
Kesavan, K., Kant, S., Singh, P. N., Pandit, J. K. (2013). Mucoadhesive chitosan-coated cationic
microemulsion of dexamethasone for ocular delivery: in vitro and in vivo evaluation. Current Eye
Research, 38(3), 342-352.
Kristen, A. V., Ajroud-Driss, S., Conceição, I., Gorevic, P., Kyriakides, T., Obici, L. (2019). Patisiran, an RNAi
therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegenerative
Disease Management, 9(1), 5–23.
Kumar, M., Misra, A., Babbar, A. K., Mishra, A. K., Mishra, P., Pathak, K. (2008). Intranasal nanoemulsion
based brain targeting drug delivery system of risperidone. International Journal of Pharmaceutics, 358(1-
2), 285–291.
Kumari, S., Dandamudi, M., Rani, S., Behaeghel, E., Behl, G., Kent, D., O’Reilly, N. J., O’Donovan, O.,
McLoughlin, P., Fitzhenry, L. (2021). Dexamethasone-Loaded Nanostructured Lipid Carriers for the
Treatment of Dry Eye Disease. Pharmaceutics, 13(6), 905.
Leonardi, A., Crasci’, L., Panico, A., Pignatello, R. (2015). Antioxidant activity of idebenone-loaded neutral
and cationic solid-lipid nanoparticles. Pharmaceutical Development and Technology, 20(6), 716–723.
Liu, Y., Hui, Y., Ran, R., Yang, G. Z., Wibowo, D., Wang, H. F., Middelberg, A. P. J., Zhao, C. X. (2018).
Synergetic Combinations of Dual-Targeting Ligands for Enhanced In Vitro and In Vivo Tumor Targeting.
Advanced Healthcare Materials, 7(15), e1800106.
Liu, Y., Yang, G., Zou, D., Hui, Y., Nigam, K., Middelberg, A. P., Zhao, C. X. (2019). Formulation of
nanoparticles using mixing-induced nanoprecipitation for drug delivery. Industrial & Engineering
Chemistry Research, 59(9), 4134-4149.
Löscher, W., Potschka, H. (2005). Blood-brain barrier active efflux transporters: ATP-binding cassette gene
family. NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics, 2(1), 86–98.
Lúcio, M., Giannino, N., Barreira, S., Catita, J., Gonçalves, H., Ribeiro, A., Fernandes, E., Carvalho, I., Pinho,
H., Cerqueira, F., Biondi, M., Lopes, C. M. (2023). Nanostructured Lipid Carriers Enriched Hydrogels for
Skin Topical Administration of Quercetin and Omega-3 Fatty Acid. Pharmaceutics, 15(8), 2078.
Maeki, M., Kimura, N., Sato, Y., Harashima, H., Tokeshi, M. (2018). Advances in microfluidics for lipid
nanoparticles and extracellular vesicles and applications in drug delivery systems. Advanced Drug
Delivery Reviews, 128, 84–100.
Mehnert, W., Mäder, K. (2001). Solid lipid nanoparticles: production, characterization and applications.
Advanced Drug Delivery Reviews, 47(2-3), 165–196.
Mehta, M., Bui, T. A., Yang, X., Aksoy, Y., Goldys, E. M., Deng, W. (2023). Lipid-Based Nanoparticles for
Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their
Industrial Development. ACS Materials Au, 3(6), 600-619.
Mitchell, M. J., Billingsley, M. M., Haley, R. M., Wechsler, M. E., Peppas, N. A., Langer, R. (2021).
Engineering precision nanoparticles for drug delivery. Nature reviews. Drug discovery, 20(2), 101–124.
Ovais, M., Zia, N., Ahmad, I., Khalil, A. T., Raza, A., Ayaz, M., Sadiq, A., Ullah, F., Shinwari, Z. K. (2018).
Phyto-Therapeutic and Nanomedicinal Approaches to Cure Alzheimer’s Disease: Present Status and
Future Opportunities. Frontiers in Aging Neuroscience, 10, 284.
Pedersen, N., Hansen, S., Heydenreich, A. V., Kristensen, H. G., Poulsen, H. S. (2006). Solid lipid
nanoparticles can effectively bind DNA, streptavidin and biotinylated ligands. European Journal of
Pharmaceutics and Biopharmaceutics, 62(2), 155–162.
Prabhakar, K., Afzal, S. M., Surender, G., Kishan, V. (2013). Tween 80 containing lipid nanoemulsions for
delivery of indinavir to brain. Acta Pharmaceutica Sinica B, 3(5), 345-353.
Rakotoarisoa, M., Angelov, B., Garamus, V. M., Angelova, A. (2019). Curcumin-and fish oil-loaded
spongosome and cubosome nanoparticles with neuroprotective potential against H2O2-induced oxidative
stress in differentiated human SH-SY5Y cells. ACS Omega, 4(2), 3061-3073.
Saad, S., Ahmad, I., Kawish, S. M., Khan, U. A., Ahmad, F. J., Ali, A., Jain, G. K. (2020). Improved
cardioprotective effects of hesperidin solid lipid nanoparticles prepared by supercritical antisolvent
technology. Colloids and Surfaces. B, Biointerfaces, 187, 110628.
110 Manasvi Saini, Gaurav Chaudhary, Chaitanay Vinayak Narayan et al.

Said, M., Aboelwafa, A. A., Elshafeey, A. H., Elsayed, I. (2021). Central composite optimization of ocular
mucoadhesive cubosomes for enhanced bioavailability and controlled delivery of voriconazole. Journal
of Drug Delivery Science and Technology, 61, 102075.
Selvaraj, K., Kuppusamy, G., Krishnamurthy, J., Mahalingam, R., Singh, S. K., Gulati, M. (2019).
Repositioning of Itraconazole for the Management of Ocular Neovascularization Through Surface-
Modified Nanostructured Lipid Carriers. Assay and Drug Development Technologies, 17(4), 178–190.
Sharif Makhmal Zadeh, B., Niro, H., Rahim, F., Esfahani, G. (2018). Ocular Delivery System for Propranolol
Hydrochloride Based on Nanostructured Lipid Carrier. Scientia Pharmaceutica, 86(2), 16.
Shepherd, S. J., Issadore, D., Mitchell, M. J. (2021). Microfluidic formulation of nanoparticles for biomedical
applications. Biomaterials, 274, 120826.
Siekmann, B., Westesen, K. (1995). Preparation and physicochemical characterization of aqueous dispersions
of coenzyme Q 10 nanoparticles. Pharmaceutical Research, 12, 201-208.
Soares, D. C. F., Domingues, S. C., Viana, D. B., Tebaldi, M. L. (2020). Polymer-hybrid nanoparticles: Current
advances in biomedical applications. Biomedicine & Pharmacotherapy, 131, 110695.
Streck, S., Neumann, H., Nielsen, H. M., Rades, T., McDowell, A. (2019). Comparison of bulk and
microfluidics methods for the formulation of poly-lactic-co-glycolic acid (PLGA) nanoparticles modified
with cell-penetrating peptides of different architectures. International Journal of Pharmaceutics: X, 1,
100030.
Trotta, M., Debernardi, F., Caputo, O. (2003). Preparation of solid lipid nanoparticles by a solvent
emulsification-diffusion technique. International Journal of Pharmaceutics, 257(1-2), 153–160.
Ura, T., Okuda, K., Shimada, M. (2014). Developments in Viral Vector-Based Vaccines. Vaccines, 2(3), 624–
641.
Wang, Y., & Wu, W. (2006). In situ evading of phagocytic uptake of stealth solid lipid nanoparticles by mouse
peritoneal macrophages. Drug Delivery, 13(3), 189–192.
William, B., Noemie, P., Brigitte, E., Geraldine, P. (2020). Supercritical fluid methods: An alternative to
conventional methods to prepare liposomes. Chemical Engineering Journal, 383, 123106.
Wissing, S. A., Müller, R. H. (2001). Solid lipid nanoparticles (SLN)--a novel carrier for UV blockers. Die
Pharmazie, 56(10), 783–786.
Yadav, M., Schiavone, N., Guzman-Aranguez, A., Giansanti, F., Papucci, L., Perez de Lara, M. J., Singh, M.,
Kaur, I. P. (2020). Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option
for age-related macular degeneration (AMD). Drug Delivery and Translational Research, 10(4), 919–
944.
Yingchoncharoen, P., Kalinowski, D. S., Richardson, D. R. (2016). Lipid-Based Drug Delivery Systems in
Cancer Therapy: What Is Available and What Is Yet to Come. Pharmacological Reviews, 68(3), 701–787.
Zhai, J., Tan, F. H., Luwor, R. B., Srinivasa Reddy, T., Ahmed, N., Drummond, C. J., Tran, N. (2020). In Vitro
and In Vivo Toxicity and Biodistribution of Paclitaxel-Loaded Cubosomes as a Drug Delivery
Nanocarrier: A Case Study Using an A431 Skin Cancer Xenograft Model. ACS Applied Bio Materials,
3(7), 4198–4207.
Zhao C. X. (2013). Multiphase flow microfluidics for the production of single or multiple emulsions for drug
delivery. Advanced Drug Delivery Reviews, 65(11-12), 1420–1446.
Chapter 8

Nanomedicine: Transforming Healthcare through

Precision, Theranostics, and Future Frontiers

Ashish Verma1,
Pradeep Kumar Sharma1
and Amit Singh2
1Mangalmay Pharmacy College, Greater Noida, Uttar Pradesh, India
2Department
of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida,
Gautam Buddha Nagar, Uttar Pradesh, India

Abstract

Nanomedicine, an innovative field at the intersection of nanotechnology and healthcare,

has revolutionized modern medicine. By employing theranostics, nanomedicine combines
diagnostics and therapy, enabling healthcare professionals to personalize treatments for
patients. Nanoparticle-based drug delivery systems are the hallmark of nanomedicine.
Lipid-based nanoparticles, inorganic nanoparticles such as gold and iron oxide, and silica-
based nanoparticles enable targeted drug delivery and controlled release, overcoming
biological barriers. This promises improved drug stability and bioavailability, particularly
in combination therapies. The future of nanomedicine holds even greater promise. It will
play an integral role in regenerative medicine and tissue engineering, promoting the
development of novel therapies and the repair of damaged tissues. The integration of
artificial intelligence and machine learning will further refine treatment strategies and
diagnostic accuracy. Nanorobotics is set to revolutionize interventions, ensuring precision
at the microscale. From precision medicine to diagnostic applications and personalized
treatments, it stands at the forefront of medical innovation. The future of nanomedicine
promises a new era in regenerative medicine, the synergy of AI and ML, and the emergence
of nanorobotics for unprecedented precision in healthcare interventions.

Keywords: nanomedicine, nanotechnology, nanoparticles, nanorobotics, drug delivery

Abbreviation

AI Artificial Intelligence
BBB Blood-Brain Barrier


Corresponding Author’s Email: ashishsing264@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
112 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

CT scan Computed Tomography

DNA Deoxyribonucleic Acid
IONPs Iron Oxide Nanoparticles
LNPs Lipid-Based Nanoparticles
ML Machine Learning
MRI Magnetic Resonance Imaging
NLCs Nanostructured Lipid Carriers
PEG Polyethylene Glycol
PET Scan Positron Emission Tomography
QDs Quantum Dots
RNA Ribonucleic Acid
SLNs Solid Lipid Nanoparticles

Introduction

Nanomedicine is a revolutionary field at the intersection of nanotechnology and medicine,

aiming to transform the treatment, prevention, and diagnosis of diseases through the application
of nanoscale materials and techniques (Anjum et al., 2008). In nanomedicine, scientists
manipulate and engineer materials at the nanoscale, typically in the order of 1 to 100
nanometers, to create innovative medical tools, therapies, and diagnostic methods (Tinkle et
al., 2014). The unique properties exhibited by materials at the nanoscale open up new avenues
for medical advancements. These properties can include increased surface area, enhanced
reactivity, improved drug delivery capabilities, and the ability to interact with biological
molecules on a molecular level. Nanomedicine holds the promise of revolutionizing healthcare
by offering more targeted and effective treatments, minimizing side effects, and providing
better diagnostic tools that enable early disease detection (Germain et al., 2020). Nanomedicine
encompasses a wide range of applications, which is discussed below: Nanoparticles, liposomes,
micelles, dendrimers, and carbon-based nanomaterials are examples of nanoscale materials
engineered for specific biomedical applications. These materials offer tunable properties like
surface charge, size, and functionality, allowing precise control over drug delivery, imaging,
and targeting (Huang et al., 2017). Nanoparticles may be intended to carry drugs directly to
specific tissues or cells, improving the effectiveness and efficiency of treatments while
lowering the toxicity and side effects on healthy tissues (Jin et al., 2007). Nanoscale contrast
agents can enhance the sensitivity and resolution of medical imaging techniques like CT scans,
MRI, ultrasound, allowing for better visualization of tissues and cellular structures (Kim et al.,
2017). Nanoparticles can be engineered for delivering therapeutic agents, including drugs, gene
therapies, and even therapeutic genes, precisely to target cells, offering the potential to treat
diseases at the molecular level (Mirza et al., 2021). Nanoparticles can selectively target cancer
cells, delivering therapeutic agents specifically to the tumor site, thereby minimizing damage
to healthy tissue. Nanoparticles can enhance the efficacy of vaccines and immunotherapies by
improving antigen presentation to the immune system and promoting a stronger immune
response. This is particularly relevant for infectious diseases and cancer immunotherapies (Zhu
et al., 2014).
 Nanomedicine 113

Significance of Nanomedicine in Modern Healthcare

Theranostics
The term ‘theranostics’ is derived from the combination of ‘therapy’ and ‘diagnostics,’
emphasizing the integration of these two aspects to improve medical outcomes. Nanomedicine
in theranostics has the potential to revolutionize personalized medicine by enabling targeted
treatments, real-time monitoring of therapeutic response, and reduced side effects (Wozniak et
al., 2022).

Antibacterial Applications
Nanoparticles with antimicrobial properties can effectively combat drug-resistant bacteria.
These nanoparticles can be integrated into wound dressings, medical devices, and coatings to
prevent infections, marking a promising application in the field of nanomedicine. Additionally,
nanocarriers facilitate targeted and controlled delivery of antibacterial agents, minimizing side
effects and optimizing drug efficacy. It emerges as a transformative force in reshaping
antibacterial approaches, providing more efficient and adaptable solutions to address the
escalating challenges posed by bacterial infections (Zhao et al., 2022).

Regenerative Medicine
Nanomedicine stands out as a transformative field within regenerative medicine, leveraging the
capabilities of nanotechnology to reshape our approach to tissue repair and regeneration.
Nanoscale materials, including nanoparticles and nanofibers, can emulate the natural
extracellular matrix, serving as scaffolds that guide cell growth and tissue formation. These
engineered materials bring forth enhanced mechanical properties, bioactivity, and
biocompatibility, all pivotal factors for the success of tissue regeneration (Mostafavi et al.,
2020).

Vaccines and Immunotherapy

Nanomedicine has facilitated the creation of innovative vaccine formulations capable of
mimicking pathogens or presenting controlled antigenic components, resulting in a more robust
and precise immune response. Engineered nanoparticles can transport antigens, adjuvants, or
other immune-stimulating molecules, enhancing antigen uptake by immune cells and fostering
a stronger and longer-lasting immune memory. Also, nanocarriers contribute to vaccine
stability, allowing for transportation and storage under challenging conditions. Immunotherapy,
which leverages the body’s immune system against diseases like cancer, has undergone a
transformation with the integration of nanomedicine. Nanoparticles act as delivery vehicles for
immunomodulatory agents, such as cytokines or immune checkpoint inhibitors, precisely
targeting immune cells or tumor microenvironments. This targeted delivery minimizes off-
target effects and amplifies the therapeutic potential of these agents. Furthermore, engineered
nanoparticles can carry tumor antigens, facilitating their presentation to immune cells and
triggering a more effective antitumor immune response (Yang et al., 2020).

Drug Stability and Bioavailability

Nanoparticles act as a protective barrier, shielding the drug from external factors such as light,
heat, and moisture, thereby preventing its degradation. This encapsulation not only extends the
114 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

drug’s shelf life but also preserves its therapeutic efficacy for an extended duration.
Nanoparticles can be designed to release medications in a controlled and sustained manner,
ensuring a consistent therapeutic effect. This controlled release profile not only enhances the
drug’s effectiveness but also reduces the frequency of administration, enhancing patient
convenience and compliance. Addressing the issue of poor solubility in certain drugs,
nanomedicine proves beneficial for bioavailability. Many drugs exhibit limited solubility in
water, hindering their absorption and bioavailability in the body. Nanoparticles can be tailored
to enhance the solubility of such drugs, increasing the likelihood of absorption through
biological barriers and facilitating their reach to target sites. This approach maximizes the
concentration of the drug at the desired location, minimizing potential side effects and
optimizing therapeutic outcomes (Emeje et al., 2012).

Combination Therapies
Combination therapies in nanomedicine offer several advantages over traditional single-agent
treatments. By combining different therapeutic agents, such as proteins and drugs, researchers
can enhance treatment efficacy while minimizing potential side effects. Nanoparticles can be
engineered to carry these agents and deliver them to specialized cells or tissues, improving their
bioavailability and reducing systemic toxicity. Moreover, combination therapies can address
the complexity of diseases involving multiple molecular pathways or cell types. Nanoparticles
used in combination therapies can be designed to release their cargo sequentially, ensuring that
each therapeutic agent is delivered at the optimal time during the treatment course. This can
lead to synergistic effects, where the combined therapies work together to achieve a more potent
therapeutic outcome. For instance, nanoparticles might deliver a chemotherapeutic drug
followed by a targeted gene therapy, aiming to sensitize cancer cells to the drug and reduce the
likelihood of resistance development (Vaughan et al., 2020).

Lipid Based Nanoparticles (LNPs)

Lipid nanoparticles, also known as lipid-based carriers or lipid-based nanoparticles, constitute

a broader category encompassing various types of nanoscale structures employed for
medication delivery (Figure 1). These nanoparticles can be composed of lipids, phospholipids,
and other lipid-based components. Two common types of lipid nanoparticles are solid lipid
nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs are nanoparticles
composed of solid lipids, providing applications such as improved stability of drugs, sustained
release, and controlled drug delivery. NLCs represent an advancement over SLNs and consist
of a mixture of liquid and solid lipids. This combination offers a higher capacity for drug
loading and improved drug release kinetics compared to traditional SLNs (Kumar et al., 2019).
LNPs are a versatile and promising class of nanoscale systems for drug delivery. Composed
primarily of lipids - natural or synthetic molecules with hydrophilic and hydrophobic regions -
LNPs provide a means to encapsulate and convey various therapeutic agents, such as drugs,
nucleic acids (RNA and DNA), and other bioactive molecules. The core structure of a LNP
typically consists of a lipid bilayer, where hydrophobic drugs or genetic material can be
embedded and protected from rapid clearance and degradation by the body’s immune system.
The hydrophilic outer layer provides stability and allows for surface modifications that can
enhance targeting specific cells or tissues (Buse et al., 2010). Recent developments in LNP
 Nanomedicine 115

composition have yielded highly effective and secure delivery systems, playing a pivotal role
in the rapid advancement and global deployment of mRNA vaccines against diseases like
COVID-19 (Mukai et al., 2022). Furthermore, in addition to their role in drug delivery, lipid-
based nanoparticles have demonstrated utility in diagnostic imaging, where they can be loaded
with contrast agents for enhanced visualization of tissues or organs. Moreover, LNPs are being
explored for their potential in cancer therapy, delivering chemotherapy drugs to tumor sites
with increased specificity, reducing off-target effects, and improving therapeutic outcomes
(Zhou et al., 2021).

Figure 1. Schematic diagram of lipid nanocarriers with their mechanism.

Inorganic Nanoparticles

Due to their distinctive characteristics and potential applications, inorganic nanoparticles have
garnered considerable attention in various sectors, emerging as a captivating and versatile class
of materials with applications spanning across diverse scientific and technological domains.
These nanoparticles typically consist of elements such as metals (silver, iron, gold), metal
oxides (zinc oxide, titanium dioxide), semiconductors (quantum dots), and other inorganic
compounds. What sets them apart is their remarkably small size, typically ranging from 1 to
100 nanometers, granting them distinctive optical, physical, and chemical properties that often
differ from their bulk equivalents (Huang et al., 2011). Some of the discussed inorganic
nanoparticles are outlined below:

Gold Nanoparticles
Gold nanoparticles have garnered significant interest in the field of nanomedicine due to their
distinctive physicochemical characteristics and versatile applications. They exhibit remarkable
116 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

stability, ease of synthesis, and tunable surface properties. In drug delivery, gold nanoparticles
can be functionalized with various molecules such as drugs, antibodies, and targeting ligands,
enabling precise and targeted delivery to specific tissues or cells. Their small size and high
surface area-to-volume ratio contribute to increased cellular absorption and higher
bioavailability (Milan et al., 2022). Their potent X-ray attenuation and light-absorbing
properties make them suitable contrast agents for imaging modalities like CT (computed
tomography) and photoacoustic imaging. This facilitates enhanced visualization of tissues and
organs, aiding in early disease detection and accurate monitoring of treatment responses.
Additionally, these nanoparticles can be engineered to respond to specific biomolecules or
environmental factors, leading to the development of biosensors for sensitive and rapid
detection of pathogens or diseases (Banstola et al., 2018).

Iron Oxide Nanoparticles (IONPs)

IONPs, composed of iron and oxygen, possess unique physical and chemical properties that
render them highly attractive for various biomedical applications. Their tunable size, surface
chemistry, and magnetic properties enable precise manipulation and targeting at the nanoscale.
In nanomedicine, IONPs find applications in a range of diagnostic and therapeutic approaches.
One notable use is in MRI, where their robust magnetic response enhances contrast in imaging,
providing detailed anatomical and functional information. Additionally, IONPs can be
functionalized with specific ligands on their surfaces, enabling targeted delivery to disease
sites. This capability is particularly valuable in cancer therapy, where targeted drug delivery
can minimize damage to healthy tissues and maximize the therapeutic effect on cancer cells
(Ansari et al., 2019; Farzin et al., 2020).

Overcoming Biological Barriers Using Nanocarriers

Nanomedicine has emerged as a revolutionary field with the goal of overcoming long-standing
biological barriers that impede effective drug delivery and treatment strategies. These
nanocarriers can be tailored to navigate through various physiological barriers, thereby
enhancing drug delivery precision and therapeutic efficacy. The first critical biological barrier
that nanocarriers can address is the body’s complex immune system. When foreign agents, such
as therapeutic drugs, are introduced into the body, the immune system often recognizes them
as threats and mounts a response, potentially neutralizing the therapeutic effect. Nanocarriers
can be designed to evade immune surveillance by modifying their surface properties, such as
coating them with polyethylene glycol (PEG). This stealth effect allows the nanocarriers to
travel in the bloodstream for an extended duration, increasing the likelihood of reaching the
intended target site (Sahu et al., 2021). Nanocarriers offer a breakthrough in overcoming the
blood-brain barrier (BBB), a formidable obstacle that inhibits the entry of many drugs into the
brain. The BBB is composed of tightly packed endothelial cells that prevent the passage of
most molecules, including potentially life-saving therapeutics. Nanocarriers can exploit various
mechanisms, such as receptor-mediated transcytosis, to transport drugs across the BBB and
into the brain tissue. Cellular barriers can also be formidable, as some drugs have difficulty
entering target cells. Nanocarriers can facilitate drug uptake by cells through a variety of
mechanisms. One approach is active targeting, where nanocarriers are engineered with ligands
that bind specifically to receptors on the surface of target cells. For instance, in the case of
HER2-positive breast cancer, antibody-conjugated liposomes like Myocet target and deliver
 Nanomedicine 117

drugs directly to cancer cells, maximizing therapeutic effects while minimizing off-target
effects (Gu et al., 2021).

Diagnostic Applications of Nanomedicine

Quantum Dots (QDs) and Fluorescent Nanoparticles for Imaging

One of the key advantages of QDs and fluorescent nanoparticles lies in their exceptional
brightness and photostability. In comparison to traditional organic dyes, QDs exhibit minimal
photobleaching and can emit light for prolonged periods, allowing for extended imaging
sessions with reduced signal loss. This endurance is crucial for tracking dynamic processes in
living systems, providing insights into cellular behaviours, protein trafficking, and even single
molecule tracking within the intricate landscape of biological tissues. Multiple types of QDs
can be excited simultaneously but emit light at distinct wavelengths, facilitating the
simultaneous observation of multiple molecular targets within the same sample. In
nanomedicine, QDs and fluorescent nanoparticles hold immense promise for rapid disease
recognition and personalized medicine. These nanoparticles can be functionalized with various
targeting ligands, including antibodies, peptides, or aptamers, enabling them to attach to
specific biomarkers on the surface of cells or inside tissues. This focused strategy improves the
specificity of imaging and allows for the precise visualization of disease-related molecular
processes. Moreover, the unique optoelectronic properties of QDs have paved the way for
breakthroughs in photoacoustic imaging, a non-invasive technique that harnesses laser-induced
acoustic waves to visualize tissues at depths previously unattainable with conventional optical
methods (Tiwari et al., 2023).

Magnetic Nanoparticles in Magnetic Resonance Imaging (MRI)

The potential applications of magnetic nanoparticles in nanomedicine are vast. In oncology, for
instance, these nanoparticles can be engineered to specifically accumulate in tumor tissues,
highlighting even the smallest lesions that might otherwise go unnoticed. This not only aids in
early detection but also enables monitoring of treatment response and the assessment of disease
progression. The therapeutic possibilities offered by magnetic nanoparticles are equally
groundbreaking. By subjecting the nanoparticles to an external magnetic field, researchers can
induce localized hyperthermia (a controlled increase in temperature) in the target tissue. This
technique holds immense potential for cancer therapy, as elevated temperatures can selectively
damage tumor cells while sparing surrounding healthy tissue. Likewise, the nanoparticles can
serve as carriers for therapeutic agents or drugs, allowing for targeted and controlled drug
delivery. The magnetic field may be used to guide nanoparticles to the desired location and
subsequently release the payload, minimizing systemic side effects and maximizing the
therapeutic impact (Tiwari et al., 2022).
118 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

Nanobiosensors for Rapid and Sensitive Detection of Biomarkers

Nanobiosensors have emerged as revolutionary tools in nanomedicine, enabling rapid and

sensitive detection of biomarkers with unprecedented precision. These miniature devices
combine the principles of nanotechnology and biorecognition elements to detect and quantify
specific molecules indicative of various physiological and pathological conditions. Their
special attributes, such as great surface area-to-volume ratios, enhanced sensitivity, and
compatibility with biological systems, make them invaluable for the diagnosis and monitoring
of diseases. The key strength of nanobiosensors lies in their ability to detect biomarkers, which
are molecules associated with specific physiological processes or diseases. Traditional methods
of biomarker detection often involve complex and time-consuming procedures, whereas
nanobiosensors offer a swift and efficient alternative. These sensors are engineered to recognize
a variety of biomolecules, including nucleic acids, proteins, and metabolites, by utilizing
various biorecognition elements such as antibodies, aptamers, and enzymes. This diversity
allows for customization to target biomarkers relevant to different diseases, offering a versatile
platform for diagnostics and personalized medicine (Singh et al., 2020). The sensitivity of
nanobiosensors is a key advantage that addresses the challenge of detecting biomarkers present
in low concentrations. The nanoscale dimensions of these sensors result in a large surface area
available for molecular interactions, enabling even trace amounts of biomarkers to be captured
and detected (Prasad et al., 2014). In addition, nanomaterials with unique properties, such as
gold nanoparticles and carbon nanotubes, can be integrated into the sensor design to amplify
signals and enhance sensitivity. This heightened sensitivity not only improves the accuracy of
biomarker detection but also facilitates early disease diagnosis when biomarker levels are
typically at their lowest (Swierczewska et al., 2012). These sensors are designed to be
biocompatible, minimizing potential interactions with living tissues and cells. This opens up
new avenues for continuous monitoring of biomarkers within the body, allowing for dynamic
tracking of disease progression and treatment efficacy. For instance, nanobiosensors could be
implanted to monitor glucose levels in diabetic patients, providing feedback for precise insulin
administration. The integration of nanobiosensors with emerging technologies further expands
their potential impact on nanomedicine. For example, advances in wearable devices and mobile
health technologies could synergize with nanobiosensors to enable remote monitoring of
biomarkers in real time. This would empower patients to take proactive control of their health
and well-being (Gaobotse et al., 2022).

Genomic and Proteomic Approaches in Nanomedicine

The field of nanomedicine has undergone a profound transformation through the integration of
genomic and proteomic methods, ushering in an entirely novel phase of personalized and
targeted medicines. Genomics provides insights into an individual’s genetic predispositions,
susceptibilities to diseases, and potential responses to treatments. Proteomics, on the other
hand, offers a dynamic view of the proteome, enabling the identification of disease-related
biomarkers and the monitoring of therapeutic responses. Integrating these approaches into
nanomedicine not only enhances our understanding of diseases at a molecular level but also
empowers the advancement of tailored nanoparticles for diagnostic, drug delivery, and
therapeutic applications (Su et al., 2021). Nanomedicine also benefits from proteomic insights
 Nanomedicine 119

through the identification of disease-specific biomarkers. The emerging field of liquid biopsies
leverages these biomarkers, enabling non-invasive monitoring of diseases like cancer through
the analysis of circulating proteins or extracellular vesicles. Nanoparticles can be engineered to
capture and analyze these biomarkers, offering real-time disease monitoring and treatment
response assessment. This approach is particularly valuable for cancers where traditional tissue
biopsies are challenging or pose risks to the patient. The integration of genomic and proteomic
information with nanotechnology transforms these liquid biopsies into powerful tools for early
detection, monitoring, and treatment adaptation (Adir et al., 2020). In drug delivery,
personalized nanomedicine takes advantage of genomics and proteomics to enhance drug
efficacy and reduce toxicity. Genetic variations can influence how individuals metabolize and
respond to drugs, affecting treatment outcomes. Nanoparticles designed using genomic
information can encapsulate drugs tailored to a patient’s genetic makeup, ensuring optimal drug
release and therapeutic effect. Proteomic data can guide the design of nanoparticles that target
cells overexpressing certain proteins, increasing drug accumulation at the disease site. This
approach maximizes drug potency while minimizing systemic unwanted effects, thereby
promoting the patient’s quality of life during medication (Manzari et al., 2021).

Customized Drug Delivery and Dosage Regimens

Customized drug delivery and dosage regimens have emerged as groundbreaking

advancements within nanomedicine, offering unprecedented precision and efficiency in
treating various medical conditions. Traditional systems for drug delivery often suffer from
limitations such as a lack of specificity, poor bioavailability, and adverse effects. However,
nanomedicine harnesses the potential of nanoscale materials, such as nanoparticles and
nanocarriers, to overcome these challenges and revolutionize therapeutic approaches
(Machtakova et al., 2022). Nanomedicine offers diverse approaches to achieving tailored drug
delivery. One prominent strategy involves utilizing stimuli-responsive nanoparticles that can
alter their properties in response to specific physiological cues. For instance, pH-sensitive
nanoparticles remain inert in the bloodstream but release their payload in the slightly acidic
environment of a tumor. This technique maximizes drug concentration at the target site while
minimizing systemic exposure, thereby enhancing efficacy and reducing side effects. Besides
that, nanocarriers equipped with targeting ligands can home in on specific cell types, enabling
highly selective drug delivery. Such precision is especially crucial in the treatment of diseases
where off-target effects can be detrimental (Elsabahy et al., 2012). The versatility of nanoscale
materials in drug delivery systems contributes to the development of multifunctional platforms
that can address several aspects of a disease simultaneously. Alongside therapeutic agents,
nanoparticles are able to carry diagnostic agents for early detection of disease, imaging agents
for precise localization of lesions, and even components that modulate the local
microenvironment to promote healing. These integrated approaches exemplify the potential of
nanomedicine to provide comprehensive and individualized care (Lee et al., 2012).
120 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

Patient-Specific Disease Monitoring Using Nanoscale Technologies

Nanomedicine has emerged as a groundbreaking field at the intersection of nanotechnology

and medicine, offering innovative solutions for disease monitoring and personalized patient
care. Patient-specific illness monitoring, which makes use of nanoscale technology to provide
instantaneous insights into a person’s health status, is one of the most promising applications
of nanomedicine. This approach has the potential to transform the way we diagnose and manage
diseases, moving beyond traditional methods that often lack the sensitivity and specificity
needed for early recognition and accurate monitoring. At the core of patient-specific disease
monitoring lies the utilization of nanoparticles and nanosensors. These nanoscale devices
possess exceptional properties due to their surface and size characteristics, enabling them to
interact with biological molecules, cells, and tissues in highly specific ways. By functionalizing
nanoparticles with biomolecules such as antibodies or aptamers, researchers can create sensors
capable of detecting disease-specific biomarkers, even at extremely low concentrations. This
level of sensitivity is essential for diseases like cancer, where early detection significantly
improves prognosis and treatment outcomes (Roco et al., 2020). The data generated by these
nanosensors can be seamlessly transmitted to healthcare providers through wireless
communication, enabling remote monitoring and reducing the need for frequent clinic visits.
Innovative data analytics, including artificial intelligence and machine learning, can process
intricate streams of information, identifying patterns, trends, and potential anomalies. This
amalgamation of nanoscale technologies and data analytics not only assists clinicians in making
informed decisions but also empowers patients to actively engage in managing their health
(Guk et al., 2019).

Nanomedicine in Regenerative Medicine and Tissue Engineering

Regenerative medicine, facilitated by nanomedicine, extends its reach to the field of gene
editing and gene therapy. Nanocarriers can be employed for the delivery of gene-editing
devices like CRISPR-Cas9 to target cells, correcting genetic mutations at their source. Inherited
disorders such as cystic fibrosis and muscular dystrophy could potentially be treated by
repairing the underlying genetic anomalies (Shahlaei et al., 2020). Moreover, nanomedicine
facilitates the delivery of nucleic acids like RNA and DNA, allowing for the manipulation of
cellular behaviors and the activation of endogenous regenerative pathways. This approach has
shown promise in cardiac regeneration, where reprogramming cells through the delivery of
specific genes has spurred tissue repair after heart attacks. Nanotechnology offers ingenious
platforms to mimic and enhance natural tissue architectures. Scaffoldings composed of
nanofibers, nanogels, or nanocomposites can closely resemble the extracellular matrix, offering
mechanical assistance and instructive cues for cell adhesion, proliferation, and differentiation.
These scaffolds, often seeded with stem cells or progenitor cells, guide tissue growth and
organization. For instance, in bone tissue engineering, biodegradable nanomaterials can serve
as templates for new bone formation, guiding the deposition of minerals and fostering the
integration of implants with native tissue (Ghanavi et al., 2019). The ability to engineer tissues
with patient-specific requirements is a tantalizing prospect. Nanomedicine enables the creation
of patient-specific implants and constructs, tailoring the biomaterials composition and
properties to match an individual’s unique physiology. By incorporating nanoscale cues, such
 Nanomedicine 121

as topographical features and biochemical signals, into these constructs, researchers can
enhance cellular integration, minimize immune responses, and foster tissue regeneration that
aligns precisely with the patient’s needs. This personalization not only enhances the therapeutic
outcomes but also reduces the risk of implant rejection, a significant hurdle in traditional tissue
transplantation (Guarino et al., 2020). Nanomedicine offers ingenious solutions to this
quandary by enabling the precise engineering of vascular networks within the constructs.
Researchers can design nanoscale channels that promote angiogenesis, facilitating the
formation of functional blood vessel networks as the engineered tissue develops. This
vascularization process enhances the constructs’ long-term viability and integration with the
host tissue, opening avenues for larger and more complex tissue regeneration (Berthiaume et
al., 2011).

Role of AI (Artificial Intelligence) and ML (Machine Learning)

In the rapidly evolving landscape of healthcare, the role of AI and ML has become
progressively prominent, especially in the study of nanomedicine. AI and ML are poised to
play a crucial role in unlocking the full potential of nanomedicine, offering novel solutions that
were previously unimaginable. One of the most significant contributions of AI and ML in
nanomedicine lies in their capability to process and analyze vast amounts of complex data
generated at the nanoscale. Nanomedicine involves working with intricate molecular structures
and interactions, requiring a comprehensive understanding of the underlying mechanisms. AI
and ML algorithms excel in identifying patterns and correlations within these intricate datasets,
providing insights that are instrumental in designing targeted drug delivery, personalized
treatment plans, and innovative diagnostic techniques (Vora et al., 2023). AI and ML-powered
nanosensors hold immense promise. These miniature devices can detect biomarkers at the
molecular level, enabling early disease detection with unprecedented sensitivity. The
integration of AI allows for real-time analysis of sensor data, facilitating rapid and accurate
diagnoses. This is particularly transformative in diseases where early intervention is critical,
such as certain types of cancer. By detecting subtle molecular changes indicative of disease
progression, these technologies can lead to timely interventions and significantly improved
patient outcomes (Dzobo et al., 2020). AI and nanomedicine hold remarkable promise in drug
development and delivery. Designing nanoscale drug carriers with precise targeting capabilities
has been a goal of nanomedicine, and AI-driven design processes can greatly expedite this
endeavor. Machine Learning algorithms can analyze vast molecular databases to predict the
interactions between nanoparticles and specific tissues or cells, leading to the creation of more
effective drug delivery. These AI-optimized nanoparticles could carry therapeutic agents
directly to the site of action, minimizing negative effects and enhancing treatment efficacy.
Further, AI-powered simulations can model drug interactions with biological systems,
streamlining the identification of potential drug candidates and accelerating the drug discovery
process (Colombo et al., 2020).
122 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

Nanorobotics for Precise Interventions

Nanorobotics in nanomedicine refers to the application of miniature robotic systems at the

nanoscale for various medical purposes. These nanorobots, also known as nanobots, are
designed to perform specific tasks within the body, offering a revolutionary approach to
treatment, diagnosis, and monitoring of diseases. The integration of nanorobotics with medicine
holds the potential to significantly improve healthcare outcomes, as it allows for precise and
targeted interventions at the cellular and molecular levels. At the convergence of
nanotechnology and robotics, nanorobotics involves the design, fabrication, and operation of
sub-micron to nanoscale devices that can perform tasks with unprecedented accuracy and
control. In medicine, these tiny, mechanized agents hold the promise of revolutionizing
diagnostics, drug delivery, and surgery. These nanoscale marvels can access confined spaces
and interact with individual cells, enabling a level of precision that was previously
inconceivable. The manufacturing industry is poised for a transformation as nanorobots can
manipulate individual atoms and molecules to create materials with tailored properties. This
level of control could lead to the development of advanced materials like super-strong yet
lightweight structures or components with unprecedented electronic properties (Ceylan et al.,
2017). Nanorobotics holds great promise for performing minimally invasive surgeries with
unparalleled precision. Traditional surgical procedures often require large incisions, causing
trauma, extended recovery periods, and increased risk of infection. Nanorobots, on the other
hand, can operate at the nanoscale and access remote areas of the body through natural openings
or tiny incisions. Equipped with imaging and sensing capabilities, these nanorobots can provide
real-time feedback to surgeons, enhancing their ability to make informed decisions during
procedures. This level of precision minimizes tissue damage, reduces scarring, and accelerates
patient recovery. Furthermore, nanorobots can manipulate biological materials at the molecular
level, enabling intricate procedures like gene editing with a level of accuracy that was once
considered science fiction (Soto et al., 2020).

Conclusion

Nanomedicine has emerged as a transformative field at the intersection of nanotechnology and

medicine, holding immense promise for revolutionizing healthcare on multiple fronts. The
current status of nanomedicine reflects significant advancements in targeted drug delivery,
imaging, diagnostics, and personalized treatments. Nanoparticles, engineered with precision at
the nanoscale, offer enhanced properties such as prolonged circulation times, increased drug
loading capacities, and the ability to bypass biological barriers. These advancements have
resulted in reduced side effects, improved therapeutic outcomes and enhanced patient
compliance. The future prospects of nanomedicine are even more exciting. As research
continues to unravel the intricacies of nanoscale interactions within biological systems, we can
anticipate the development of more sophisticated and multifunctional nanomaterials. These
materials will likely enable real-time monitoring of physiological parameters, early disease
detection, and targeted interventions at a cellular or molecular level. The integration of
nanomedicine with other cutting-edge technologies like artificial intelligence and gene editing
 Nanomedicine 123

holds the potential to unlock entirely new treatment modalities, such as personalized nano
therapies tailored to an individual’s genetic makeup.

References

Adir, O., Poley, M., Chen, G., Froim, S., Krinsky, N., Shklover, J., Roitman, J. S., Lammers, T., Schroeder,
A., (2020). Integrating artificial intelligence and nanotechnology for precision cancer medicine. Advanced
Materials 32, no. 13: 1901989.
Ansari, S. A. M. K., Ficiarà, E., Ruffinatti, F. A., Stura, I., Argenziano, M., Abollino, O., Cavalli, R., Guiot,
C., D’Agata, F., (2019). Magnetic iron oxide nanoparticles: synthesis, characterization and
functionalization for biomedical applications in the central nervous system. Materials 12, no. 3: 465.
Anjum, S., Ishaque, S., Fatima, H., Farooq, W., Hano, C., Abbasi, B. H., Anjum, I., (2021). Emerging
applications of nanotechnology in healthcare systems: Grand challenges and perspectives.
Pharmaceuticals 14, no. 8: 707.
Banstola, A., Emami, F., Jeong, J., Yook, S., (2018). Current applications of gold nanoparticles for medical
imaging and as treatment agents for managing pancreatic cancer. Macromolecular Research 26: 955-964.
Berthiaume, F., Maguire, T. J., Yarmush, M. L., (2011). Tissue engineering and regenerative medicine: history,
progress, and challenges. Annual review of chemical and biomolecular engineering 2: 403-430.
Ceylan, Hakan., Giltinan, Joshua., Kozielski, Kristen., Sitti. Metin., (2017). Mobile microrobots for
bioengineering applications. Lab on a Chip 17, no. 10: 1705-1724.
Colombo, S., (2020). Applications of artificial intelligence in drug delivery and pharmaceutical development.
In Artificial Intelligence in Healthcare, pp. 85-116.
Dzobo, K., Adotey, S., Thomford, N. E., Dzobo, W., (2020). Integrating artificial and human intelligence: a
partnership for responsible innovation in biomedical engineering and medicine. Omics: a journal of
integrative biology 24, no. 5: 247-263.
Elsabahy, M., Wooley, K. L., (2012). Design of polymeric nanoparticles for biomedical delivery applications.
Chemical Society Reviews 41, no. 7: 2545-2561.
Emeje, M. O., Ifeoma, C.O., Akpabio, E.I., Ofoefule, S.I., (2012). Nanotechnology in drug delivery. Recent
advances in novel drug carrier systems 1, no. 1.
Farzin, A., Etesami, S. A., Quint, J., Memic, A., Tamayol, A., (2020). Magnetic nanoparticles in cancer therapy
and diagnosis. Advanced healthcare materials 9, no. 9: 1901058.
Gaobotse, G., Mbunge, E., Batani, J., Muchemwa, B., (2022). Non-invasive smart implants in healthcare:
Redefining healthcare services delivery through sensors and emerging digital health technologies. Sensors
International 3: 100156.
Germain, M., Caputo, F., Metcalfe, S., Tosi, G., Spring, K., Aslund, A. K., Pottier, A., Schiffelers, R., Ceccaldi,
A., Schmid, R., (2020). Delivering the power of nanomedicine to patients today. Journal of Controlled
Release 326: 164-171.
Ghanavi, J., Farnia, P., Velayati, A. A., (2019). Nano design of extracellular matrix for tissue engineering.
Nanoarchitectonics in Biomedicine, pp. 547-583. William Andrew Publishing.
Gu, W., Meng, F., Haag, R., Zhong, Z., (2021). Actively targeted nanomedicines for precision cancer therapy:
Concept, construction, challenges and clinical translation. Journal of controlled release 329, 676-695.
Guarino, V., Iafisco, M., Spriano, S., (2020). Introducing biomaterials for tissue repair and regeneration.
Nanostructured biomaterials for regenerative medicine, pp. 1-27. Woodhead Publishing.
Guk, K., Han, G., Lim, J., Jeong, K., Kang, T., Lim, E., Jung, J., (2019). Evolution of wearable devices with
real-time disease monitoring for personalized healthcare. Nanomaterials 9, no. 6: 813.
Huang, H., Lovell, J. F., (2017), Advanced functional nanomaterials for theranostics. Advanced functional
materials 27, no. 2: 1603524.
Huang, H., Barua, S., Sharma, G., Dey, S. K.., Rege, K.., (2011). Inorganic nanoparticles for cancer imaging
and therapy.” Journal of controlled Release 155, no. 3: 344-357.
Jin, S., Ye, K., (2007). Nanoparticle‐mediated drug delivery and gene therapy. Biotechnology progress 23, no.
1: 32-41.
124 Ashish Verma, Pradeep Kumar Sharma and Amit Singh

Kim, J., Chhour, P., Hsu, J., Harold I., Ferrari, V. A., Popovtzer, R., Cormode, D. P., (2017). Use of
nanoparticle contrast agents for cell tracking with computed tomography. Bioconjugate chemistry 28, no.
6: 1581-1597.
Kumar, R., (2019). Lipid-based nanoparticles for drug-delivery systems. In Nanocarriers for drug delivery, pp.
249-284. Elsevier.
Lee, D., Koo, H., Sun, I., Ryu, J. H., Kim, K., Kwon, I. C., (2012). Multifunctional nanoparticles for multimodal
imaging and theragnosis. Chemical Society Reviews 41, no. 7: 2656-2672.
Liu, X., Chen, S., Zhang, H., Zhou, J., Fan, H., Liang, X., (2019). Magnetic nanomaterials for advanced
regenerative medicine: the promise and challenges. Advanced materials 31, no. 45: 1804922.
Machtakova, M., Aubin, H. T., Landfester, K., (2022). Polymer nano-systems for the encapsulation and
delivery of active biomacromolecular therapeutic agents. Chemical society reviews 51, no. 1: 128-152.
Manzari, M.T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., Heller, D. A., (2021). Targeted drug delivery
strategies for precision medicines. Nature Reviews Materials 6, no. 4: 351-370.
Milan, J., Niemczyk, K., Liśkiewicz, M. K., (2022). Treasure on the Earth—gold nanoparticles and their
biomedical applications. Materials 15, no. 9: 3355.
Mirza, Z., Karim, S., (2021). Nanoparticles-based drug delivery and gene therapy for breast cancer: Recent
advancements and future challenges. In Seminars in cancer biology, vol. 69, pp. 226-237. Academic Press.
Mostafavi, E., Cruz, D. M., Kalantari, K., Pooneh Soltantabar, A. T., Webster, T. J., (2020). Electroconductive
nanobiomaterials for tissue engineering and regenerative medicine. Bioelectricity 2, no. 2: 120-149.
Mukai, H., Ogawa, K., Kato, N., Kawakami, S., (2022). Recent advances in lipid nanoparticles for delivery of
nucleic acid, mRNA, and gene editing-based therapeutics. Drug Metabolism and Pharmacokinetics 44:
100450.
Prasad, S., (2014). Nanobiosensors: the future for diagnosis of disease? Nanobiosensors in Disease Diagnosis:
1-10.
Rajan, A., Sahu, N. K.., (2020). Review on magnetic nanoparticle-mediated hyperthermia for cancer therapy.
Journal of Nanoparticle Research 22: 1-25.
Ross, S., Anand, S. S., Joseph, P., Paré, G., (2012). Promises and challenges of pharmacogenetics: an overview
of study design, methodological and statistical issues. JRSM cardiovascular disease 1, no. 1: 1-13.
Sahu, T., Ratre, Y. K., Chauhan, S., Bhaskar, L. V. K. S., Nair, M. P., Verma, H. K., (2021). Nanotechnology
based drug delivery system: Current strategies and emerging therapeutic potential for medical science.
Journal of Drug Delivery Science and Technology 63: 102487.
Shahlaei, M., Asl, S. M., Saeidifar, M., (2020) Nanotechnology in gene delivery for neural regenerative
medicine.” Neural Regenerative Nanomedicine, pp. 123-157.
Singh, P., Yadava, R. D. S., (2020). Nanosensors for health care. In Nanosensors for Smart Cities, pp. 433-
450.
Soto, F., Wang, J., Ahmed, R., Demirci, U., (2020). Medical micro/nanorobots in precision medicine. Advanced
Science 7, no. 21: 2002203.
Su, M., Zhang, Z., Zhou, L., Han, C., Huang, C., Nice, E. C., (2021). Proteomics, personalized medicine and
cancer. Cancers 13, no. 11: 2512.
Swierczewska, M., Liu, G., Lee, S., Chen, X., (2012). High-sensitivity nanosensors for biomarker detection.
Chemical Society Reviews 41, no. 7: 2641-2655.
Tinkle, S., McNeil, S. E., Mühlebach, S., Bawa, R., Borchard, G., Barenholz, Y., Tamarkin, L., Desai, N.,
(2014). Nanomedicines: addressing the scientific and regulatory gap. Annals of the New York Academy of
Sciences 1313, no. 1: 35-56.
Tiwari, A. K., Yadav, P. K., Mishra, K., Singh, P. K., Chourasia, M. K., (2022). Magnetic nanoparticles:
challenges and practical considerations. Multifunctional Nanocarriers, pp. 235-257.
Tiwari, H., Rai, N., Singh, S., Gupta, P., Verma, A., Singh, A. K., Kajal., Salvi, P., Singh, S. K., Gautam, V.,
(2023). Recent Advances in Nanomaterials-Based Targeted Drug Delivery for Preclinical Cancer
Diagnosis and Therapeutics. Bioengineering 10, no. 7: 760.
Vaughan, H. J., Green, J. J., Tzeng, S. Y., (2020). Cancer‐targeting nanoparticles for combinatorial nucleic
acid delivery. Advanced Materials 32, no. 13: 1901081.
Vora, L. K., Gholap, A. D., Jetha, K., Thakur, R. S., Solanki, H. K., Chavda, V. P., (2023). Artificial
Intelligence in Pharmaceutical Technology and Drug Delivery Design. Pharmaceutics 15, no. 7: 1916.
 Nanomedicine 125

Wozniak, M., Płoska, A., Siekierzycka, A., Dobrucki, L. W., Kalinowski, L., Dobrucki, I. T., (2022). Molecular
Imaging and Nanotechnology—Emerging Tools in Diagnostics and Therapy. International journal of
molecular sciences 23, no. 5: 2658.
Yang, Z., Ma, Y., Zhao, H., Yuan, Y., Kim, B. Y. S., (2020). Nanotechnology platforms for cancer
immunotherapy. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 12, no. 2:
e1590.
Zhao, X., Tang, H., Jiang, X., (2022). Deploying gold nanomaterials in combating multi-drug-resistant bacteria.
ACS nano 16, no. 7: 10066-10087.
Zhou, J., Chen, L., Chen, L., Zhang, Y., Yuan, Y., (2022). Emerging role of nanoparticles in the diagnostic
imaging of gastrointestinal cancer. In Seminars in Cancer Biology, vol. 86, pp. 580-594.
Zhu, M., Wang, R., Nie, G., (2014). Applications of nanomaterials as vaccine adjuvants. Human vaccines &
immunotherapeutics 10, no. 9: 2761-2774.
Chapter 9

Lipid Nanocarriers in Ocular Drug Delivery

Hiti
Varneet Sandhu
Sonia Dhiman
and Thakur Gurjeet Singh
Chitkara College of Pharmacy, Chitkara University, Punjab, India

Abstract

The ocular drug delivery route poses a significant challenge for researchers due to its
unique anatomical and physiological constraints. Conventional approaches like ointments
and eye drops have limitations related to their limited bioavailability. Factors such as rapid
drainage, inadequate permeability of the cornea, the influence of nasolacrimal drainage,
dilution by tears, and short retention time in the pre-corneal region contribute to these
limitations. In recent times, there has been growing interest among experts in the field of
nanoformulation regarding the potential use of lipid-based nanocarriers as ocular drug
delivery systems. These nanocarriers offer several advantages, including protecting drugs
and therapeutic agents against degradation by tear enzymes, facilitating targeted drug
delivery to specific sites within the eye to enhance bioavailability, reducing inefficient
absorption, enabling controlled release of drugs, and improving drug absorption through
the cornea. This book chapter provides an overview of key characteristics of solid lipid
nanoparticles, nanostructured lipid carriers, cubosomes, niosomes, liposomes,
nanoemulsions, and self-nanoemulsifying drug delivery systems. It highlights the benefits
and obstacles associated with lipid nanocarriers in the context of ocular medication
delivery. Furthermore, it emphasizes the role of nanotechnology in overcoming ocular
barriers.

Keywords: ocular drug delivery, barriers, solid lipid nanoparticles, nanostructured lipid
carriers, lipid drug conjugates

Abbreviations

SLN Solid lipid nanocarriers

NLCs Nanostructured lipid carriers


Corresponding Author’s Email: soniadhmn6@[Link]; [Link]@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
128 Hiti, Varneet Sandhu, Sonia Dhiman et al.

SNEDDS self-nanoemulsifying drug delivery systems

BRB Blood-retinal barrier
BAB Blood aqueous barrier
RPE Retinal pigment epithelium

Introduction

The eye is a highly intricate and essential component of the human body that facilitates the
sense of vision (Sharma et al., 2023). Ocular disorders can significantly impair visual acuity,
impacting an individual’s daily schedule. Statistically, it is estimated that a minimum of 2.2
billion individuals worldwide have some form of visual impairment in the year 2023, presenting
a substantial economic burden on a global scale with projected yearly costs of productivity as
high as US$ 411 billion (Vashist et al., 2022). The predominant medical care for ocular
disorders involves the administration of topically applied drugs, constituting approximately
90% of the existing available formulations. This preference for topical usage is primarily
attributed to its safety, simplicity, and patient compliance due to its ease of use (Ross et al.,
2023). However, the bioavailability of drugs administered topically is significantly impeded by
efficient defensive mechanisms protecting the functioning of the eye. Factors such as transient
residence time, non-productive absorption, the cornea’s relative impermeability, and tear
dynamics contribute to the poor efficacy of drugs administered through eye drops (Sanyal and
Ravula et al., 2023). As a result, only a small proportion, approximately 5% of the applied dose,
is absorbed by the cornea and reaches the intraocular tissues. The majority of the instilled dose
is directed toward the nasolacrimal duct for drainage (Qi et al., 2023). To overcome these
challenges and increase the therapeutic effectiveness of topical therapy, the development of
strategies remains a fundamental concern. Efficient drug delivery systems that stay on the
ocular surface for a longer duration, thereby improving bioavailability in the anterior cavity,
are crucial. Recent advancements support the usage of nanocarriers as a means of administering
drugs for treating ocular disorders. Nanoscale-based delivery systems offer various advantages,
including extended drug release and targeted drug delivery (Han et al., 2023). Due to their small
size, nanoparticles can pass through the blood-retinal barriers, improving ocular absorption and
bioavailability. Examples of these approaches that have gained traction as ophthalmic drug
delivery systems include solid lipid nanoparticles (SLN), liposomes, nanostructured lipid
carriers (NLCs), cubosomes, self-nanoemulsifying drug delivery systems (SNEDDS),
niosomes, and more.

Anatomy and Physiology of the Eye

The eye is a highly intricate and multi-structured organ designed specifically for visual
perception. It meticulously analyzes and interprets variations in light before transmitting them
to the brain as neuroelectric impulses. The most superficial structures include the pupil, retina,
and sclera. Simultaneously, the conjunctiva is a translucent film encircling the entire eye
surface. Furthermore, the optic nerves, retina, posterior chamber, and anterior chamber
collectively contribute to the eye’s functionality, as illustrated in Figure 1. A translucent
 Lipid Nanocarriers in Ocular Drug Delivery 129

mucous membrane, referred to as the conjunctiva, functions as a protective barrier. This

membrane forms a continuous layer covering the internal surface of the eyelids and extends to
envelop the frontal region of the eyeball. The structure comprises two distinct layers: a
supportive stroma and an outer epithelium (Downie et al., 2021). The epithelium is composed
of microvilli and exhibits a stratified arrangement with nearly fifteen layers of epithelial cells.
These cells strongly interact through tight junctions, playing a crucial role in establishing a
permeability barrier around the membrane (Das Neves et al., 2020). Simultaneously, the stroma
comprises cellular elements such as arteries and nerves loosely connected to the sclera. The
sclera, one of the outermost layers of the eyes, is a white-colored opaque sheet enveloping the
eye. It primarily consists of glycoproteins, collagen fibers, and proteoglycans. On average, its
thickness ranges between 0.5 to 1 mm, although it may vary along the structure of the eye.
Another prominent feature of the eye is the iris, which functions as the pigmented portion
responsible for absorbing and subsequently reflecting light (Corbett et al., 2022).

Figure 1. Schematic illustration of Anatomy of Eye.

Furthermore, the iris plays a crucial role in regulating the diameter of the pupil. Serving as
the primary opening within the iris, the pupil facilitates the transmission of light deeper into the
eye. Simultaneously, the cornea encompasses the entire anterior portion of the eye,
safeguarding the inner ocular structures. It enhances the eye’s refractive abilities by accurately
focusing light onto the retina, thus minimizing scattering and optical distortion. Irregularities
on the corneal epithelium are shielded by a uniform tear film (Pflugfelder et al., 2020). The first
layer of the cornea actively interacts with light, providing moisture and lubrication to the eye’s
surface. Light enters through the cornea, initiating the visual process. The lens, situated just
behind the iris, is a transparent structure that plays a pivotal role in focusing light onto the
retina. It is a biconvex and flexible structure, enabling us to focus on objects at varying
130 Hiti, Varneet Sandhu, Sonia Dhiman et al.

distances. Following the lens is a dense, gel-like structure known as the vitreous humor. This
uniform and viscoelastic hydrogel matrix are located in the posterior region of the eye. The
vitreous humor plays a crucial role in maintaining the structural integrity of the eyeball by
establishing and sustaining continuous interaction with the retina through the inner limiting
membrane. Moreover, it serves as a protective barrier, shielding the lens and retina from
physical injury by absorbing external forces. Additionally, the vitreous humor plays a crucial
role in protecting against oxidative damage (Mishra et al., 2023). The choroid serves as another
vital supportive structure of the eye, being a highly vascular layer that provides nourishment to
various ocular structures. Within the choroid, the choriocapillaris layer, situated in the deepest
region, plays a crucial role in supplying sufficient blood to the retina. Additionally, it contains
melanin, aiding in the absorption of excess light and preventing visual glare (Invernizzi et al.,
2020). Positioned in the innermost section of the eye, the retina is responsible for processing
visual stimuli, converting light energy in the form of photons into neuroelectric signals. With a
dual blood supply, the retina is divided into outer and inner layers. It consists of six distinct cell
lines distributed across ten layers, each playing specific roles in vision. These cells form
specialized pathways for detecting changes in the motion of light. Through the process of
transduction, photoreceptor cells in the retina convert light energy or electromagnetic waves
into neural impulses, which are then picked up by the optic nerve (Yu et al., 2023).

Various Routes Employed for Ocular Delivery

Topical Route
The predominant method for managing ophthalmic diseases is through topical treatments,
constituting over 95% of eye products available in the market. Traditional formulations such
as ointments, suspensions, and eye drops are commonly employed due to their ease of
administration and enhanced patient compliance. Despite being non-invasive, this approach
presents challenges in achieving high bioavailability (Ahmed et al., 2023). Approximately 5%
of the medication is absorbed through the eye’s surface, hindered by factors like lachrymation,
precorneal loss, and tear dynamics. Anatomical barriers further impede drug absorption,
leading to reduced bioavailability. Consequently, frequent administration of eye drops becomes
necessary to maintain adequate drug levels on the ocular surface, but this may result in side
effects, potentially causing patient reluctance. Intravitreal route- Intravitreal injection involves
the direct administration of the formulation into the vitreous humor, bypassing both scleral
blood vessels and the cornea. This method is commonly used for delivering 20–100 ml of
solution or suspension, typically with a 27 or 30-gauge needle. The body eliminates the
medication through two pathways: either via the retina or the anterior chamber using aqueous
humor. The elimination process follows a first-order rate of decay. There is a direct correlation
between the elimination rate and the weight of the drug. Drug molecules with a molecular
weight below 500 Da have a shorter retention time, whereas larger linear molecules exceeding
40 kDa and globular molecules (over 70 kDa) demonstrate increased retention within the
vitreous region.
 Lipid Nanocarriers in Ocular Drug Delivery 131

Juxtascleral Route
The periocular route employs a curved cannula with a blunt tip to administer the formulation
into the macular region (Varela-Fernández et al., 2020). The macular region, also known as
macula lutea, is a specialized area located near the center of the human retina responsible for
high-acuity vision in the central field. This technique is particularly useful for addressing
specific posterior segment conditions that may not be effectively managed through traditional
topical methods. The approach enables the placement of a depot in proximity to and above the
macula, facilitating effective and prolonged drug delivery to the macular region.

Subconjunctival Route
By employing this method, the formulation is positioned beneath the conjunctiva, providing
direct access to the sclera while bypassing both the cornea and conjunctiva. This approach
effectively addresses the challenge presented by tight junctions within the conjunctival
epithelium, which may hinder the absorption of hydrophilic molecules during topical
application. Consequently, this method is well-suited for administering hydrophilic drugs. A
needle with a diameter of up to 25-30 gauge and a length of 30mm, along with a volume of up
to 0.5 ml, can be utilized for this specific mode of administration. The subconjunctival route
enables the administration of the drug to both the anterior and posterior portions of the eye
(Agban et al., 2019).

Intracameral Route
The intracameral route is utilized for injecting the drug directly into the anterior chamber of the
eye. This precise method of delivery overcomes ocular obstructions, thereby increasing
therapeutic concentration at the desired region and improving clinical results. It is commonly
employed for administering antibiotics such as moxifloxacin, cefuroxime, and vancomycin
(Gautam et al., 2023).

Retrobulbar Route
This delivery method involves placing the needle between the orbital fascia and the eyelid to
administer the drug directly into the retrobulbar region, situated behind the eye (Battaglia et al.,
2018). To prevent damage to the optic nerves, a blunt needle is utilized, ensuring it does not
penetrate deeper than 1.5 cm behind the eye. This route is employed for the delivery of
antibiotics and corticosteroids to the posterior part of the eyeball.

Sub-Tenon Route
The sub-tenon injection is a medical procedure utilized to administer medication into the ocular
region as needed. The sub-tenon is an anatomical region situated between the sclera and the
tenon capsule (Alpay et al., 2021). The tenon capsule, a thin membranous structure surrounding
the eyeball, serves as a socket for ocular rotation. Subretinal route- The subretinal space is
situated in the region between the photoreceptors and the retinal pigment epithelium (RPE).
Medication administration can be directly performed, visualizing it with the assistance of a
microscope. This route of delivery is advantageous due to its ability to yield an enhanced
pharmacological effect on the cells within the subretinal space and the retinal layer (Kim et al.,
2021).
132 Hiti, Varneet Sandhu, Sonia Dhiman et al.

Barriers to the Ocular Drug Delivery

The challenge of achieving effective therapeutic dosages within the eye is attributed to the
presence of several barriers. Whether the dosage form is applied topically or systemically, it
encounters numerous obstacles before reaching the intended site of action. Generally, the
bioavailability of a given dose through the topical route is only 1-7%. These barriers can be
further categorized as corneal, pre-corneal, and blood-ocular barriers.

Pre-Corneal Barriers

Constrained Capacity of Cul-de-sac

The junction of the bulbar conjunctiva and palpebral within the lower eyelid is recognized as a
‘cul-de-sac,’ forming a shallow pocket that creates a deeper indentation in the upper eyelid. In
this cul-de-sac region, humans can hold up to 30 µL, making it a common area for administering
eye drops. However, the capacity decreases to about 70 to 80% when the lower eyelid returns
to its initial position. Additionally, medical conditions such as inflammation and allergies may
further decrease the retention capacity. Consequently, this limitation poses a challenge to the
therapeutic efficacy of ocular formulations. The restricted volume of the cul-de-sac results in a
lower concentration of medicine in the eye, thereby limiting the therapeutic effect.

Drug Dissipation from Lacrimal Fluid

The primary challenge in the precorneal area involves the depletion of the applied ocular
solution due to the outflow of lacrimal fluid. In this specific region, the removal of medications
is mainly facilitated by mechanisms such as solution drainage, lacrimation, and unproductive
absorption in the conjunctiva (Dosmar et al., 2022). Additionally, the presence of drug-binding
proteins and drug metabolic mechanisms might hinder the absorption of the administered
medication. To optimize the efficacy of the medication, it is crucial to prolong the duration of
the provided formulation inside the body. This objective can be achieved through the
implementation of various methods.

Corneal Barriers
The cornea serves the dual purpose of directing light into the retina and acting as a protective
barrier against various chemical and physical hazards. It is composed of three distinct layers:
the epithelium, stroma, and endothelium. The epithelium consists of five to seven
interconnected layers of cells, providing protection against hydrophilic medications or larger
molecules. Conversely, the stroma is an aqueous, thick layer that performs a similar protective
function for lipophilic medications (Ahmed et al., 2022). The endothelium is crucial for
maintaining corneal transparency and facilitating the selective movement of hydrophilic drugs
within the aqueous humor. The ability of drugs to traverse the cornea is influenced by factors
such as charge, hydrophobicity, molecular weight, and degree of ionization. Consequently,
trans-corneal permeation is recognized as a critical factor determining the rate at which
medication crosses from tear fluid into the aqueous humor.
 Lipid Nanocarriers in Ocular Drug Delivery 133

Blood-Ocular Barriers
These barriers limiting the entry of foreign elements into the bloodstream are broadly
categorized as the blood-retinal barrier (BRB) and the blood-aqueous barrier (BAB). The BRB
acts as an obstacle that regulates the passage of medication into the retina from the circulation.
Comprising retinal pigment epithelial cells and retinal vein endothelial cells, the structure
includes a subretinal gap that separates the monolayer of retinal pigment epithelium (RPE) from
the multilayered neural retina. The RPE monolayer envelops the external surface of the neural
retina and the borders of the choroid. The RPE plays a crucial role in maintaining the integrity
and function of the retina. It is responsible for eliminating fluid from the subretinal region,
ensuring the maintenance of retinal adhesion, and keeping the retina hydrated (Singh et al.,
2019). The BAB serves as a protective mechanism for the aqueous humor. Derived from the
ciliary muscle and the endothelium of vasculature in the iris, this barrier exhibits poor
permeability due to sealed cellular connections, limiting the passage of large-sized molecules.
Smaller molecules, however, can mediate across the barrier through the existing gaps.

Lipid-Based Nanocarriers
Lipids are essential building blocks found in all life forms, playing crucial roles as structural
components in the body, including the formation of the blood-brain barrier. These organic
compounds, derived from both animal and plant sources, encompass cholesterol, fatty acids,
bile acids, and triglycerides. Lipids are characterized by poor aqueous solubility but exhibit
high solubility in organic solvents. Therefore, enhancing the lipid solubility of specific drugs
is essential for their efficient and easy passage through the blood-brain barrier. Lipids are
commonly used as excipients to enhance the bioavailability of various formulations, leveraging
their inherent properties. Lipid-based nanocarriers offer advantages such as site-specific
targeting, sustained/controlled release, and stability (Duan et al., 2020). These lipidic systems
can be broadly categorized into two main types: nanoparticles (such as solid lipid nanoparticles
- SLNs, and nanostructured lipid carriers - NLCs) and nano vesicular systems (including self-
nanoemulsifying drug delivery systems - SNEDDS, liposomes, cubosomes, and niosomes).
Several patented lipid-based nanocarriers are already in existence, as listed in Table 1 (Sawant
& Dodiya, 2008), showcasing the diversity and potential of these systems in pharmaceutical
applications.

SLN
Solid lipid nanoparticles (SLNs) are characterized by their distinctive spherical morphology,
with an average diameter ranging from 10-1000 nm. Composed of biocompatible lipids, they
are non-toxic and exceptionally stable. SLNs offer numerous advantages as a drug delivery
system, as outlined in Table 2. These advantages include high entrapment efficiency for both
lipophilic and hydrophilic drugs, enhanced stability, longer shelf life, and controlled or
sustained release. The nanoscale size of SLNs presents a potential strategy for improving trans-
corneal absorption and enhancing bioavailability. The hydrophobic nature of SLNs facilitates
effective and easy transmembrane transport of encapsulated drugs through the epithelial
membrane. Additionally, cationic SLNs, owing to their slight negative charge on the
epithelium, have been demonstrated to effectively prolong retention within the cornea and
enhance drug uptake (Das et al., 2022).
134 Hiti, Varneet Sandhu, Sonia Dhiman et al.

NLCs
Novel lipid nanoparticles, commonly referred to as nanostructured lipid carriers (NLCs), are
formulated through the controlled incorporation of liquid lipid into the solid lipid component.
This approach allows for a greater quantity of the drug to be accommodated, leading to an
improved release profile. NLCs demonstrate a higher drug load capacity due to the increased
solubility of drugs within liquid lipids compared to solid lipids (Giri et al., 2023).

Cubosomes
Cubosomes possess a distinctive structure formed through the dispersion of self-assembled
lipid molecules with amphiphilic properties, resulting in a liquid crystalline phase characterized
by cubic crystallographic symmetry in an aqueous environment. The unique characteristics of
cubosomes stem from their elevated surface area, which arises from the presence of two
consecutive aqueous channels separated by a convoluted lipid bilayer. These distinctive
features enhance the ability of drugs to overcome barriers within the eye, making cubosomes a
promising platform for ocular drug delivery (Teba et al., 2021).

Niosomes
Niosomes are self-assembled vesicular structures composed of non-ionic surfactants. Their
structural makeup allows for the incorporation of drugs with diverse solubility profiles, thanks
to the presence of hydrophobic, hydrophilic, and amphiphilic groups. The inclusion of non-
ionic surfactants contributes to their chemical stability and minimal or negligible toxicity.
These qualities make niosomes well-suited for ophthalmic administration, as highlighted by
Verma et al. (2021).

Liposomes
Liposomes consist of a bilayer assembly of phospholipids and typically exhibit vesicle sizes
ranging from 0.08 to 10.00µm. These vesicles fall into three categories based on their size:
unilamellar, large unilamellar, and multi-lamellar vesicles, the latter comprising several
phospholipid bilayers. Liposomes have demonstrated high efficiency as carriers for ocular
delivery due to their ability to effectively incorporate both hydrophobic and hydrophilic
molecules. Additionally, they exhibit excellent compatibility with ocular surfaces (Sanarova et
al., 2019).

Nanoemulsions
Nanoemulsions are colloidal dispersions made up of droplets that exhibit a diameter of less
than 1µm. They enhance the therapeutic efficacy of the administered drugs while concurrently
minimizing the occurrence of adverse effects (Dhahir et al.,2021).

SNEDDS - are homogenized blends of drugs, surfactant, oil, and co-surfactant. These isotropic
mixtures spontaneously emulsify in situ upon contact with aqueous fluids, resulting in the
formation of nanoemulsions with droplet sizes less than 150nm. They act as optimal carriers to
enhance the transcorneal permeability of drugs, leading to increased bioavailability and a
sustained release pattern of the drug.
 Table 1. Patented formulations of lipid-based nano-carriers

Sr. No. Patent No. Patent Title Key points

1 US10925892B2 Lipid-based ophthalmic emulsion • Emulsion consists of a higher concentration of a mucoadhesive polymer
(galactomannan)
• Prolonged protection against dehydration and maintenance of moisture levels
2 US10272040B2 Liposomal formulation for ocular drug delivery • Liposomal formulation comprises one lipid bilayer
• Includes a methodology for treatment or prevention of an ocular condition
• Administration of liposomal formulation/pharmaceutical composition
3 US20190151236A1 Liposomal corticosteroids for topical injection in • Administration of topical injection of liposomal corticosteroids for inflammatory
inflamed lesions or areas lesions
4 US20170246175A1 Sustained timolol maleate delivery from liposomes for • Encapsulation of higher concentration of timolol maleate i.e., up to 1.5 mg/ml within
glaucoma therapy and ocular hypertension the core of liposomes through the use of ammonium sulphate gradient.
• Controlled release of timolol maleate for a duration exceeding three weeks
5 US11285148B1 Ketoconazole ophthalmic preparations containing • Composition consists of phospholipid, ethanol, an edge activator, and ketoconazole
trans-ethosomal drug nanoparticles • Modification of transethosome’s surface through a cationic charge-producing agent
• Sustained release of ketoconazole to the posterior cavity of the eye
 Table 2. Literature instances of lipid-based nanocarriers

Nanocarrier Drug Lipid Inference Reference

SLN Econazole Tripalmitic glyceride, • Prepared by microemulsion method (Liang et al., 2023)
stearylamine • Ecaonazole encapsulated cationic, anionic and nearly neutral SLNs exhibited an
average size of 18.73 ± 0.14,18.54 ± 0.10 and 19.05 ± 0.28 nm.
• SLNs exhibited increased corneal penetration, sustained release, and increased
inhibition of fungi
SLN Ciprofloxacin Compritol • Formulated through a blend of melt emulsion sonication followed by low low- (Onugwu et al., 2022)
temperature solidification method
• SLNs displayed a particle size in the range of 141-213 nm and zeta potential in the
range of +24.6-35.6 mV
• Drug release demonstrated an initial release succeeded by a sustained release for 24
hours
SLN Ofloxacin Compritol, Gelucire 44/14, • Formulated by hot homogenization followed by ultrasonication (Alhakamy et al.,
stearyl amine • Ofloxacin-loaded SLNs displayed an average particle size of 34nm, entrapment 2022)
efficiency of 82%, and zeta potential of 22mV.
• Once daily dose of an SLN dispersion resulted in extended transcorneal permeability,
improved ocular bioavailability, and reduced necessity for frequent dosing
NLCs Sorafenib Monolaurin, Capryol-90 • Formulated by spontaneous emulsion method (Luo et al., 2022)
• Sorafenib-loaded NLCs exhibited an average size of 111.87 ± 0.93nm with spherical
morphology
• NLCs demonstrated sustained release and increased ocular bioavailability
NLCs Itraconazole Stearic acid, oleic acid • Fabricated by high-speed homogenization Kumar et al., 2022)
• NLCs exhibited an average particle size of 150.67 nm, entrapment efficiency was
found to be 94.65% and cumulative drug release was 68.67%
NLCs Lactoferrin Glycerol monostearate, soy • Formulated through double emulsion/solvent evaporation method (Varela-Fernández
lecithin, compritol 888, • NLCs displayed a particle size and PDI of 119.45 ± 11.44 nm and 0.045 respectively et al., 2022)
cholesterol, miglyol 812, • In vitro drug release study revealed a controlled release trend
capryol 90
NLCs laden Timolol Capmul MCMC8 • Timolol-loaded NLCs exhibited a mean particle size of 130-138nm with a spherical (Tian et al., 2022)
contact lens structure.
• NLC laden lens were found to be safe
Nanocarrier Drug Lipid • Inference Reference
Cubosomes Vancomycin Glyceryl monooleate • Vancomycin-loaded cubosomes displayed an internal cubic structure (Kaul et al., 2022)
• Cubosomes exhibited a range of particle size from 51.11 ± 0.96 nm to
158.73 ± 0.46nm
• Cubosomes revealed increased permeability, controlled drug release pattern,
improved pre ocular residence time
Cubosomes Gatifloxacin Glycerol monooleate • Formulated gatifloxacin-loaded cubosomes displayed a particle size of about (Nasr et al., 2022)
197.46 ± 9.40 nm and entrapment efficiency was found to be 52.8%
• The cubosomal particles resulted in a fourfold decrease in minimum
inhibitory concentration value in comparison to gatifloxacin aqueous
dispersion
Cubosomes Voriconazole Glycerol monooleate • Formulated by melt dispersion emulsification method (Said et al., 2021)
• Voriconazole-loaded cubosomes exhibited a particle size of 160 nm
• In addition, the vitreous humour exhibited a higher concentration of
cubosomal nanoparticles in comparison to a drug suspension, reflecting a
greater extent of penetration into the ocular tissue
Niosomes in situ Fluconazole Cholesterol • Niosomes exhibited a particle size of 392 nm (Elmotasem et al.,
gel • Sustained release for 24 h through the in situ gel 2020)
Niosomes Azithromycin Cholesterol • Formulated through thin film hydration method (Eid et al., 2021)
• Azithromycin-loaded niosomes exhibited an average diameter of 376nm,
mucoadhesion force of 3114 dyne/cm, and surface charge of 32.1mV
• Formulated niosomes revealed a three-fold rise in azithromycin
concentration in the eyes of rabbits in comparison to azithromycin
commercial drops
Niosomes Pilocarpine Cholesterol • Prepared by ether injection method (Owodeha-Ashaka
hydrochloride- • Sonication resulted in reduced particle size, an increase in zeta potential by et al., 2021)
28% and entrapment efficiency found to increase by 61%
Liposome Thymoquinone Phosphatidylcholine, Plurol • Formulated liposomes exhibited a particle size of less than 200nm and an (Landucci et al., 2021)
oleique entrapment efficiency of about 70%
• Liposome resulted in two-fold in thymoquinone solubility
 Table 2. (Continued)

Nanocarrier Drug Lipid • Inference Reference

Liposome Sunitinib 1,2-distearoyl-sn-glycero-3- • Formulated by thin film hydration technique (Tavakoli et al., 2022)
phosphocholine, • Sunitinib-loaded liposomes exhibited a mean size of 104nm and an
1,2+-distearoyl-sn-glycero-3- entrapment efficiency of 95%
phosphoethanolamine-N- • Sustained release was observed for 3 days
[amino(polyethylene glycol)-
2000
1,2-dieoleoyl-sn-glycero-3-
phosphocholine,
1,2-distearoyl-sn-glycero-3-
phosphoglycerol.
Nano-emulsions- Acyclovir Triacetin • Formulated nanoemulsion exhibited an average droplet size of 28nm and (Mahboobian et al.,
in situ gel polydispersity index of 0.38 2020)
• A sustained release pattern was observed
• Drug permeation through nanoemulsion exhibited a 2.8-fold increase
Nano-emulsion Besifloxacin Triacetin • Formulated by low-energy emulsification method (Kassaee et al., 2022)
• Besifloxacin-loaded nanoemulsion exhibited a particle size of 14nm
• A sustained release pattern was observed
• Drug permeation through nanoemulsion exhibited a 1.7-fold increase
Nano-emulsion Dorzolamide Isopropyl myristate • Formulated through high-speed homogenization followed by ultrasonication (Kassem et al., 2022)
hydrochloride • Dorzolamide hydrochloride-loaded nanoemulsion exhibited a droplet size of
336.3nm and a zeta potential of 32.5mV
• A sustained release pattern was observed
SNEDD Brimonidine tartrate Capmul MCM • Formulated snedd exhibited a droplet size of 118.3nm and a polydispersity (Vikash et al., 2023)
index of 0.251
• Enhanced permeability coefficient(7.078±0.218×10- 6cm/s) was observed in
comparison to marketed formulation
SNEDD Voriconazole Isopropyl myristate • Voriconazole loaded snedds exhibited a droplet size 21.447±0.081nm and a (Rasoanirina et al.,
polydispersity index of 0.156 ± 0.004 2020)
• Formulation demonstrated remarkable stability
• An increase in permeability coefficient (1.982 ± 0.187×10-6cm/s) was
observed in comparison to the commercially available formulation
 Lipid Nanocarriers in Ocular Drug Delivery 139

Conclusion

Ocular disorders pose a significant risk to visual well-being and impact overall quality of life.
However, the unique anatomical structure of the eye poses a substantial challenge to effective
drug delivery. Conventional medical therapies often require frequent administrations with
limited effectiveness, leading to incomplete patient satisfaction. The integration of
nanotechnology in ocular research has shown great promise due to its ability to enhance the
solubility and bioavailability of drugs with low water solubility. In this study, various
nanocarriers were employed, encompassing different morphologies such as liposomes, SLNs,
cubosomes, niosomes, NLCs, and SNEDDS. Particularly, lipid-based nanocarriers demonstrate
a promising approach for ensuring efficient drug delivery to the eye. Alongside improved
solubilization, these nanosized delivery systems enhance permeability, stability, site-specific
delivery, and reduce toxicity. Moreover, these approaches benefit patients by reducing the need
for frequent drug administration.

References

Agban, Y., Thakur, S. S., Mugisho, O. O., Rupenthal, I. D. (2019). Depot formulations to sustain periocular
drug delivery to the posterior eye segment. Drug discovery today, 24(8), 1458-1469.
Ahmed, S., Amin, M. M., El-Korany, S. M., Sayed, S. (2022). Corneal targeted fenticonazole nitrate-loaded
novasomes for the management of ocular candidiasis: preparation, in vitro characterization, ex vivo and
in vivo assessments. Drug Delivery, 29(1), 2428-2441.
Alhakamy, N. A., Hosny, K. M., Aldryhim, A. Y., Rizg, W. Y., Eshmawi, B. A., Bukhary, H. A., Khallaf, R.
A. (2022). Development and optimization of ofloxacin as solid lipid nanoparticles for enhancement of its
ocular activity. Journal of Drug Delivery Science and Technology, 72, 103373.
Alpay, A., Güney, T. (2021). Evaluating the effectiveness of localized sub-Tenon’s anesthesia in 23-gauge
vitreoretinal surgery. International Ophthalmology, 41 ,195-201.
Battaglia, L., Gallarate, M., Serpe, L., Foglietta, F., Muntoni, E., del Pozo Rodriguez, A., Aspiazu, M. A. S.
(2018). Ocular delivery of solid lipid nanoparticles. Lipid Nanocarriers for Drug Targeting, 269-312.
Battaglia, L., Gallarate, M., Serpe, L., Foglietta, F., Muntoni, E., Del Pozo Rodriguez, A., Aspiazu, M. A. S.
(2018). Ocular delivery of solid lipid nanoparticles. Lipid Nanocarriers for Drug Targeting, 269-312.
Das Neves, J., Arzi, R. S., Sosnik, A. (2020). Molecular and cellular cues governing nanomaterial–mucosae
interactions: from nanomedicine to nanotoxicology. Chemical Society Reviews, 49(14), 5058-5100.
Das Neves, J., Arzi, R. S., Sosnik, A. (2020). Molecular and cellular cues governing nanomaterial–mucosae
interactions: from nanomedicine to nanotoxicology. Chemical Society Reviews, 49(14), 5058-5100.
Das, B., Nayak, A. K., Mallick, S. (2022). Lipid-based nanocarriers for ocular drug delivery: An updated
review. Journal of Drug Delivery Science and Technology, 76, 103780.
Dhahir, R. K., Al-Nima, A. M., Fadia, A. B. (2021). Nanoemulsions as ophthalmic drug delivery systems.
Turkish Journal of Pharmaceutical Sciences, 18(5), 652-664.
Dosmar, E., Walsh, J., Doyel, M., Bussett, K., Oladipupo, A., Amer, S., Goebel, K. (2022). Targeting ocular
drug delivery: an examination of local anatomy and current approaches. Bioengineering, 9(1), 41.
Downie, L. E., Bandlitz, S., Bergmanson, J. P., Craig, J. P., Dutta, D., Maldonado-Codina, C., Wolffsohn, J. S.
(2021). BCLA CLEAR-Anatomy and physiology of the anterior eye. Contact Lens and Anterior Eye,
44(2), 132-156.
Duan, Y., Dhar, A., Patel, C., Khimani, M., Neogi, S., Sharma, P., Vekariya, R. L. (2020). A brief review on
solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. RSC advances, 10(45),
26777-26791.
140 Hiti, Varneet Sandhu, Sonia Dhiman et al.

Eid, H. M., Naguib, I. A., Alsantali, R. I., Alsalahat, I., Hegazy, A. M. (2021). Novel chitosan-coated niosomal
formulation for improved management of bacterial conjunctivitis: a highly permeable and efficient ocular
nanocarrier for azithromycin. Journal of Pharmaceutical Sciences, 110(8), 3027-3036.
Elmotasem, H., Awad, G. E. (2020). A stepwise optimization strategy to formulate in situ gelling formulations
comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit
nanoparticles for enhanced antifungal activity and prolonged ocular delivery. Asian journal of
pharmaceutical sciences, 15(5), 617-636.
Gautam, M., Gupta, R., Singh, P., Verma, V., Verma, S., Mittal, P., Sharma, B. (2023). Intracameral Drug
Delivery: A Review of Agents, Indications, and Outcomes. Journal of Ocular Pharmacology and
Therapeutics, 39(2), 102-116.
Giri, S., Badwaik, H., Giri, T. K. (2023). Breaking the ocular barrier through nano-lipid carriers to treat
intraocular diseases. Journal of Drug Delivery Science and Technology,87, 104867.
Han, H., Li, S., Xu, M., Zhong, Y., Fan, W., Xu, J., Yao, K. (2023). Polymer-and lipid-based nanocarriers for
ocular drug delivery: Current status and future perspectives. Advanced Drug Delivery Reviews, 196,
114770.
Invernizzi, A., Pellegrini, M., Cornish, E., Teo, K. Y. C., Cereda, M., Chabblani, J. (2020). Imaging the choroid:
from indocyanine green angiography to optical coherence tomography angiography. The Asia-Pacific
Journal of Ophthalmology, 9(4), 335-348.
Kassaee, S. N., Mahboobian, M. M. (2022). Besifloxacin-loaded ocular nanoemulsions: Design, formulation
and efficacy evaluation. Drug Delivery and Translational Research, 1-11.
Kassem, A. A., Salama, A., Mohsen, A. M. (2022). Formulation and optimization of cationic nanoemulsions
for enhanced ocular delivery of dorzolamide hydrochloride using Box-Behnken design: In vitro and in
vivo assessments. Journal of Drug Delivery Science and Technology, 68, 103047.
Kaul, S., Nagaich, U., Verma, N. (2022). Preclinical assessment of nanostructured liquid crystalline particles
for the management of bacterial keratitis: in vivo and pharmacokinetics study. Drug Delivery and
Translational Research, 1-19.
Kim, H. M., Woo, S. J. (2021). Ocular drug delivery to the retina: current innovations and future perspectives.
Pharmaceutics, 13(1), 108.
Kumar, M., Tiwari, A., Asdaq, S. M. B., Nair, A. B., Bhatt, S., Shinu, P., Sreeharsha, N. (2022). Itraconazole
loaded nano-structured lipid carrier for topical ocular delivery: Optimization and evaluation. Saudi
Journal of Biological Sciences, 29(1), 1-10.
Landucci, E., Bonomolo, F., De Stefani, C., Mazzantini, C., Pellegrini-Giampietro, D. E., Bilia, A. R.,
Bergonzi, M. C. (2021). Preparation of liposomal formulations for ocular delivery of thymoquinone: in
vitro evaluation in HCEC-2 e HConEC cells. Pharmaceutics, 13(12), 2093.
Liang, Z., Zhang, Z., Lu, P., Yang, J., Han, L., Liu, S., Zhang, J. (2023). The effect of charges on the corneal
penetration of solid lipid nanoparticles loaded econazole after topical administration in rabbits. European
Journal of Pharmaceutical Sciences, 187, 106494.
Luo, Q., Yang, J., Xu, H., Shi, J., Liang, Z., Zhang, R., Zhang, J. (2022). Sorafenib-loaded nanostructured lipid
carriers for topical ocular therapy of corneal neovascularization: development, in-vitro and in vivo study.
Drug Delivery, 29(1), 837-855.
Mahboobian, M. M., Mohammadi, M., Mansouri, Z. (2020). Development of thermosensitive in situ gel
nanoemulsions for ocular delivery of acyclovir. Journal of Drug Delivery Science and Technology, 55,
101400.
Mishra, D., Gade, S., Glover, K., Sheshala, R., Singh, T. R. R. (2023). Vitreous humor: composition,
characteristics and implication on intravitreal drug delivery. Current Eye Research, 48(2), 208-218.
Nasr, M., Saber, S., Bazeed, A. Y., Ramadan, H. A., Ebada, A., Ciorba, A. L., Elagamy, H. I. (2022).
Advantages of cubosomal formulation for gatifloxacin delivery in the treatment of bacterial keratitis: in
vitro and in vivo approach using clinical isolate of methicillin-resistant Staphylococcus aureus. Materials,
15(9), 3374.
Onugwu, A. L., Attama, A. A., Nnamani, P. O., Onugwu, S. O., Onuigbo, E. B., Khutoryanskiy, V. V. (2022).
Development and optimization of solid lipid nanoparticles coated with chitosan and poly (2-ethyl-2-
oxazoline) for ocular drug delivery of ciprofloxacin. Journal of Drug Delivery Science and Technology,
74, 103527.
 Lipid Nanocarriers in Ocular Drug Delivery 141

Owodeha-Ashaka, K., Ilomuanya, M. O., Iyire, A. (2021). Evaluation of sonication on stability-indicating

properties of optimized pilocarpine hydrochloride-loaded niosomes in ocular drug delivery. Progress in
Biomaterials, 10, 207-220.
Pflugfelder, S. C., Stern, M. E. (2020). Biological functions of tear film. Experimental Eye Research, 197,
108115.
Qi, Q., Wei, Y., Zhang, X., Guan, J., Mao, S. (2023). Challenges and strategies for ocular posterior diseases
therapy via non-invasive advanced drug delivery. Journal of Controlled Release, 361, 191-211.
Rasoanirina, B. N. V., Lassoued, M. A., Kamoun, A., Bahloul, B., Miladi, K., Sfar, S. (2020). Voriconazole-
loaded self-nanoemulsifying drug delivery system (SNEDDS) to improve transcorneal permeability.
Pharmaceutical Development and Technology, 25(6), 694-703.
Ross, M., Sheardown, L., Muirhead, B., Mofford, J., Tian, J., Sheardown, H. (2023). Mucoadhesive thermogel
platform for treating anterior ocular conditions. Journal of Biomedical Materials Research Part A, 111(9),
1390-1405.
Said, M., Aboelwafa, A. A., Elshafeey, A. H., Elsayed, I. (2021). Central composite optimization of ocular
mucoadhesive cubosomes for enhanced bioavailability and controlled delivery of voriconazole. Journal
of Drug Delivery Science and Technology, 61, 102075.
Sanarova, E., Lantsova, A., Oborotova, N., Orlova, O., Polozkova, A., Dmitrieva, M., Nikolaeva, N. (2019).
Liposome drug delivery. Journal of Pharmaceutical Sciences and Research, 11(3), 1148-1155.
Sanyal, S., Ravula, V. (2023). Mitigation of pesticide-mediated ocular toxicity via nanotechnology-based
contact lenses: a review. Environmental Science and Pollution Research, 1-23.
Sawant, K. K., Dodiya, S. S. (2008). Recent advances and patents on solid lipid nanoparticles. Recent Patents
on Drug Delivery & Formulation, 2(2), 120-135.
Sharma, Y., Patel, P., Kurmi, B. D. (2023). A Mini-review on New Developments in Nanocarriers and
Polymers for Ophthalmic Drug Delivery Strategies. Current Drug Delivery, 21, 488-508.
Singh, A., Dogra, T. S., Mandal, U. K., Narang, R. K. (2019). Novel approaches for ocular drug delivery: a
review. International Journal of Bio-Pharma Research, 8(7), 2722-2732.
Tavakoli, S., Puranen, J., Bahrpeyma, S., Lautala, V. E., Karumo, S., Lajunen, T., Urtti, A. (2022). Liposomal
sunitinib for ocular drug delivery: A potential treatment for choroidal neovascularization. International
Journal of Pharmaceutics, 620, 121725.
Teba, H. E., Khalil, I. A., El Sorogy, H. M. (2021). Novel cubosome based system for ocular delivery of
acetazolamide. Drug Delivery, 28(1), 2177-2186.
Tian, C., Zeng, L., Tang, L., Yu, J., Ren, M. (2021). RETRACTED ARTICLE: Sustained Delivery of Timolol
Using Nanostructured Lipid Carriers-Laden Soft Contact Lenses. AAPS PharmSciTech, 22(6), 212.
Varela-Fernández, R., García-Otero, X., Díaz-Tomé, V., Regueiro, U., López-López, M., González-Barcia, M.,
Otero-Espinar, F. J. (2022). Lactoferrin-loaded nanostructured lipid carriers (NLCs) as a new formulation
for optimized ocular drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 172, 144-
156.
Vashist, P., Senjam, S. S., Gupta, V., Gupta, N., Shamanna, B. R., Wadhwani, M., Bharadwaj, A. (2022).
Blindness and visual impairment and their causes in India: Results of a nationally representative survey.
PLoS One, 17(7), e0271736.
Verma, A., Tiwari, A., Saraf, S., Panda, P. K., Jain, A., Jain, S. K. (2021). Emerging potential of niosomes in
ocular delivery. Expert opinion on drug delivery, 18(1), 55-71.
Vikash, B., Pandey, N. K., Kumar, B., Wadhwa, S., Goutam, U., Alam, A., Singh, S. K. (2023). Formulation
and evaluation of ocular self-nanoemulsifying drug delivery system of brimonidine tartrate. Journal of
Drug Delivery Science and Technology, 81, 104226.
Yu, J., Yin, Y., Leng, Y., Zhang, J., Wang, C., Chen, Y., Fan, Y. (2023). Emerging strategies of engineering
retinal organoids and organoid-on-a-chip in modeling intraocular drug delivery: current progress and
future perspectives. Advanced Drug Delivery Reviews, 114842.
Chapter 10

Therapeutic Valuation and Challenges of Lipid

Nanocarriers in Oral Drug Delivery System

Manisha Bhatti
and Jasneek Kaur Kaloti
University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali

Abstract

Drugs with low solubility result in lower oral bioavailability and decreased metabolic
stability in the digestive system. To overcome the poor bioavailability of drugs, lipid-based
nanocarrier formulations have garnered significant interest. These types of drugs exhibit
lower toxicity, high drug-loading efficiency, and cost-effective manufacturing scale-ups.
Additionally, lipid-based nanocarriers can enhance drug permeability, solubility, and
stability. However, challenges persist in the oral drug delivery system, such as enzymatic
degradation and the acidic environment of the stomach. Lipid-based nanocarriers also
facilitate targeted drug delivery, improving the mucosal adherence properties of drugs and
widening the pharmacokinetic profile for their use. Moreover, the biodegradable nature of
lipid-based formulations enhances the safety of these drugs. This chapter specifically
addresses the primary difficulties associated with orally administered drugs, emphasizing
the approaches employed by lipid nanocarriers to mitigate these challenges and enhance
their therapeutic value.

Keywords: lipid-based nanocarriers, oral drug delivery, bioavailability, solid lipid particles,
emulsions

Abbreviations

SLN Solid Lipid Nanoparticles,

NLC Nanostructured Lipid Carriers
NLBC Nano Lipid-Based Carriers
SMEDDS Self Micro Emulsifying Drug Delivery Systems
SNEDDS Self Nano Emulsifying Drug Delivery Systems
SEDDS Self Emulsifying Drug Delivery Systems
LPHN Lipid Polymer Hybrid Nanoparticles
IBD Inflammatory Bowel Disease


Corresponding Author’s Email: [Link]@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
144 Manisha Bhatti and Jasneek Kaur Kaloti

Introduction

The most prevalent route of medication delivery is the oral route, as it avoids the negative
effects associated with intravenous administration, such as drug or blood extravasations,
catheter infections, and thrombosis. Advances in drug design have resulted in a wide variety of
molecules with significant therapeutic uses. However, many newly discovered entities face
challenges, including poor solubility, low dissolution, low absorption, high molecular weight,
and high membrane permeability. These challenges contribute to poor oral bioavailability, lack
of dosage proportionality, and considerable inter- and intra-subject variability in formulations.
Various measures to address solubility and permeability issues have been reported (Niu et al.,
2016). Lipid-based nanocarriers represent a significant and highly promising method for
overcoming restrictions related to the partition coefficient, drug solubility, and the
bioavailability or absorption of drugs, among various physicochemical properties.
Additionally, this approach meets a range of product criteria and helps overcome limitations
imposed by disease symptoms, diverse drug administration methods, pricing concerns,
increasing product potency, harmful or adverse effects of drugs, and dose efficacy. A
commercially viable method for creating various dosage forms intended for oral, ophthalmic,
pulmonary, transdermal or topical and parenteral administration is the lipid nano system, which
also formulates aqueous drugs in lipid bases (Feeney et al., 2016; Plaza-Oliver et al., 2021).
The distribution of clinically active biological molecules via nanocarriers holds enormous
promise for the treatment of various illnesses. Due to its intriguing characteristics that could
aid in achieving the goal of site-specific and controlled drug delivery, solid lipid nanoparticles
(SLN) have garnered the interest of numerous researchers. There has been a surge in fascination
with medicinal peptides and proteins in the last 20 years due to their ability to modulate the
immune system through either additive or antigenic characteristics, providing them with a
distinct advantage over small chemicals. However, therapeutic peptides, having a limited half-
life in physiological fluids, are often administered parenterally and require regular dosages
(Calderon‐Colon et al., 2023). Due to their ease of passage through membranes and the
phenomenon of prolonged circulation duration in the reticuloendothelial system,
nanomedicines hold excellent potential in the field of theranostics for treating various diseases.
Nano lipid-based carriers (NLBCs) offer advantages over traditional targeting for therapeutic
administration, including improved biocompatibility, inherent penetrating capacity, simple
production, and non-toxicity. With advancements in nanotechnology, it is now possible to
administer therapeutic peptides and proteins via selected routes, which is of significant
importance in treating a range of illnesses. NLBCs provide several benefits, including drug
protection, increased oral bioavailability, reduced dosage requirements, improved treatment,
and flexibility in surface modification. They can transport both hydrophobic and hydrophilic
medications in a controlled and regulated manner, offering therapeutic advantages. Various
types of NLBCs, such as niosomes, liposomes, nanostructured lipid carriers (NLCs), lipid
polymer hybrid nanoparticles (LPHNs), and solid lipid nanoparticles (SLNs), are employed in
different disease theranostics. Examples of lipid-based nanocarriers include nanocapsules, self-
nano and micro-emulsifying drug delivery systems, nanoemulsions, and liposomes. Several
vitamins cannot be effectively absorbed orally due to the chemical composition and enzymes
of the gastrointestinal (GI) membrane. Various antioxidant drugs also face low permeability,
influenced by the GI epithelium. Lipophilic vitamins, dissolving poorly in the gastrointestinal
 Therapeutic Valuation and Challenges of Lipid Nanocarriers … 145

system, experience limited bioavailability. Nanomedicine holds the potential to enhance the
oral delivery efficacy of vitamins. For instance, lipid nanocarriers can provide improved
solubility, chemical stability, half-life, targeted delivery, epithelial permeability, and overall
bioavailability. This approach may also result in fewer side effects for specific orally taken
vitamins. The use of non-toxic excipients and innovative lipid nanosystem component
engineering, allowing control over the physicochemical properties of nanocarriers, facilitates
enhanced gastrointestinal absorption through lymphatic or mucosal transport. Furthermore,
similar lipid nanocarriers employed for vitamins can efficiently deliver derivatives of vitamins,
thereby increasing the oral bioavailability of the latter (Hsu et al., 2019). While orally consumed
formulations are preferable and can enhance patient compliance, achieving adequate drug
stability and absorption through this method remains challenging. The U.S. Food and Drug
Administration’s broadly accepted as safe (GRAS) surfactants and lipids can be utilized in their
creation, and they have been demonstrated to be suitable for delivering a variety of chemically
active substances in an organized manner. Lipid nanocarriers filled with medication have the
ability to accumulate in the lymphatic system and transcellularly permeate epithelial barriers,
thereby enhancing the oral bioavailability of encapsulated medicines. Various factors,
including the characteristics of the medication, the physical attributes of the particles, and the
synthetic composition of the particles, ultimately determine the clinical efficacy of therapeutic
nano formulations. Polymer nanocarriers exhibit low cytotoxicity, while the components of
Solid Lipid Nanoparticles (SLNs) are recognized as safe (GRAS) and well-tolerated
mechanically, significantly reducing toxicity. Due to its relatively low toxicity, SLN can be
administered through various routes, including parenterally, topically, orally, and in the lungs.
However, a lack of fundamental understanding regarding the effects of synthesis processes and
formulation factors on drug cargo release, targeting, and bioavailability contributes to the poor
clinical translation of these nanocarriers (Calderon‐Colon et al., 2023). Any lipid nanocarrier
can have its formulation modified to meet the requirements and restrictions of oral
administration. The majority of the fats and oils present in these formulations are derived from
food-based lipids, promoting oral penetration and biodegradable properties (Plaza-Oliver et al.,
2021). Lipid-based drug delivery systems are developed using additives like glyceride blends,
triglyceride oils, hydrophilic and lipophilic surfactants, and aqueous co-solvents. These
systems enhance absorption from the gastrointestinal tract (GIT) while protecting the absorbed
medicine by expediting a breakdown process. This is facilitated by smaller molecules, which
provide a solid-state arrangement within the carrier system and modify the way medications
are absorbed (Nabi et al., 2019). Moreover, nanoformulations can enhance enterocyte
permeability, thereby boosting absorption. It has been demonstrated that nanocarriers create a
barrier to maintain stability in the gastrointestinal (GI) tract, allowing for dosage reduction. The
characteristics of a nanocarrier’s surface influence and regulate both release and absorption
rates. Additionally, nanocarriers can transport a diverse range of materials, including
antioxidants, smaller molecular medicines, proteins, RNAs, vitamins, minerals, and peptides.
Lipid-based nanocarriers prove useful in the oral administration of bioactive compounds to
address the low water solubility of active medicines. Furthermore, lipid excipients, such as
surfactants or emulsifiers, can enhance bioavailability. The primary challenge with orally
delivering hydrophobic drugs is that many potential medications exhibit poor solubility in
water, limited bioavailability, and sensitivity to stomach acid, rendering them unsuitable for
this mode of administration. This indicates that even if they are pharmacologically efficacious,
hydrophobic drugs are either not absorbed in sufficient amounts to be effective or end up being
146 Manisha Bhatti and Jasneek Kaur Kaloti

inactivated by stomach acid. This is due to the high-water content in the gastrointestinal tract,
hindering these substances’ ability to diffuse and be absorbed by the intestinal wall. To address
this challenge, alternatives for hydrophobic drug delivery have been developed using
nanostructured lipid carriers (NLCs). In these systems, the target medication is distributed as
nanometric droplets within a hydrophilic matrix. These carriers offer various pharmacological
administration forms, including topical, oral, parenteral, and even ocular formulations. It has
been demonstrated that these systems both enhance drug absorption and provide protection
from enzyme metabolism (Senna et al., 2018).

Types of Nanocarriers

Liposomes

Liposomes are spherical, mono- or multilamellar vesicles containing phospholipids derived

from either animal or plant sources. Initially referred to as smectic mesophase, liposomes were
first discovered by AD Bangham, and the second discovery was attributed to Allison and
Gregoriad. The spherical vesicles known as liposomes consist of bilayer lipids. Due to their
unique structure, they can encapsulate hydrophilic medications within the lipid bilayer,
protecting pharmaceuticals from degradation in the watery core. The primary structural
elements of liposomes, phospholipids, are amphiphilic in nature. Liposomes support the
pharmacokinetics of loaded pharmaceuticals, offering benefits such as enhanced loading
efficiency, increased biological stability, controlled release of medication, and biologically
compatible formulations. These amphiphilic lipids dissolve in aqueous media, and beyond a
specific concentration, liposomes aggregate due to an increase in process entropy. Early
descriptions of liposomes indicated a lack of surface modifications; however, over time,
changes in lipid content were introduced to provide liposomes with different stiffness, sizes,
and other characteristics. Despite their advantages, liposomes, like other transporter systems,
have several drawbacks. When developing a formulation to enhance the therapeutic efficacy of
a medicine, factors such as development costs and other attentions must be taken into account
(Jain et al., 2021). Liposomes are potential carrier systems composed of cholesterol and
phospholipids. Resembling biological membranes, liposomes offer numerous advantages,
including high biocompatibility, biodegradability, the ability to entrap drugs with adjustable
release rates, and the capacity to carry both lipophilic and hydrophilic payloads. Additionally,
liposomes can be produced at a commercial scale. Pro-liposomal systems, in the form of
fluidless powders, transform into liposomes upon contact with human fluids after oral
administration. Enriching these systems with bile salts can neutralize physiological bile acids
in the gastrointestinal (GI) tract, potentially promoting the transformation of vesicles into mixed
micelles. The mesophases resulting from this process serve as excellent carriers for
hydrophobic medicinal compounds (Babadi et al., 2021).
 Therapeutic Valuation and Challenges of Lipid Nanocarriers … 147

Solid Lipid Nanoparticles

Submicrometer-sized solid lipid nanoparticles (SLNs), delivered in an aqueous surfactant

solution, possess the capability to provide a stable product for both hydrophilic and lipophilic
pharmaceuticals. This is attributed to their composition of biologically compatible and
biodegradable bulk lipids. Due to their flexibility, high drug loading efficiency, potential for
personalized response, and increased bioavailability, SLNs have been extensively explored for
therapeutic drug administration. Research and development of SLNs have been significant,
considering their applicability in various delivery methods, including cutaneous, parenteral,
ocular, and rectal routes (Soppimath et al., 2001).

Nanostructured Lipid Carriers

The subsequent generations of innovative transporter systems, identified as Nanostructured

Lipid Carriers (NLCs), are composed of both liquid and solid lipids. Unlike the original
generation of lipid nanoparticles known as solid lipid nanoparticles (SLNs), NLCs address
issues related to storage stability and reduced drug encapsulation. Regulatory agencies permit
the use of surfactants in various medicine delivery systems, and NLCs, being composed of both
liquid and solid lipids that are biologically compatible and biodegradable, fall within this
category. NLCs offer significant advantages, including enhanced drug transfer capacity,
improved delivery mechanisms for drugs across various routes, the ability to regulate
medication release, potential as future pharmaceutical carriers, and the need for fewer or no
surfactants. Typically, NLCs have sizes ranging from 10 to 1000 nm (Ranpise et al., 2014).

Nano Emulsion

A nanoemulsion typically has a droplet diameter ranging between 50 and 500 nm, classifying
it as an oil-in-water (o/w) emulsion. The term “nanoemulsion” refers to the dispersion of water
and oil, two immiscible liquids, combining to create a system that is isotropically transparent
and thermodynamically stable. It must also include an inner core that is either a water-in-oil
(w/o) or oil-in-water (o/w) emulsion of water or oil. The components of nanoemulsions usually
consist of FDA-approved surfactants, recognized as Generally Recognized as Safe (GRAS).
Nanoemulsions, with their extensive surface area, are favored for use in various routes and are
consequently employed for efficient drug administration throughout the body. They are stable
and have the ability to dissolve more lipophilic drugs, along with specific vectors that prevent
their hydrolysis and enzyme destruction. Nanoscale droplets exhibit various remarkable
physical characteristics, including unusual elastic behavior and optical transparency (Jaiswal et
al., 2015). Nanoemulsions are prepared using oil and aqueous phases, along with drugs,
surfactants/co-surfactants, and additives. The stability of the formulation and the performance
of these components are significantly influenced by their physical and chemical properties.
When selecting a surfactant, both the hydrophilic-lipophilic balance (HLB) and crucial factors
must be considered. Surfactants with higher HLB (8–18) are utilized to produce nanoemulsions,
while those with lower HLB (3–6) can be employed to prepare solutions without
148 Manisha Bhatti and Jasneek Kaur Kaloti

nanoemulsions. A stable nanoemulsion is achieved by combining high and low HLB

surfactants in the appropriate proportion. Hybrid nanoemulsions, created by employing both
low- and high-energy emulsifying techniques, are particularly favored as drug delivery systems
due to their ability to dissolve drugs in the oil core without premature leaking. The interactions
between lipid droplets on delivery pathways further illustrate their potential applications,
including oral, transdermal, cancer prevention, and vaccine medication administration.
Nanoemulsions enable effective local and systemic targeting (Jaiswal et al., 2015).

SMEDDS, SEDDS, and SNEDDS

Various methods can be employed to increase the oral bioavailability of insufficiently soluble
medicines. The oral route of delivery is a primary choice for the long-term treatment of many
disorders due to its high level of patient tolerance. However, approximately 50% of medicines
are often hindered from oral administration because of their high lipophilicity. The use of
different carrier systems constructed from lipids, such as the self-nanoemulsifying drug
delivery system (SNEDDS), the self-microemulsifying drug delivery system (SMEDDS), and
the self-emulsifying drug delivery system (SEDDS), is considered one of the most promising
ways to enhance the bioavailability of drugs that are poorly soluble in the lipophilic phase.
SMEDDS, in particular, exhibits a distinctive characteristic. It is characterized as an isotropic
formulation of ultrafine micro-emulsion, typically oil-in-water (o/w) type, composed of
surfactants, lipids, and drug complexes. When subjected to moderate agitation in aqueous
media, SMEDDS forms a stable and finely dispersed micro-emulsion. Researchers have a
particular interest in systems like SNEDDS, SMEDDS, and SEDDS because of their potential
for drug delivery by incorporating various drug molecules inside the carrier. These systems
play a crucial role in enhancing oral bioavailability. SMEDDS, for instance, creates transparent
microemulsions with surfactant concentrations ranging from more than 12 to less than 50 nm
of oil. SEDDS have been utilized to improve medication absorption when administered orally,
rapidly producing fine droplets of oil-in-water emulsions or microemulsions when diluted in
water. They exhibit rapid distribution across the entire gastrointestinal tract (GIT) due to their
formulation and provide agitation for emulsification, influencing motility in the stomach and
small intestine. SEDDS typically consist of a mixture of oil, surfactant, and other constituents
along with medications. The lipid and surfactant are chosen in their optimal ratio for the
formulation’s best self-emulsifying characteristic. Moreover, the emulsifying qualities of
surfactant blending have been shown to be superior compared to using a single surfactant with
a specific hydrophilic-lipophilic balance (HLB), an essential component of the emulsification
process. SNEDDS is crucial for oral absorption during the formulation of medium-chain
glyceride oils and non-ionic surfactants. SNEDDS, stable nanoemulsions, provide a substantial
interfacial area between the aqueous and oil phases, accelerating medication absorption and
enhancing the bioavailability of medicinal formulations. In commerce, these formulations are
often added to gelatin capsules (soft or hard) or hydroxypropylmethyl cellulose capsules,
providing patient compliance. The volume should be no more than 1 g when manufacturing
liquid soft gelatin capsules (Maurya et al., 2017). Several instances of lipid nanocarrier’s
medicinal values with enhanced drug effects are given in Table 1.
 Table 1. A few examples of therapeutic valuation of lipid nanocarriers with improved drug effect

Lipid nanocarriers Drug Therapeutic effect Reference

Liposomes Doxorubicin Greater anti-proliferative efficacy was observed in targeted SA-5Dox-LP (Naik et al., 2021)
Liposomes Insulin Improved Bioavailability was observed upon oral administration of insulin-containing liposomes. (Agrawal et al., 2016)
SLN Paclitaxel A lowered nonspecific toxicity was observed in rats and also increase in bioavailability via oral administration (Pooja et al., 2016)
by 3.9-fold was seen.
SLN Doxorubicin An improvement in bioavailability via oral administration and mucodiffusion by 7.5 times was seen in rats. (Yuan et al., 2013)
SLN Thymoquinone The PK findings showed an improvement in bioavailability via oral route by 6 times. (Babadi et al., 2021)
SLN Thymoquinone Significantly decreased the levels of the enzymes (SGOT, SGPT, and ALP) in liver cirrhosis caused by paracetamol (Babadi et al., 2021)
when compared to control and commercial formulations.
SLN Diacerein Boosted drug oral bioavailability by 2.7-fold and minimise the diarrhoeal side effect by up to 37%. (Babadi et al., 2021)
Nano emulsion Curcumin Showed a 7.3-fold increase in bioavailability. (Wan et al., 2016)
Nano emulsion Dabigatran Increased Solubility by 22.7 and 21.1 times, respectively, in phosphate and water buffer (pH 6.8). (Babadi et al., 2021)
Etexilate Also showed increased oral bioavailability by 6.1 times.
Nano capsule Captopril Showed renal function preservation and a sustained antihypertensive impact. (Michalowski et ak.,
2020)
SEDDS, SMEDDS Valsartan Showed 4.1 and 4.7-fold higher digestive tract permeability and bioavailability through the oral route as compared (Goo et al., 2020)
to free drug in rats.
150 Manisha Bhatti and Jasneek Kaur Kaloti

Methods for Preparation

Hot Homogenization Method

Once the medication-containing lipid has melted to a temperature that is roughly 50°C above
its melting point, it is dispersed in an aqueous surfactant solution at the same temperature. At
that point, the drug is dissolved or solubilized in the melted lipid. The resulting pre-emulsion
is then passed through a homogenizer at high pressure. This process produces a heated oil-and-
water emulsion, which, upon cooling, causes the lipid to crystallize, forming a solid lipid
nanocarrier (Basha et al., 2021).

Cold Homogenization Method

The drug is added in the initial phase, which includes melting the lipid and cooling the mixture
until it solidifies. The solid is then pulverized in a mortar mill, and the resulting lipid
microparticles are distributed at ambient temperature or, in certain instances, below room
temperature in a cold surfactant configuration. The drug’s incorporation into the water phase is
mimicked by the solid-state of the matrix. Over-heat homogenization is excellent because the
trapping efficiency remains unchanged when the aqueous solid lipid dispersion is stored
(Pragati et al., 2009).

Solvent Evaporation Method

The emulsion and evaporation processes are combined in the production of Solid Lipid
Nanoparticles (SLNs). An organic solvent, immiscible in water and emulsified in an aqueous
phase, dissolves the main lipophilic components. The precipitation of the lipid in the water-
based solution causes the solvent to evaporate, resulting in the formation of nanocarriers. High-
pressure homogenization was employed to emulsify the solution in an aqueous phase.
Subsequently, the organic solvent in the emulsion was extracted through evaporation at low
pressure (about 40–60 bar) (Chen et al., 2001).

Double Emulsion Method

This technique is utilized in the production of SLNs and is based on the incorporation of an
evaporation method for loading hydrophilic medicines. It also relies on solvent emulsification.
This approach prevents drug separation from occurring in the external aqueous phase following
the evaporation of the solvent by encapsulating the hydrophilic medication within the internal
water phase of the water-in-oil-in-water (w/o/w) double emulsion, along with a stabilizing
agent. This method is employed in the manufacturing of SLNs containing sodium cromoglycate
(Liu et al., 2007).
 Therapeutic Valuation and Challenges of Lipid Nanocarriers … 151

Solvent Injection Method

The basic principles of the solvent injection technique are similar to those of the solvent
diffusion method, and it is employed in the creation of Solid Lipid Nanoparticles (SLNs). With
the solvent injection technique, lipids are rapidly injected by a needle into a solution consisting
of surfactants after being dissolved in a water-miscible solvent or a water-miscible solvent
combination. Currently, the medication and lipid are dissolved in a water-miscible organic
solvent. The resulting mixture is then introduced into water using a syringe needle while being
stirred, causing the lipid to precipitate, and simultaneously encapsulating the drug (Das et al.,
2011).

Improvement of the Gastrointestinal Stability

Adding hydrophilic polymers, such as PEG, to the surface of lipid-based nanocarriers is a

common strategy employed to enhance their gastrointestinal stability. Steric stabilization
provided by polymer chains can counteract electrostatic instability, while the hydrophilic
surface may increase stability by reinforcing hydration forces. Additionally, it may help prevent
enzymes and other molecules with surface activity from adhering to the nanocarriers. The
composition of a lipid-based nanocarrier is believed to determine the nature and extent of its
interaction with digestive enzymes, influencing favorable effects like solubilization or
unfavorable effects like precipitation on the oral bioavailability of cargo payloads.
Furthermore, the enzymatic corona formed due to enzymes adhering to the nanocarriers’
surface may impact the particles’ behavior as they diffuse mucosally (Plaza-Oliver et al., 2021).

Drug Incorporation

Utilizing the cold homogenization approach and incorporating highly lipophilic medicinal
products into SLNs using the hot homogenization method are considered the primary methods
to generate a homogeneous substrate containing a drug that is molecularly dispersed or present
in amorphous aggregates. During the cold homogenization process, high-pressure
homogenization essentially breaks down the dissolved drug into a molecularly distributed state
throughout the entire lipid matrix. In the hot homogenization process, cooling and
crystallization of the oil droplet occur. If phase separation occurs during the cooling process, a
medicament-enriched exterior shell may emerge from the oil droplet to form a solid lipid-based
nanocarrier. Furthermore, as the core of lipids forms, the percentage of the active ingredient in
the lipid solution steadily increases. Eventually, the compound-enriched envelope develops,
and this framework is believed to provide rapid release, which is highly desirable in various
scenarios involving SLNs (Akanda et al., 2023).
152 Manisha Bhatti and Jasneek Kaur Kaloti

Challenges During Oral Delivery of Lipid Nanocarriers

Harsh Gastric Environment of the Stomach and Abundant Enzymes in the Intestine
The physical and chemical stability of nanocarriers is initially assessed across a wide pH
gradient. The stomach presents a more acidic environment (pH 1-2.5), while the colon has a
pH of 7-8 (Homayun et al., 2019). Moreover, variations in the salt and electrolyte content of
gastrointestinal fluids can negatively impact the surface charge of nanocarriers. Consequently,
such variations may induce instability, leading to aggregation in gastrointestinal fluids.
Secondly, the stability of nanocarriers may be compromised by gastrointestinal enzymes such
as pepsin or gelatinase. The duodenum, with its higher enzymatic load due to abundant
pancreatic and bile secretions containing amylases, lipases, and peptidases, is particularly
significant in this regard. Additionally, the long-chain fatty acids present in the carriers’ lipids
can form insoluble salts with cationic ions like Ca2+ or Mg2+, causing them to be removed
and allowing lipases to break them down (Jantratid et al., 2008, Lozano et al., 2020).

Mucus and Epithelial Barriers

The subepithelial mucus layer represents the second barrier encountered by nanocarriers in the
gastrointestinal tract. The complex hydrogel that is mucus primarily consists of water and
proteins. Mucins, the predominant proteins in mucus, form a viscoelastic gel with shear-
thinning properties. Due to glycosylation, the majority of mucins in intestinal mucus carry a
negative charge. Consequently, electrostatic interactions may cause positively charged
nanocarriers to adhere to mucus. Intestinal mucus consists of two distinct layers: a loosely
adherent first layer closer to the intestinal lumen and a firmly adherent second layer in contact
with the epithelium. The regularly renewed loosely adherent layer plays a protective role by
preventing contact between foreign objects and epithelial cells, thereby safeguarding the
epithelial cell. Consequently, the rapid removal of nanocarriers from the digestive system
reduces the likelihood of them reaching the epithelium (Ensign et al., 2012, Lock et al., 2018).

Gut Microbiota
The population of microbes residing in mucus is diverse and dynamic, providing the host with
various benefits, including energy production, regulation of the immune system, defense
against pathogens, and protection. The number and diversity of bacterial strains vary along the
digestive tract, with the colon having the highest concentration and variety. Altered microbial
populations have been linked to several diseases and pathological conditions, including obesity,
cancer, and inflammatory bowel disease (IBD). There is limited information available
regarding how bacteria interact with nanocarriers. It is crucial to recognize that gut bacteria can
significantly impact oral nanocarriers. For instance, metabolism or retention by gut bacteria
may alter the fate and ultimate utility of nanocarriers, either positively or negatively. Moreover,
nanocarriers may influence the microbiota by functioning in a prebiotic or antibiotic-like
manner (Ensign et al., 2012, Santander-Ortega et al., 2017).

Intestinal Epithelium
The final barrier for allowing medicines into the bloodstream is the gut epithelium. The
majority of the intestinal epithelium is composed of absorptive enterocytes, but there are also
other cells present, such as enteroendocrine cells, goblet cells, Paneth cells, and M cells.
 Therapeutic Valuation and Challenges of Lipid Nanocarriers … 153

Enterocytes typically use transcellular or paracellular absorption processes to transport

substances into or out of cells. Hydrophobic nanocarriers and medicines can be transported
through transcellular pathways. The primary transcellular mechanisms involve endocytosis,
which can be carried out by immune or M cells, phagocytosis, or pinocytosis. Subsequently,
nanocarriers may undergo various intracellular trafficking and transformation paths, potentially
leading to the transportation of nanocarriers and/or cargo molecules across the intestinal
epithelium into the circulatory system (Karavolos et al., 2016, Thursby et al., 2017, Santalices
et al., 2018, Plaza-Oliver et al., 2020).

Approaches to Overcome Challenges of Lipid-Based Nanocarriers During Oral

Drug Delivery
Strengthening lipid nanocarriers’ resistance to the harsh gastrointestinal environment, which
includes salts, enzymes, and microorganisms, can be achieved through the inner solid core of
solid lipid nanoparticles or the polymeric shell of nanocapsules. Additionally, medium and
short-chain fatty acids have slower rates of breakdown in the lipid matrix compared to long-
chain fatty acids. Furthermore, stability testing during the early development stages of lipid-
based nanocarriers is essential. Researchers can simulate these conditions by utilizing fluids
with pH values, electrolyte concentrations, and enzyme concentrations comparable to those of
gastrointestinal fluids (Chen et al., 2013, Niu et al., 2016). A stronger mucoadhesion results in
longer retention of nanocarriers in the mucus, prolonging their residence period and potentially
leading to the release of the cargo molecule. Various in vitro and in vivo techniques can be
employed to assess how well nanocarriers interact with mucus. These techniques include the
particle mucin technique, particle tracking, fluorescence recovery after photobleaching
(FRAP), and dynamic light scattering (DLS). DLS, mucin droplet technique, drop tracking, and
FRAP are among the in vitro and in vivo techniques used to evaluate the substance associations
of a nanocarrier with mucus (Lai et al., 2009). Lipid-based nanocarriers containing
mucoadhesive components have been specifically engineered for this purpose. Chitosan, a
polysaccharide derived from chitin, is extensively utilized in the development of lipid
nanocarriers due to its biological compatibility, biodegradability, and mucoadhesive properties.
Positively charged chitosan-modified lipid-derived nanocarriers enhance interactions with the
intestinal mucus through electrostatic forces, but van der Waals forces, hydrogen bonding, and
hydrophobic interactions may also be involved. This modification not only improves
mucoadhesion but also enhances oral absorption and transport (Federer et al., 2020).
Mucodiffusion is enhanced when nanocarriers diffuse through the mucus. The likelihood of
contact between nanocarriers and the epithelium increases as they navigate the mucus matrix.
Nanocarriers must avoid direct contact with mucus and navigate through its matrix. Coating
nanocarriers with hydrophilic neutral polymers can reduce hydrophobic interactions with
mucus. To create mucodiffusive nanocarriers, low molecular weight (10 kDa) thick coatings of
PEG are particularly recommended (Lai et al., 2009). Suppression of P-glycoprotein: Effective
drug absorption may increase by reducing drug efflux. Administering Pgp inhibitors and Pgp
substrates together has been employed in nanotechnology, with a wide range of nanocarriers,
including lipid-based carriers, considered (Akhtar et al., 2011). Active Targeting: Lipid-based
nanocarriers can act as targeted ligands by themselves (Xu et al., 2020). Improvement of
lymphatic movement, avoidance of the first-pass effect in transportation: Lipid-based
nanocarriers could facilitate enhanced lymphatic transfer of hydrophobic cargo molecules
carried by chylomicrons, particularly those containing unsaturated longer-chain fatty acids.
154 Manisha Bhatti and Jasneek Kaur Kaloti

Additives like phospholipids, Tween 80, or TPGS frequently included in formulating lipid-
based nanocarriers may improve lymphatic transport (Trevaskis et al., 2008).
Conclusion

The development of lipid nanoparticle formulations has significantly advanced the oral delivery
of poorly water-soluble medications, offering superior therapeutic applicability, bio-
acceptability, and biodegradability. Despite their lower toxicity, they are considered the most
effective and challenging method for encapsulating potent lipophilic drugs in the
pharmaceutical industry. Notably, they amalgamate the advantages of colloidal drug delivery
methods and other lipid-based formulations. Composed of physiological lipids, these
nanoparticles closely mimic the biological fate of lipids in vivo. Consequently, their stability in
the harsh gastrointestinal environment is heightened, accompanied by a decrease in toxicity.
The nano-size of these formulations facilitates enhanced bioavailability owing to the increased
surface area. Furthermore, their ability to enhance drug concentration in the bloodstream
through lymphatic and systemic transport positions them as a reliable and promising delivery
method for poorly water-soluble medications.

References

Agrawal, A. K., Harde, H., Thanki, K., Jain, S. (2014). Improved stability and antidiabetic potential of insulin
containing folic acid functionalized polymer stabilized multilayered liposomes following oral
administration. Biomacromolecules, 15(1), 350-360.
Akanda, M., Mithu, M. S. H., & Douroumis, D. (2023). Solid lipid nanoparticles: An effective lipid-based
technology for cancer treatment. Journal of Drug Delivery Science and Technology, 104709.
Akhtar, N., Ahad, A., Khar, R. K., Jaggi, M., Aqil, M., Iqbal, Z., Talegaonkar, S. (2011). The emerging role of
P-glycoprotein inhibitors in drug delivery: a patent review. Expert Opinion on Therapeutic Patents, 21(4),
561-576.
Babadi, D., Dadashzadeh, S., Osouli, M., Abbasian, Z., Daryabari, M. S., Sadrai, S., Haeri, A. (2021).
Biopharmaceutical and pharmacokinetic aspects of nanocarrier-mediated oral delivery of poorly soluble
drugs. Journal of Drug Delivery Science and Technology, 62, 102324.
Basha, S. K., Dhandayuthabani, R., Muzammil, M. S., Kumari, V. S. (2021). Solid lipid nanoparticles for oral
drug delivery. Materials Today: Proceedings, 36, 313-324.
Calderon‐Colon, X., Zhang, Y., Tiburzi, O., Wang, J., Hou, S., Raimondi, G., Patrone, J. (2023). Design and
characterization of lipid nanocarriers for oral delivery of immunotherapeutic peptides. Journal of
Biomedical Materials Research Part A, 111(7), 938-949.
Chen, C., Fan, T., Jin, Y., Zhou, Z., Yang, Y., Zhu, X., Huang, Y. (2013). Orally delivered salmon calcitonin-
loaded solid lipid nanoparticles prepared by micelle–double emulsion method via the combined use of
different solid lipids. Nanomedicine, 8(7), 1085-1100.
Chen, D. B., Yang, T. Z., Lu, W. L., Zhang, Q. (2001). In vitro and in vivo study of two types of long-circulating
solid lipid nanoparticles containing paclitaxel. Chemical and Pharmaceutical Bulletin, 49(11), 1444-1447.
Choudhury, H., Gorain, B., Karmakar, S., Biswas, E., Dey, G., Barik, R., Pal, T. K. (2014). Improvement of
cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from
a nanoemulsion platform. International Journal of Pharmaceutics, 460(1-2), 131-143.
Cui, J., Yu, B., Zhao, Y., Zhu, W., Li, H., Lou, H., Zhai, G. (2009). Enhancement of oral absorption of curcumin
by self-micro emulsifying drug delivery systems. International Journal of Pharmaceutics, 371(1-2), 148-
155.
Das, S., & Chaudhury, A. (2011). Recent advances in lipid nanoparticle formulations with solid matrix for oral
drug delivery. American Association of Pharmaceutical Scientists, 12, 62-76.
 Therapeutic Valuation and Challenges of Lipid Nanocarriers … 155

Ensign, L. M., Cone, R., Hanes, J. (2012). Oral drug delivery with polymeric nanoparticles: the gastrointestinal
mucus barriers. Advanced Drug Delivery Reviews, 64(6), 557-570.
Federer, C., Kurpiers, M., Bernkop-Schnurch, A. (2020). Thiolated chitosans: A multi-talented class of
polymers for various applications. Biomacromolecules, 22(1), 24-56.
Feeney, O. M., Crum, M. F., McEvoy, C. L., Trevaskis, N. L., Williams, H. D., Pouton, C. W., Porter, C. J.
(2016). 50 years of oral lipid-based formulations: provenance, progress and future perspectives. Advanced
Drug Delivery Reviews, 101, 167-194.
Goo, Y. T., Song, S. H., Yeom, D. W., Chae, B. R., Yoon, H. Y., Kim, C. H., Choi, Y. W. (2020). Enhanced
oral bioavailability of valsartan in rats using a supersaturable self-microemulsifying drug delivery system
with P-glycoprotein inhibitors. Pharmaceutical Development and Technology, 25(2), 178-186.
Han, H. K., Shin, H. J., Ha, D. H. (2012). Improved oral bioavailability of alendronate via the mucoadhesive
liposomal delivery system. European Journal of Pharmaceutical Sciences, 46(5), 500-507.
Homayun, B., Lin, X., Choi, H. J. (2019). Challenges and recent progress in oral drug delivery systems for
biopharmaceuticals. Pharmaceutics, 11(3), 129.
Hsu, C. Y., Wang, P. W., Alalaiwe, A., Lin, Z. C., Fang, J. Y. (2019). Use of lipid nanocarriers to improve oral
delivery of vitamins. Nutrients, 11(1), 68.
Jain, V., Kumar, H., Chand, P., Jain, S. (2021). Lipid‐Based Nanocarriers as Drug Delivery System and Its
Applications. Nanopharmaceutical Advanced Delivery Systems, 1-29.
Jaiswal, M., Dudhe, R., Sharma, P. (2015). Nanoemulsion: an advanced mode of drug delivery system. 3
Biotech, 5, 123–127.
Jantratid, E., Janssen, N., Reppas, C., Dressman, J. B. (2008). Dissolution media simulating conditions in the
proximal human gastrointestinal tract: an update. Pharmaceutical Research, 25, 1663-1676.
Karavolos, M., Holban, A. (2016). Nanosized drug delivery systems in gastrointestinal targeting: interactions
with microbiota. Pharmaceuticals, 9(4), 62.
Lai, S. K., Wang, Y. Y., Hanes, J. (2009). Mucus-penetrating nanoparticles for drug and gene delivery to
mucosal tissues. Advanced Drug Delivery Reviews, 61(2), 158-171.
Liu, J., Gong, T., Wang, C., Zhong, Z., & Zhang, Z. (2007). Solid lipid nanoparticles loaded with insulin by
sodium cholate-phosphatidylcholine-based mixed micelles: preparation and characterization.
International Journal of Pharmaceutics, 340(1-2), 153-162.
Lock, J. Y., Carlson, T. L., Carrier, R. L. (2018). Mucus models to evaluate the diffusion of drugs and particles.
Advanced Drug Delivery Reviews, 124, 34-49.
Lozano, M. V., Santander-Ortega, M. J., Alonso, M. J. (2020). In vitro relevant information for the assessment
of nanoparticles for oral drug administration. Nanotechnology for Oral Drug Delivery, 419-458.
Maurya, S. D., Arya, R. K. K., Rajpal, G., Dhakar, R. C. (2017). Self-micro emulsifying drug delivery systems
(SMEDDs): A review on physico-chemical and biopharmaceutical aspects. Journal of Drug Delivery and
Therapeutic,7, 55–65.
Michalowski, C. B., Arbo, M. D., Altknecht, L., Anciuti, A. N., Abreu, A. S., Alencar, L. M., Guterres, S. S.
(2020). Oral treatment of spontaneously hypertensive rats with captopril-surface functionalized
furosemide-loaded multi-wall lipid-core nanocapsules. Pharmaceutics, 12(1), 80.
Nabi, B., Rehman, S., Baboota, S., Ali, J. (2019). Insights on oral drug delivery of lipid nanocarriers: a win-
win solution for augmenting bioavailability of antiretroviral drugs. American Association of
Pharmaceutical Scientists, 20, 1-11.
Naik, H., Sonju, J. J., Singh, S., Chatzistamou, I., Shrestha, L., Gauthier, T., Jois, S. (2021). Lipidated
peptidomimetic ligand-functionalized HER2 targeted liposome as nano-carrier designed for doxorubicin
delivery in cancer therapy. Pharmaceuticals, 14(3), 221.
Niu, Z., Conejos-Sánchez, I., Griffin, B. T., O’Driscoll, C. M., Alonso, M. J. (2016). Lipid-based nanocarriers
for oral peptide delivery. Advanced Drug Delivery Reviews, 106, 337-354.
Plaza-Oliver, M., Santander-Ortega, M. J., Castro-Vazquez, L., Rodriguez-Robledo, V., González-Fuentes, J.,
Marcos, P., Arroyo-Jiménez, M. M. (2020). The role of the intestinal-protein corona on the mucodiffusion
behaviour of new nanoemulsions stabilised by ascorbyl derivatives. Colloids and Surfaces B:
Biointerfaces, 186, 110740.
Plaza-Oliver, M., Santander-Ortega, M. J., Lozano, M. V. (2021). Current approaches in lipid-based
nanocarriers for oral drug delivery. Drug Delivery and Translational Research, 11, 471-497.
156 Manisha Bhatti and Jasneek Kaur Kaloti

Pooja, D., Kulhari, H., Kuncha, M., Rachamalla, S. S., Adams, D. J., Bansal, V., Sistla, R. (2016). Improving
efficacy, oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles.
Molecular Pharmaceutics, 13(11), 3903-3912.
Pragati, S., Kuldeep, S., Ashok, S., Satheesh, M. (2009). Solid Lipid Nanoparticles, A Promising Drug Delivery
Technology, International Journal of Pharmaceutical Sciences and Nanotechnology, 2(2), 509-16.
Ranpise, N. S., Korabu, S. S., Ghodake, V. N. (2014). Second-generation lipid nanoparticles (NLC) as an oral
drug carrier for delivery of lercanidipine hydrochloride. Colloids and Surfaces B: Biointerfaces, 116, 81–
87.
Santalices, I., Torres, D., Lozano, M. V., Arroyo-Jiménez, M. M., Alonso, M. J., Santander-Ortega, M. J.
(2018). Influence of the surface properties of nanocapsules on their interaction with intestinal barriers.
European Journal of Pharmaceutics and Biopharmaceutics, 133, 203-213.
Santander-Ortega, M. J., Plaza-Oliver, M., Rodriguez-Robledo, V., Castro-Vazquez, L., Villaseca-González,
N., González-Fuentes, J., Arroyo-Jiménez, M. M. (2017). PEGylated nanoemulsions for oral delivery:
role of the inner core on the final fate of the formulation. Langmuir, 33(17), 4269-4279.
Senna, J. P., Barradas, T. N., Cardoso, S., Castiglione, T. C., Serpe, M. J., e Silva, K. G. D. H., Mansur, C. R.
E. (2018). Dual alginate-lipid nanocarriers as oral delivery systems for amphotericin B. Colloids and
Surfaces B: Biointerfaces, 166, 187-194.
Soppimath, K. S., Aminabhavi, T. M., Kulkarni, A. R., Rudzinski, W. E. (2001). Biodegradable polymeric
nanoparticles as drug delivery devices. Journal of Controlled Release, 70, 1–20.
Thursby, E., Juge, N. (2017). Introduction to the human gut microbiota. Biochemical Journal, 474(11), 1823-
1836.
Trevaskis, N. L., Charman, W. N., Porter, C. J. (2008). Lipid-based delivery systems and intestinal lymphatic
drug transport: a mechanistic update. Advanced Drug Delivery Reviews, 60(6), 702-716.
Wan, K., Sun, L., Hu, X., Yan, Z., Zhang, Y., Zhang, X., Zhang, J. (2016). Novel nanoemulsion based lipid
nanosystems for favorable in vitro and in vivo characteristics of curcumin. International Journal of
Pharmaceutics, 504(1-2), 80-88.
Xu, Y., Shrestha, N., Préat, V., Beloqui, A. (2020). Overcoming the intestinal barrier: A look into targeting
approaches for improved oral drug delivery systems. Journal of Controlled Release, 322, 486-508.
Yuan, H., Chen, C. Y., Chai, G. H., Du, Y. Z., Hu, F. Q. (2013). Improved transport and absorption through
gastrointestinal tract by PEGylated solid lipid nanoparticles. Molecular Pharmaceutics, 10(5), 1865-1873.
Chapter 11

Lipid-Based Nanoparticles in Cancer Therapy:

Enhancing Efficacy and Minimizing Toxicity

Abhinav Singhal1
Anjali Sharma1
Vishnu Mittal1
Devkant Sharma2,
and Prabhjot Singh Bajwa2
1Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, India
2Ch. Devi Lal College of Pharmacy, Jagadhari, Haryana, India

Abstract

Lipid-based nanoparticles have emerged as a promising strategy in cancer therapy, offering

significant advantages over traditional drug delivery methods. These nanoparticles, which
include liposomes, nanoemulsions, and NLCs, have demonstrated substantial potential in
enhancing the efficacy of anticancer agents while minimizing systemic toxicity. Their
ability to encapsulate a wide range of hydrophobic and hydrophilic drugs enables the
delivery of multiple treatments to cancer cells simultaneously, enhancing synergistic
effects and overcoming drug resistance. Moreover, lipid-based nanoparticles protect
encapsulated drugs from degradation in the bloodstream, prolonging circulation time and
improving drug bioavailability. They also enable controlled drug release, facilitating
prolonged and localized delivery to tumor sites, thereby enhancing treatment efficacy and
reducing side effects. In recent years, several lipid-based nanoparticle formulations have
advanced to preclinical and clinical studies, showing promising outcomes in cancer
treatment. These nanoparticles have been utilized to deliver chemotherapeutic drugs,
targeted medications, and nucleic acids for gene therapy, providing a versatile platform for
personalized cancer treatment. The focus of this chapter is on various lipid-based
nanoparticles, exploring their essential characteristics, recent advances, and applications in
cancer treatment. This comprehensive review provides valuable insights into the diverse
potential of lipid-based nanoparticles in revolutionizing cancer therapy.

Keywords: Lipid- based nanoparticles, tumour, bioavailability, targeted drug delivery, toxicity


Corresponding Author’s Email: devkant2088@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
158 Abhinav Singhal, Anjali Sharma, Vishnu Mittal et al.

Abbreviations

BBB Blood brain barrier

EPR Enhanced permeability and retention
LNPs Lipid based nanoparticle
MDR Multi-drug resistance
MPS Mononuclear phagocyte system
NIR Near-infrared
NLCs Nanostructured lipid carriers
PEG Polyethylene glycol
pH Potential of hydrogen
PDT Photodynamic therapy
siRNA Small interfering RNA
SLNs Solid lipid nanoparticles
TLR Toll-like receptor

Introduction

Cancer is a formidable adversary, distinguished by its complex and diverse nature. It

encompasses over a hundred distinct types, each originating from different tissues or organs.
This uncontrolled cell division leads to the genesis of tumors, which can vary in size and
invasiveness (Martin et al., 2013). These approaches often bring about severe side effects and
possess certain limitations, spurring the search for more innovative and targeted therapeutic
strategies (Pinel et al., 2019). Within this context, lipid-based nanoparticles have emerged as a
promising frontier in cancer treatment. These nanoparticles, including liposomes and lipid
nanoparticles, serve as channels for delivering drugs directly to tumor sites (Tenchov et al.,
2021). Nanotechnology holds immense significance in the realm of cancer treatment,
particularly when harnessed through lipid-based nanoparticles. This cutting-edge approach
capitalizes on the unique properties of nanoscale materials to address some of the most pressing
challenges in cancer therapy (Wang et al., 2014). This precision is crucial, as it not only
increases the concentration of drugs at the malignant site but also mitigates the danger of
harming healthy surrounding tissues (Li et al., 2017). This targeted therapy approach
maximizes therapeutic effects while minimizing side effects (Cao et al., 2015). Rationale for
incorporating lipid-based nanoparticles into cancer treatment is rooted in their exceptional
versatility and their potential to address several critical challenges in traditional cancer therapy.
These nanoparticles, primarily liposomes and lipid nanoparticles, offer a promising platform
for drug delivery and innovative therapeutic approaches against cancer. This property of
nanoparticles significantly reduces the risk of adverse reactions and makes them an excellent
choice for delivering therapeutic agents, especially in cancer treatment, where minimizing
collateral damage to healthy tissues is paramount (Yu et al., 2016).
 Lipid-Based Nanoparticles in Cancer Therapy 159

Fundamentals of Lipid-Based Nanoparticles

Lipid-based nanoparticles, at the heart of innovative therapeutic approaches in cancer therapy,

are a class of nanoscale drug delivery systems designed to enhance the bioavailability and
effectiveness of therapeutic agents (Ahmad et al., 2017).

• Liposomes: Liposomes are highly versatile and can encapsulate both hydrophilic and
hydrophobic drugs, making them suitable for a wide range of therapeutic
implementations (Nassir et al., 2019).
• Solid lipid nanoparticles (SLNs): Solid lipid nanoparticles are made of lipids in a solid
state at ambient temperature (Tekade et al., 2017). They offer a robust matrix for drug
encapsulation and release. SLNs are advantageous in terms of being essential for long-
term drug exposure in cancer treatment (Montoto et al., 2020).
• Nanostructured lipid carriers (NLCs): They consist of a pair of solid and liquid lipids,
creating a more flexible matrix for drug encapsulation.

Properties and Advantages of Lipid-Based Nanoparticles

Lipid-based nanoparticles offer a multitude of properties and advantages that make them a
promising and versatile platform for innovative cancer treatments. These nanoparticles are
uniquely positioned to address several critical challenges in the field of oncology (Guo et al.,
2014).

• Biocompatibility: One of the key properties of lipid-based nanoparticles is their high

biocompatibility.
• Controlled drug release: This feature ensures that therapeutic agents are released
gradually and in a sustained manner, maintaining therapeutic levels within the tumor
over an extended period (Bordat et al., 2019).
• Targeted drug delivery: The surface of lipid-based nanoparticles can be modified to
carry particular targeting ligands, like antibodies or peptides (Simon et al., 2018).

Various Types of Lipid-Based Nanocarriers

In the realm of lipid-based nanoparticles for cancer therapy, various types of lipid-based
nanocarriers have been developed, each with its unique attributes and applications. These
diverse platforms offer researchers and clinicians a range of options to tailor drug delivery
systems for specific therapeutic goals (Dima et al., 2020).

• Liposomes: Liposomes are among the most extensively studied lipid-based

nanocarriers (Nicolas et al., 2013).
• Solid lipid nanoparticles (SLNs): These nanoparticles provide a stable matrix for drug
encapsulation and release (Jahangir et al., 2020).
160 Abhinav Singhal, Anjali Sharma, Vishnu Mittal et al.

• Nanostructured lipid carriers (NLCs): NLCs incorporate both solid and liquid lipids
in their matrix, making them more flexible and accommodating higher drug payloads
(Guimaraes et al., 2021). They are particularly valuable in enhancing drug solubility
and sustaining drug release, offering prolonged therapeutic action (Raemdonck et al.,
2014).
• Nanoemulsions: Nanoemulsions are lipid-based systems that consist of oil-in-water
(o/w) and water-in-oil (w/o) droplets balanced by surfactants. They are well-suited for
delivering hydrophobic drugs and improving drug solubility (Lima et al., 2021).
• Micelles: Micelles are small, self-assembled lipid structures that form in aqueous
solutions. Micelles are known for their ease of formulation and stability, and they are
used to enhance drug bioavailability (Cheng et al., 2021).

Methods of Preparation and Characterization

In the growth of lipid-based nanoparticles in cancer treatment, methods of preparation and

characterization are critical steps to ensure the effective and safe delivery of therapeutic agents.
These processes are essential for tailoring the nanoparticles for specific therapeutic goals and
assessing their quality.

Methods of Preparation
Several techniques are commonly employed for the preparation of lipid-based nanoparticles,
each offering unique advantages:

• Thin-Film Hydration: Hydration with an aqueous phase led to the evolution of

liposomes or lipid nanoparticles. Thin-film hydration is a versatile and widely used
technique for drug encapsulation (Less et al., 1991).
• Solvent Emulsification-Evaporation: Subsequent vaporization of the organic solvent
forms nanoparticles. This technique is suitable for hydrophobic drug delivery (Leu et
al., 2000).
• Coacervation/Phase Separation: This method relies on the phase separation of lipid
components when brought into contact with an aqueous phase. The phase-separated
lipids self-assemble into nanoparticles.

Characterization Techniques
Characterizing lipid-based nanoparticles is crucial to ensure their quality, stability, and
suitability for cancer treatment. Several characterization techniques are commonly employed:

• Particle Size and Size Distribution Analysis: These analyses are used to determine the
particle size and size distribution of lipid-based nanoparticles. This information is
essential for assessing their suitability for drug delivery and targeting (Li et al., 2019).
• Drug Encapsulation Efficiency: This parameter measures the efficiency of the drug
loading process (Li et al., 2016).
 Table 1. Clinical Trials on Lipid-Based Nanoparticles for Cancer Treatment

Phase Drug Name Title of Trials Disease Summary of Trials

I/II Doxorubicin Study of Phase I & II to Evaluate Metastatic Breast The trial is evaluating safety & efficacy of doxorubicin - loaded lipid nanoparticles
Safety & Efficacy of Doxorubicin- Cancer (Dox-LNPs) for treatment of metastatic breast cancer. Dox-LNPs designed to deliver
Loaded Lipid Nanoparticles doxorubicin, a chemotherapy drug, to cancer cells more effectively than traditional
formulations, while reducing side effects.
II Paclitaxel Study of Phase II to Evaluate Safety & Advanced The trial is evaluating safety & efficacy of paclitaxel-loaded lipid nanoparticles (Pac-LNPs)
Efficacy of Paclitaxel-Loaded Lipid Pancreatic for treatment of advanced pancreatic cancer. Pac-LNPs designed to deliver paclitaxel, a
Nanoparticles Cancer chemotherapy drug, to the pancreas more effectively than traditional formulations.
II Irinotecan Study of Phase II to Evaluate Safety & Advanced The trial is evaluating safety & efficacy of irinotecan-loaded lipid nanoparticles (Iri-LNPs)
Efficacy of Irinotecan-Loaded Lipid Colorectal for treatment of advanced colorectal cancer. Iri-LNPs designed to deliver irinotecan, a
Nanoparticles Cancer chemotherapy drug, to cancer cells more effectively than traditional formulations.
I/II Gemcitabine Study of Phase I & II to Evaluate Advanced Non- The trial is evaluating safety & efficacy of gemcitabine-loaded lipid nanoparticles (Gem-
Safety & Efficacy of Gemcitabine- Small Cell Lung LNPs) for treatment of advanced non-small cell lung cancer. Gem-LNPs designed to deliver
Loaded Lipid Nanoparticles Cancer gemcitabine, a chemotherapy drug, to the lungs more effectively than traditional
formulations.
II Cisplatin Study of Phase II to Evaluate Safety & Advanced The trial is evaluating safety & efficacy of cisplatin-loaded lipid nanoparticles (Cis-LNPs) for
Efficacy of Cisplatin-Loaded Lipid Ovarian Cancer treatment of advanced ovarian cancer. Cis-LNPs designed to deliver cisplatin, a
Nanoparticles chemotherapy drug, to cancer cells more effectively than traditional formulations.
II 5-Fluorouracil Study of Phase II to Evaluate Safety & Advanced Head The trial is evaluating safety & efficacy of 5-fluorouracil-loaded lipid nanoparticles (5-FU-
Efficacy of 5-Fluorouracil-Loaded & Neck Cancer LNPs) for treatment of advanced head & neck cancer. 5-FU-LNPs are designed to deliver 5-
Lipid Nanoparticles fluorouracil, a chemotherapy drug, to the head and neck more effectively than traditional
formulations.
I/II Doxorubicin & Study of Phase I & II to Evaluate Advanced Breast The trial is evaluating safety & efficacy of doxorubicin- & paclitaxel-loaded lipid
Paclitaxel Safety & Efficacy of Doxorubicin- Cancer nanoparticles (Dox-Pac-LNPs) for treatment of advanced breast cancer. Dox-Pac-LNPs are
and Paclitaxel-Loaded Lipid designed to deliver doxorubicin and paclitaxel, two chemotherapy drugs, to cancer cells more
Nanoparticles effectively than traditional formulations.
I/II Gemcitabine & Study Phase I & II to Evaluate Safety Advanced The trial is evaluating safety & efficacy of gemcitabine- & nab-paclitaxel-loaded lipid
Nab-Paclitaxel & Efficacy of Gemcitabine- & Nab- Pancreatic nanoparticles (Gem-Nab-Pac-LNPs) for treatment of advanced pancreatic cancer. Gem-Nab-
Paclitaxel-Loaded Lipid Nanoparticles Cancer Pac-LNPs are designed to deliver gemcitabine and nab-paclitaxel, two chemotherapy drugs,
to the pancreas more effectively than traditional formulations.
I/II Irinotecan & 5- Study Phase I & II to Evaluate Safety Advanced The trial is evaluating safety & efficacy of irinotecan- & 5-fluorouracil-loaded lipid
Fluorouracil & Efficacy of Irinotecan- and 5- Colorectal nanoparticles (Iri-5-FU-LNPs) for treatment of advanced colorectal cancer. Iri-5-FU-LNPs
Fluorouracil-Loaded Lipid Cancer are designed to deliver irinotecan and 5-fluorouracil, two chemotherapy drugs, to cancer cells
Nanoparticles more effectively than traditional formulations.
 Table 1. (Continued)

Phase Drug Name Title of Trials Disease Summary of Trials

I/II Cisplatin & Study Phase I & II to Evaluate the Advanced The trial is evaluating safety & efficacy of cisplatin- & doxorubicin-loaded lipid
Doxorubicin Safety and Efficacy of Cisplatin- and Ovarian Cancer nanoparticles (Cis-Dox-LNPs) for treatment of advanced ovarian cancer. Cis-Dox-LNPs are
Doxorubicin-Loaded Lipid designed to deliver cisplatin and doxorubicin, two chemotherapy drugs, to cancer cells more
Nanoparticles effectively than traditional formulations.
I/II Gemcitabine & Study Phase I & II to Evaluate Safety Non-Small Cell The trial is evaluating safety & efficacy of gemcitabine- & cisplatin-loaded lipid
Cisplatin & Efficacy of Gemcitabine- and Lung Cancer nanoparticles (Gem-Cis-LNPs) for treatment of advanced non-small cell lung cancer. Gem-
Cisplatin-Loaded Lipid Nanoparticles Cis-LNPs are designed to deliver gemcitabine and cisplatin, two chemotherapy drugs, to the
lungs more effectively than traditional formulations.
I/II 5-Fluorouracil & Study of Phase I & II to Evaluate Advanced Head The trial is evaluating safety & efficacy of 5-fluorouracil- and irinotecan-loaded lipid
Irinotecan Safety & Efficacy of 5-Fluorouracil- and Neck Cancer nanoparticles (5-FU-Iri-LNPs) for treatment of advanced head & neck cancer. 5-FU-Iri-LNPs
& Irinotecan-Loaded Lipid are designed to deliver 5-fluorouracil & irinotecan, two chemotherapy drugs, to the head and
Nanoparticles neck more effectively than traditional formulations.
 Lipid-Based Nanoparticles in Cancer Therapy 163

• Morphological Analysis: Morphological analyses are utilized to visualize the

morphology and structure of lipid-based nanoparticles, confirming their integrity and
uniformity.
• Drug Release Profiles: In vitro drug release studies are conducted to ensure that they
meet the desired controlled release criteria (Lu et al., 2012).
• Stability Testing: Stability studies, including storage under various conditions, are
performed to assess the shelf-life of lipid-based nanoparticles (Lucky et al., 2015).

Encapsulation Techniques for Anti-Cancer Agents

Encapsulation techniques for anti-cancer agents within lipid-based nanoparticles are critical
components of innovative therapeutic approaches in cancer treatment (Table 1). These
techniques ensure the efficient loading and protection of therapeutic agents, enhancing their
effectiveness while minimizing side effects. Several methods are commonly used for
encapsulating anti-cancer agents:

• Passive Loading: Passive loading involves co-dissolving the anti-cancer drug and the
lipid components in a common solvent, allowing the drug to partition into the lipid
bilayer during nanoparticle formation. This method is particularly suitable for
hydrophobic drugs, as they naturally incorporate into the lipid matrix (Luo et al.,
2017).
• Active Loading: For hydrophilic drugs or those with limited lipid solubility, active
loading techniques are employed. This involves creating a pH or concentration
gradient to drive the drug into the lipid-based nanoparticles. For example, pH gradient-
driven loading uses a pH difference between the drug solution and nanoparticle
dispersion to facilitate drug encapsulation.
• Remote Loading: Remote loading, known as transmembrane pH gradient-driven
loading, is a method typically employed for weakly basic drugs. It involves adjusting
the pH of the aqueous phase during nanoparticle formation, causing the drug to be
drawn into the nanoparticle core as the pH gradient is dissipated. Remote loading can
achieve high drug encapsulation efficiencies (Ma et al., 2016).

Biological Barriers and Overcoming Challenges

Physiological Barriers in Cancer Drug Delivery

In the pursuit of innovative therapeutic approaches using lipid-based nanoparticles for cancer
treatment, it is essential to address the physiological barriers that hinder the effective delivery
of anticancer drugs to tumor sites (Liu et al., 2017).

• Blood-Brain Barrier (BBB): This protective barrier, formed by tightly packed

endothelial cells, limits the passage of many therapeutic agents into the brain tissue.
When properly engineered, lipid-based nanoparticles can enhance drug permeation
through the BBB, opening new avenues for treating brain cancers or preventing
metastases (Lee et al., 2016).
164 Abhinav Singhal, Anjali Sharma, Vishnu Mittal et al.

• Multi-Drug Resistance (MDR): Many cancer cells develop resistance to chemotherapy

drugs, diminishing treatment effectiveness. This approach offers the potential to
circumvent drug resistance and improve treatment outcomes (Wu et al., 2017).
• Clearance by the Mononuclear Phagocyte System (MPS): The MPS, a part of the
immune system, can rapidly clear nanoparticles from the bloodstream. Surface
modifications, such as PEGylation, can help lipid-based nanoparticles evade MPS
clearance (Liu et al., 2023).

Role of Lipid-Based Nanoparticles in Overcoming Biological Barriers

Lipid-based nanoparticles play a vital role in overcoming biological barriers in the context of
cancer treatment, offering innovative therapeutic approaches that aim to intensify effectiveness.

Therapeutic Applications

Lipid-Based Nanoparticles for Chemotherapy

Lipid-based nanoparticles have emerged as a promising platform for improving chemotherapy,
a cornerstone of cancer treatment. These nanoparticles offer innovative therapeutic approaches
by addressing several limitations associated with traditional chemotherapy.

Lipid Nanoparticles for Gene Delivery and Gene Therapy

Lipid nanoparticles have become influential tools for gene delivery and gene treatment in the
context of innovative approaches to cancer treatment. Lipid-based nanoparticles can
encapsulate and protect nucleic acids, such as DNA, RNA, or small interfering RNA (siRNA),
essential components of gene therapy.

Immunotherapy Approaches Utilizing Lipid-Based Nanoparticles

Lipid-based nanoparticles are being utilized in innovative immunotherapy approaches in cancer
treatment. They can encapsulate tumor-specific antigens or neoantigens, unique to cancer cells
(Lyer et al., 2020).

Preclinical and Clinical Studies

Studies involving lipid-based nanoparticles for cancer treatment have been pivotal in advancing
our understanding of their safety, efficacy, and therapeutic potential. These studies provide
valuable insights into the development and application of innovative therapeutic approaches.

• Preclinical Studies: Laboratory and animal studies of lipid-based nanoparticles as

potential cancer treatments have been successful. Researchers have tested various drug
payloads, including chemotherapeutic agents, gene therapies, and immunotherapeutic
agents within lipid-based nanoparticles.
• Clinical Studies: Clinical trials involving lipid-based nanoparticles serve as the critical
bridge between laboratory research and the application of these innovative therapies
in human patients. They encompass multiple phases, from early-phase trials assessing
safety and dosage to later-phase trials measuring treatment efficacy and long-term
outcomes. These trials have revealed reduced side effects, improved patient
 Lipid-Based Nanoparticles in Cancer Therapy 165

tolerability, and encouraging results in terms of tumor response and overall survival
(Harrington et al., 2001).

Conclusion

In the realm of cancer therapy, the utilization of NLCs in topical and transdermal delivery
systems offers several compelling advantages. Firstly, the topical application of NLCs provides
a direct and localized approach to treating superficial cancers, ensuring precise drug delivery
to the affected area while minimizing systemic exposure. The unique physicochemical
properties of NLCs enable them to encapsulate a wide spectrum of anticancer agents, allowing
for a tailored approach to individual patient needs. In the case of transdermal delivery, NLCs
offer an innovative solution for overcoming the challenges associated with traditional systemic
treatments. In conclusion, the integration of NLCs into topical and transdermal delivery
systems represents a cutting-edge approach in cancer treatment. By harnessing the potential of
these lipid-based nanoparticles, clinicians and researchers are paving the way for more
effective, personalized, and patient-friendly cancer therapies. The continuous exploration of
NLC-based topical and transdermal formulations holds the promise of revolutionizing cancer
treatment paradigms, offering hope and improved quality of life for patients battling this
devastating disease.

References

Ahmad, Gulzar, Rana El Sadda, Galina Botchkina, Iwao Ojima, James Egan, and Mansoor Amiji. (2017).
Nanoemulsion Formulation of a Novel Taxoid DHA-SBT-1214 Inhibits Prostate Cancer Stem Cell-
Induced Tumor Growth. Cancer Letters, 406, 71–80.
Bordat, Alexandre, Tanguy Boissenot, Julien Nicolas, and Nicolas Tsapis. (2019). Thermoresponsive Polymer
Nanocarriers for Biomedical Applications. Advanced Drug Delivery Reviews, 138, 167–92.
Cao, X., Jingwen Luo, Tao Gong, Zhi-Rong Zhang, Xun Sun, and Yao Fu. (2015). Coencapsulated
Doxorubicin and Bromotetrandrine Lipid Nanoemulsions in Reversing Multidrug Resistance in Breast
Cancer In Vitro and In Vivo. Molecular Pharmaceutics, 12(1), 274–86.
Cheng, Zhe, Maoyu Li, Raja Dey, and Yongheng Chen. (2021). Nanomaterials for Cancer Therapy: Current
Progress and Perspectives. Journal of Hematology & Oncology, 14(1), 85.
Conde, João, Chenchen Bao, Yeqi Tan, Daxiang Cui, Elazer R. Edelman, Helena S. Azevedo, Hugh J. Byrne,
Natalie Artzi, and Furong Tian. (2015). Dual Targeted Immunotherapy via In Vivo Delivery of Biohybrid
RNAi-Peptide Nanoparticles to Tumour-Associated Macrophages and Cancer Cells. Advanced Functional
Materials, 25(27), 4183–94.
Dima, C., E. Assadpour, S. Dima, and S. M. Jafari. (2020). Nutraceutical Nanodelivery; an Insight into the
Bioaccessibility/Bioavailability of Different Bioactive Compounds Loaded Within Nanocarriers. Critical
Reviews in Food Science & Nutrition, 1–35.
Fan, H., G. Liu, Y. Huang, Y. Li, and Q. Xia. (2014). Development of a Nanostructured Lipid Carrier
Formulation for Increasing Photo-stability and Water Solubility of Phenylethyl Resorcinol. Applied
Surface Science, 288, 193–200.
García-Pinel, Beatriz, Cristina Porras-Alcalá, Alicia Ortega-Rodríguez, Francisco Sarabia, Jose Prados,
Consolación Melguizo, and Juan M. López-Romero. (2019). Lipid-Based Nanoparticles: Application and
Recent Advances in Cancer Treatment. Nanomaterials, 9(4), 638.
Guimarães, Diana, Artur Cavaco-Paulo, and Eugénia Nogueira. (2021). Design of Liposomes as Drug Delivery
System for Therapeutic Applications. International Journal of Pharmaceutics, 601, 120571.
166 Abhinav Singhal, Anjali Sharma, Vishnu Mittal et al.

Guo, Peng, Jin-Oh You, Jiang Yang, D. Jia, Marsha A. Moses, and Debra T. Auguste. (2014). Inhibiting
Metastatic Breast Cancer Cell Migration via the Synergy of Targeted, pH-Triggered siRNA Delivery and
Chemokine Axis Blockade. Molecular Pharmaceutics, 11(3), 755–65.
Harrington, K. J., S. Mohammadtaghi, P. S. Uster, D. Glass, A. M. Peters, R. G. Vile, and J. S. Stewart. (2001).
Effective Targeting of Solid Tumors in Patients with Locally Advanced Cancers by Radiolabeled
Pegylated Liposomes. Clinical Cancer Research, 7(2), 243–54.
Iyer, Arun K., Greish Khaled, Jun Fang, and Hiroshi Maeda. (2006). Exploiting the Enhanced Permeability
and Retention Effect for Tumor Targeting. Drug Discovery Today, 11(17–18), 812–8.
Jahangir, Mohammed Asadullah, Mohamad Taleuzzaman, Chandra Kala, and Sadaf Jamal Gilani. (2020).
Advancements in Polymer and Lipid-Based Nanotherapeutics for Cancer Drug Targeting. Current
Pharmaceutical Design, 26(40), 5119–27.
Johnston, Michael J. W., Sean C. Semple, Sandra K. Klimuk, Katarina Edwards, Merete L. Eisenhardt, Esther
C. Leng, Göran Karlsson, Daniel Yanko, and Pieter R. Cullis. (2006). Therapeutically Optimized Rates
of Drug Release Can Be Achieved by Varying the Drug-to-Lipid Ratio in Liposomal Vincristine
Formulations. Biochimica & Biophysica Acta, 1758(1), 55–64.
Lee, Min Hee, Eun-Joong Kim, Hyunseung Lee, Hyun Min Kim, Min Jung Chang, Sun Young Park, Kwan
Soo Hong, Jong Seung Kim, and Jonathan L. Sessler. (2016). Liposomal Texaphyrin Theranostics for
Metastatic Liver Cancer. Journal of the American Chemical Society, 138(50), 16380–7.
Less, J. R., T. C. Skalak, E. M. Sevick, and R. K. Jain. (1991). Microvascular Architecture in a Mammary
Carcinoma: Branching Patterns and Vessel Dimensions. Cancer Research, 51(1), 265–73.
Leu, A. J., D. A. Berk, A. Lymboussaki, K. Alitalo, and R. K. Jain. (2000). Absence of Functional Lymphatics
Within a Murine Sarcoma: a Molecular and Functional Evaluation. Cancer Research, 60(16), 4324–7.
Li, Hong-Jun, Jin-Zhi Du, Xiao-Jiao Du, Cong-Fei Xu, Chun-Yang Sun, Hong-Xia Wang, Zhi-Ting Cao, Xian-
Zhu Yang, Yan-Hua Zhu, Shuming Nie, and Jun Wang. (2016). Stimuli-Responsive Clustered
Nanoparticles for Improved Tumor Penetration and Therapeutic Efficacy. Proceedings of the National
Academy of Sciences of the United States of America, 113(15), 4164–9.
Li, Hongyan, Qing Liu, Bart J. Crielaard, Jan W. de Vries, Mark Loznik, Zhuojun Meng, Xintong Yang, Robert
Göstl, and Andreas Herrmann. (2019). Fast, Efficient, and Targeted Liposome Delivery Mediated by DNA
Hybridization. Advanced Healthcare Materials, 8(14), e1900389.
Li, Tong, Y. Zhang, Yuan-Pu Meng, Li-Shan Bo, and Wen-Bo Ke. (2017). miR-542-3p Appended
Sorafenib/All-Trans Retinoic Acid (ATRA)-Loaded Lipid Nanoparticles to Enhance the Anticancer
Efficacy in Gastric Cancers. Pharmaceutical Research, 34(12), 2710–9.
Lima, P. H. C., Anna Paola Butera, Luis Fernando Cabeça, and Renato Márcio Ribeiro-Viana. (2021).
Liposome Surface Modification by Phospholipid Chemical Reactions. Chemistry & Physics of Lipids,
237, 105084.
Liu, Yang, Fang Yang, Chuxiao Yuan, Mingxi Li, Tuantuan Wang, B. Chen, Juan Jin, Peng Zhao, Jiayi Tong,
Shouhua Luo, and Ning Gu. (2017). Magnetic Nanoliposomes as In Situ Microbubble Bombers for
Multimodality Image-Guided Cancer Theranostics. ACS Nano, 11(2), 1509–19.
Liu, Yifan, Wenxu Cheng, HongYi Xin, Ran Liu, Qinqi Wang, Wenqi Cai, Xiaochun Peng, Fuyuan Yang, and
HongWu Xin. (2023). Nanoparticles Advanced from Preclinical Studies to Clinical Trials for Lung Cancer
Therapy. Cancer Nanotechnology, 14(1), 28.
Lu, Hongyun, Shengliang Zhang, Jinling Wang, and Qihe Chen. (2021). A Review on Polymer and Lipid-
Based Nanocarriers and Its Application to Nano-pharmaceutical and Food-Based Systems. Frontiers in
Nutrition, 8, 783831.
Lu, Jie, Zongxi Li, Jeffrey I. Zink, and Fuyuhiko Tamanoi. (2012). In Vivo Tumor Suppression Efficacy of
Mesoporous Silica Nanoparticles-Based Drug-Delivery System: Enhanced Efficacy by Folate
Modification. Nanomedicine: Nanotechnology, Biology, & Medicine, 8(2), 212–20.
Lucky, Sasidharan Swarnalatha, Khee Chee Soo, and Yong Zhang. (2015). Nanoparticles in Photodynamic
Therapy. Chemical Reviews, 115(4), 1990–2042.
Luo, Nana, Jeffrey K. Weber, Shuang Wang, Binquan Luan, Hua Yue, Xiaobo Xi, Jing Du, Zaixing Yang, Wei
Wei, Ruhong Zhou, and Guanghui Ma. (2017). Pegylated Graphene Oxide Elicits Strong Immunological
Responses Despite Surface Passivation. Nature Communications, 8, 14537.
 Lipid-Based Nanoparticles in Cancer Therapy 167

Ma, Xiaowei, Ningqiang Gong, Lin Zhong, Jiadong Sun, and Xing-Jie Liang. (2016). Future of
Nanotherapeutics: Targeting the Cellular Sub-organelles. Biomaterials, 97, 10–21.
Martin, Tracey A., Ye Lin, Andrew J. Sanders, Jane Lane, and Wen G. Jiang. (2013). Cancer Invasion and
Metastasis: Molecular and Cellular Perspective. In Madame Curie Bioscience Database. Landes
Bioscience.
Miranda, Dyego, Kevin Carter, Dandan Luo, Shuai Shao, Jumin Geng, Changning Li, Upendra Chitgupi,
Steven G. Turowski, Nasi Li, G. Ekin Atilla-Gokcumen, Joseph A. Spernyak, and Jonathan F. Lovell.
(2017). Multifunctional Liposomes for Image-Guided Intratumoral Chemo-phototherapy. Advanced
Healthcare Materials, 6(16).
Nassir, A. M., and I. A. A. Ibrahim, MD S. (2019). Shahzad N. Surface Functionalized Folate Targeted
Oleuropein Nano-liposomes for Prostate Tumor Targeting: In Vitro and In-Vivo Activity, Waris M., Ain
M. R., Ahmad I. Life Sciences, 220, 136–46.
Nicolas, Julien, Simona Mura, Davide Brambilla, Nicolas Mackiewicz, and Patrick Couvreur. (2013). Design,
Functionalization Strategies and Biomedical Applications of Targeted Biodegradable/Biocompatible
Polymer-Based Nanocarriers for Drug Delivery. Chemical Society Reviews, 42(3), 1147–235.
Raemdonck, Koen, Kevin Braeckmans, J. Demeester, and Stefaan C. De Smedt. (2014). Merging the Best of
Both Worlds: Hybrid Lipid-Enveloped Matrix Nanocomposites in Drug Delivery. Chemical Society
Reviews, 43(1), 444–72.
Scioli, Montoto Sebastián, Giuliana Muraca, and Ruiz María. (2020). Esperanza Solid Lipid Nanoparticles for
Drug Delivery: Pharmacological and Biopharmaceutical Aspects. Frontiers in Molecular Biosciences, 7.
Simon, J., S. Christmann, V. Mailänder, F. R. Wurm, and K. Landfester. (2018). Protein Corona Mediated
Stealth Properties of Biocompatible Carbohydrate-Based Nanocarriers. Israel Journal of Chemistry,
58(12), 1363–72.
Tekade Rakesh, K., Rahul Maheshwari, Tekade Muktika, and Mahavir B. Chougule. (2017). Solid Lipid
Nanoparticles for Targeting and Delivery of Drugs and Genes. Academic Press, 256–86.
Tenchov, Rumiana, Robert Bird, Allison E. Curtze, and Qiongqiong Zhou. (2021). Lipid Nanoparticles─ from
Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACS Nano,
15(11), 16982–7015.
Wang, Jiao, Rongrong Zhu, Xiaoyu Sun, Yanjing Zhu, Hui Liu, and Shi-Long Wang. (2014). Intracellular
Uptake of Etoposide-Loaded Solid Lipid Nanoparticles Induces an Enhancing Inhibitory Effect on Gastric
Cancer Through Mitochondria-Mediated Apoptosis Pathway. International Journal of Nanomedicine, 9,
3987–98.
Wu, B., Bing Wan, Shu-Ting Lu, Kai Deng, Xiao-Qi Li, Bao-Lin Wu, Yu-Shuang Li, Ru-Fang Liao, Shi-Wen
Huang, and Hai-Bo Xu. (2017). Near-Infrared Light-Triggered Theranostics for Tumor-Specific
Enhanced Multimodal Imaging and Photothermal Therapy. International Journal of Nanomedicine, 12,
4467–78.
Yu, DongMei, Wei Li, Yueying Zhang, and Bin Zhang. (2016). Anti-tumor Efficiency of Paclitaxel and DNA
When Co-delivered by pH Responsive Ligand Modified Nanocarriers for Breast Cancer Treatment.
Biomedicine & Pharmacotherapy, 83, 1428–35.
Chapter 12

Lipid-Based Nanoparticles for Topical and Transdermal

Drug Delivery

Ashima Ahuja
Yogesh Murti
and Meenakshi Bajpai
Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India

Abstract

The delivery of drugs through the skin poses both challenges and exciting possibilities. The
skin acts as a barrier against various environmental factors, making it a formidable obstacle
for drug absorption. Recent advancements in drug delivery have led to the exploration of
innovative carriers for topical applications. Solid lipid nanoparticles (SLNs) represent a
novel class of drug carriers extensively investigated for both cosmetic and pharmaceutical
purposes. Nanocosmetics incorporating carriers like SLNs offer advantages such as
targeted drug delivery, controlled release, improved physical stability, and solutions to
penetration challenges. This chapter delves into the types of dermal infections, fabrication
methods for SLNs, and the pathways and mechanisms involved in skin absorption.
Nanoparticles, particularly SLNs, contribute multifaceted outcomes for skin protection
against infections, wound healing, and overall natural care enhancement. SLNs play a
crucial role in assisting herbal industries in the discovery of new antimicrobials,
antifungals, antibiotics, and antivirals, thereby improving drug delivery. Scientific research
conducted by scholars explores novel avenues for industries to commercialize therapeutics,
focusing on novel drug delivery targets for topicals in treating various infectious diseases
such as acne, psoriasis, pemphigus, hyperpigmentation, and fungal infections.
Additionally, the chapter covers regulatory aspects and patented applications of
nanoparticles in cosmeceuticals, emphasizing their role in topical and transdermal delivery.
This comprehensive exploration underscores the potential and significance of SLNs in
revolutionizing drug delivery for skin-related issues.

Keywords: skin, dermal infections, topicals, transdermal delivery, SLNs, nanocosmetics,

health sciences


Corresponding Author’s Email: [Link]@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
170 Ashima Ahuja, Yogesh Murti and Meenakshi Bajpai

Abbreviations

AgNPs Silver Nanoparticles

AmB DNs Amphotericin B dendrimers
AmB Amphotericin B
ASCP-LCs Ascorbyl palmitate-Liquid crystals
AuNPs Gold Nanoparticles
CUR-LPs Curcumin loaded-Liposomes
DNs Dendrimers
EC Ethyl cellulose
ETs Ethosomes
HPMC Hydroxy propyl methyl cellulose
ITZ Itraconazole
ITZ-NPs Itraconazole-Nanoparticles
LPs Liposomes
NEEM-LPs Neem-Liposomes
NLCs Nanostructure lipid carriers
NMR Nuclear magnetic resonance
NPs Nanoparticles
PAC-NCs Paclitaxel-Nanocarriers
PAMAM Poly (amidoamine)
PEA Palmitoyl ethanol amide
PEA-NLCs Palmitoyl ethanol amide-Nanostructure lipid carriers
PEGylated Polyethylene glycol
PGLA-NPs Poly(lactic-co-glycolic acid)-Nanoparticles
PLGA-PEG-NPs Poly(lactic acid-co-glycolic acid)-PEGylated-Nanoparticles
PMMA Poly(methylmethacrylate)
PNPs Polymeric nanoparticles
POS-DNs Posaconazole-dendrimers
Quer-EC-NPs Quercetin loaded-Ethyl cellulose-Nanoparticles
RES Resveratrol
RES-LPs Resveratrol loaded-Liposome
SEM Scanning electron microscope
SLNPs Solid lipid nanoparticles
TEM Transmission electron microscope
TFs Transferosomes
UV-VIS Ultraviolet-visible
VIT C-EC-NPs Vitamin C loaded-Ethyl cellulose-Nanoparticles
VIT C-NPs Vitamin C loaded-Nanoparticles

Introduction

Skin infections affect millions of people worldwide. As a result, the dermatological industry is
an emerging field that is growing and leading the pharmaceutical market. Human skin
 Lipid-Based Nanoparticles for Topical and Transdermal Drug Delivery 171

comprises lipids, carbohydrates, amino acids, and hairs that form a barrier against pathogenic
microbes. Wound healing is another issue caused by the interruption of the epithelial mucosa.
Advancements in science, technology, and medication options allow dermatologists to explore
newer therapeutic targets for managing skin disorders. One such approach can be managed
through an alternative system of medicine involving nanoherbals and nanocarriers for topical
application and transdermal delivery. In recent years, alternative systems of medicine have
gained immense popularity among the masses compared to allopathic medicine (Kwan et al.,
2020; Choudhary et al., 2017). The skin serves as a natural barrier against the external
environment, promoting healing and preventing microbial growth. Conventional medication
has been employed for centuries to manage patients with dermatological conditions such as
acne, psoriasis, pemphigus, shingles, vitiligo, skin cancer, and fungal and bacterial infections.
Due to the drawbacks of conventional medication, such as poor penetration, toxicity of
synthetic drugs, solubility, and bioavailability issues, attention is now diverted towards
exploring newer therapeutic alternatives. This shift is contributing to the development of a new
era of drug delivery systems for managing skin disorders. Clinical solutions to previously
unsolved problems are now provided through novel drug delivery carriers. The anticipation of
nanotechnology is an emerging trend among researchers and scientists in the healthcare and
skincare product domains. Furthermore, nanoformulations are designed to be target-oriented
using nanoengineered or nano-structured devices, promoting the controlled release of drugs at
active sites. These formulations have multifaceted functions that can repair and rejuvenate skin
while preventing infection at the molecular level. Lipid-based nanoparticles are employed for
target-oriented, customized, and patient-tailored delivery, significantly improving patient
compliance and overcoming the drawbacks of conventional medication (Tiwari et al., 2020;
Serafini et al., 2014; Kumar et al., 2012; Aburjai et al., 2003). Lipid-based nanoformulations
are designed to enhance delivery mechanisms, with liposomes, nanoparticles, niosomes,
cubosomes, and nanosponges leading the way in topical pharmaceutical delivery by improving
solubility and bioavailability. Lipid-based nanosystems consist of biocompatible,
biodegradable drugs, and polymers that facilitate target delivery, control release, and enhance
permeability and absorption through transdermal and topical routes (Akombaetwa et al., 2023).
Furthermore, researchers and scientists are increasingly focused on exploring nanotargets for
topical and transdermal delivery to improve patient compliance. Nanotechnology-based
formulations can modify drug release, enhance skin tolerance, and improve permeation across
the stratum corneum, contributing to the preservation of natural skin (Nasir et al., 2010;
Venugopal et al., 2008). Lipid-based nanoparticles have demonstrated significant potential in
the healthcare industry for topical delivery. However, the governing absorption mechanism of
the topical route for lipid-based carriers requires further attention and investigation. This
chapter primarily focuses on exploring nanoformulations for topical and transdermal delivery
in the management of dermal infections, their mechanisms of action, and the selection of
suitable novel carriers for delivery. Additionally, it highlights the application of lipid-based
nanoparticles for topical delivery in the management of skin disorders and discusses the
physiochemical properties of lipid carriers. Moreover, researchers face regulatory challenges
in developing nanocarriers for cosmetics delivery and addressing issues related to drug
absorption through the skin (Liu et al., 2020; Goyal et al., 2016).
172 Ashima Ahuja, Yogesh Murti and Meenakshi Bajpai

Skin Anatomy and Drug Absorption Mechanism

Skin acts as a natural barrier and is considered the largest organ in the body with coverage of
around 2m2 area. It has multiple functions of preventing a microbial attack, protecting against
hydration and mechanical shock, stress, and promoting cooling by sweat; it is mainly composed
of 3 layers: the outer layer is termed the epidermis, the dermis, and the inner layer is
subcutaneous. Each skin layer can perform multiple functions, and drug release can be
governed through various pathways and mechanisms (Mohamed et al., 2022; Dehdashtian et
al., 2018).

Types of Skin Disorders, Their Management and Exploring Newer Paths in Cosmetics
for Topical and Transdermal Delivery
Researchers and scientists focus on various skin disorders and their possible management
through medication that has clinical answers in cosmetic industries for topical and transdermal
delivery. Different types of skin disorders for topical delivery are broadly explained in
Table 1.

Nanotherapeutics: Exploration and Revolution in Dermatology for Topical Delivery

Scientists have done extensive research in proving nanocarriers efficacy in dermatology
involving novel drug delivery carriers. Nanotherapeutics like nanoparticles have gained
immense popularity as they help to solve problems encountered with conventional medication,
helping academic researchers to frame newer target-based formulations that promote
permeation across stratum corneum, improving drug residence time. They have recently gained
the limelight as they can solve many hurdles associated with conventional medication. This
innovative technology fosters better therapeutic outcomes for topical and transdermal delivery
(Ma et al., 2000; Zeb et al., 2019). Furthermore, nanotechnology bridges the gap between novel
delivery carriers and conventional medication. Biosensing devices, tissue engineering,
molecular docking, and predicting surface morphology are gaining interest among researchers
to achieve more advanced clinical answers to unexplored paths (Nene et al., 2021; Muller et
al., 2000).

Nanoparticles for Topicals and Transdermal Delivery: Treatment, Applications and

Therapeutic Outcomes
Nanoparticles (NPs) are explored for a wide range of biomedical applications due to their
nanosized that offer an advantage over other carriers. They can deliver hydrophilic and
lipophilic drug carriers, improving permeation and retention. Further, the NPs are widely
designed for controlled and targeted drug delivery, promoting drug release into deeper tissues
(Nami and Aghebati-Maleki, 2021; Akhtar et al., 2015). NPs are topically employed for various
biomedical applications and topical delivery that are elaborated in Figure 1. In addition,
commonly used NPs for transdermal delivery are dendrimers, liposomes, multiple emulsions,
nano-emulsions, and polymeric nanoparticles. Different types of NPs for topical and
transdermal delivery are explained in Figure 2.
 Lipid-Based Nanoparticles for Topical and Transdermal Drug Delivery 173

Figure 1. Biomedical applications of nanoparticles (NPs) for various diseases and topical delivery.

Figure 2. Different types of nanoparticles (NPs) for topical applications.

 Table 1. Types of dermal infection, major attributes and treatment option

Type of Infection Affected areas Major Attributes Treatment options References

Skin Wrinkles Near eyes, neck and Skin becomes dry, less elastic and thick, on Herbal remedies like tulsi leaves combined with (Chaiyana et al., 2019)
cheeks exposure to sun, causes break down of skin water improves skin, wrinkles and aging (antiga)
connective tissue, develops wrinkles
Psorasis Scaly patches on skin due Increase mitosis and lesions, Itching, allergic Aloe vera used as Topical agents, acupuncture, (Rajeswari et al, 2012;
to hyperproliferation of reaction, pain and fracture, damage to Curcumin reduces skin inflammation and helpful in Kumar et al., 2010; Yadav
keratinocytes epidermal layer psoriasis et al., 2021; Chibm and
Pathak, 2023)
Acne Fat, wax, oil deposition on Overproduction of sebum, cause Probiotics, prebiotics, topical agents prevent skin (Sathish et al., 2011;
skin, block hair follicle, inflammation, acne infection and redness. microbiome, Aloe, barbaloin prevents acne, eczema, Singh et al., 2020; Khan and
dark spots on skin Allergic, irritating and discomforting, clot insect bite by reducing sebum production, Tulsi Mukhtar, 2007)
pores and cause bacterial growth leave poultices promotes acne healing
Wound healing Curing fungal, bacterial and viral infection Garlic, onion act as a powerful antioxidant, promotes (Beauty Glimpse, 2023)
promotes wound healing healing
 Table 2. Nanoformulations for topical and transdermal delivery and their applications

Nanoformulations Drugs and Herbs Prepared formulation Methods Delivery and disease Outcomes References
targeted
Resveratrol loaded Resveratrol Chitosan based hydrogel Thin film Topical delivery and useful Hydrogel prepared promotes (Jøraholmen
Liposomes (RES-LPs) hydration in the management of inflammation and effectively et al., 2020)
vaginal infection in female treats vaginal infection
Curcumin loaded Azelaic acid Phospholipid based Dispersion Topical delivery prepared Optimized formulation showed (Burchacka
Liposomes (CUR-LPs) Hydrogel was prepared method for management of Acne increased bioavailability and et al., 2016)
and hyperpigmentation antimicrobial potency
Posaconazole based Posaconazole PEGylated DNs were Conjugation Topically formulated for Antifungal activity was observed (Tang et al.,
dendrimers (POS-DNs) prepared for topical method antifungal effects with prolonged effect for 72hours 2021)
application
Amphotericin based Amphotericin Polyamidoamine Solubilization Topically formulated for Improved solubility of antifungal (Jose and
dendrimers (Amp-DNs) dendrimers were prepared method antifungal effects drug and with sustained release Charyul, 2016)
for topical application
Paclitaxel based Paclitaxel Carbopol based Vacuum Transdermal application for Melanoma was improved with (Raahuln et al.,
nanocarriers (PAC-NCs) transdermal gel for skin evaporation skin cancer enhanced permeation 2019)
infection method
Cryptotanshinone based Cryptotanshinone Carbopol based ethosomal Thin film Topical gel formulated for Topical gel improves transdermal (Yu et al., 2016)
Ethosomes (CRY-ETs) gel for acne and hydration antibacterial and acne flux and effectively manages
antibacterial effects for method acne and have potent antibacterial
topical application effect, reducing skin irritation in
rabbits
Vitamin C-based Ethyl Vitamin C HPMC and EC based Solvent Hyperpigmentation and Skin permeation and enhanced (Duarah et al.,
cellulose Nanoparticles VITC -NPs for topical evaporation photoaging was topically bioavailability was observed, 2017)
(VITC-EC-NPs) delivery managed controlled release 8h
Rosemary extract based Rosemary extract Cholesterol, linoleic acid Encapsulation Antioxidant and antiwrinkle Topical application reduces (Ezzat et al.,
transferosomes and Span-60 were used for method effects were managed antiwrinkle score, provides free 2016)
(ROS-TFs) topical formulation topically radicle scavenging effect, with
inhibition in expression MMP-2
and 9, skin irritation was
decreased
176 Ashima Ahuja, Yogesh Murti and Meenakshi Bajpai

Polymeric Lipid-Based NPs

Liposomes (LPs)
They are composed of phospholipid bilayers having aqueous pores and are phospholipid-based
nanocarriers. Spherical in nature are capable of trapping both hydrophobic and hydrophilic
drugs. They are formulated using methods like thin-film hydration, ultrasonication, reverse-
phase evaporation, and extrusion. They are explored for multifaced pathological diseases like
skin ailments, cancers, topical and transdermal delivery providing controlled and sustained
release like skin cancers, neurogenerative disorders, diabetes, fungal invasions, and topical
delivery (Bozzuto and Molinari, 2015).

Solid-Lipid Nanoparticles (SLNPs)

SLNPs contain three main components, including surfactant, water, and lipid, with 50-1000 nm
diameters. They were developed in the early 1990s and act as promising drug delivery carriers
that are explored for cutaneous permeation. SLNPs are formulated for controlled and sustained
release effect, and their surface is modified with polymers for topical applications for enhancing
skin permeation (Jeon et al., 2013).

Ethosomes (ETs)
They are soft flexible, and consist of phospholipids combined with water and ethanol. They are
more effective than LPs as ethanol can fluidize stratum corneum protein. They are explored for
topical, transdermal delivery and skin infections like acne, aging, and psoriasis (Akhtar et al.,
2016).

Transferosomes (TFs)
These are self-optimized novel drug delivery systems widely explored for topical, transdermal
delivery, and other therapeutic potentials. TFs are also termed deformed liposomes, composed
of edge activators like span and tweens). Antifungal activity was reported in Sprague-Dawley
rats using miconazole nitrate TFs, showing reduced toxicity (Pandit et al., 2014). Griseofulvin
transferosomes were formulated for dermatophytosis infection and improved skin permeation
in guinea pigs (Aggarwal and Goindi, 2012).

Sillica and Metallic Based Nanoparticles

With advancements in science and technology, the attention of researchers is moving towards
metallic NPs like AgNPs for antibacterial and antifungal applications, with a size range of 1-
100 nm (Marin et al., 2015). Another example of AuNPs-based nano preparation was targeted
for improving subcutaneous delivery (Huang et al., 2010). Furthermore, Zinc oxide and
Titanium dioxide NPs have been employed for cosmetic practices like sunscreen, promoting
wound healing (Chigurupati et al., 2013). Due to the smaller particle size range of metallic NPs,
they become invisible over the skin surface, providing efficacy in targeted drug delivery for
topical application (Anselmann, 2001).

Dendrimers (DNs)
These are synthetic macromolecules, branched and explored in the nanomedicine field for skin
infections; commonly used are polyamidoamines (PAMAM) and polyesters (PGLSA-OH)
 Lipid-Based Nanoparticles for Topical and Transdermal Drug Delivery 177

derivatives for topical applications (Mignani et al., 2013). Various Nano formulations for
topical delivery are broadly explained in Table 2.

Toxicity, Safety and Regulatory Concerns for NPs

However, certain NPs cause lung toxicity and are carcinogenic. So, promoting regulatory
concerns and generating data for their safety is essential. One example is nano titanium dioxide
(TiO2), which produces carcinogenic and inhalation problems (SCCS, 2018), Furthermore,
Nanocarbon black decreases skin absorption and acts as carcinogenic (SCCS, 2013) and nano
zinc oxide causes lung inflammation when used for cosmetics or UV protection effects as
sunscreens (SCCS, 2012).

Conclusion

Nano-drug delivery is a driving force in the biomedical field as it is target-specific and offers
advantages in bioavailability and low dose frequency. Nanoparticles are an innovative delivery
carrier that can successfully overcome the drawbacks of conventional medication. Moreover,
it provides flexibility in curing various ailments and is utilized for transdermal and topical
delivery of drugs. Pharmaceutical industries, researchers, and scientists have shown keen
interest in Nanoparticles therapeutics as a future for drug delivery due to their application in
multifaced therapeutic outcomes. Furthermore, nanoparticles unraveled mechanisms and
demand the attention of researchers to screen the unexplored path, providing a valuable
innovative method for researchers to explore newer therapeutics with topical and transdermal
delivery.

References

Aburjai, T., Natsheh, F. M. (2003). Plants used in cosmetics. Phytotherapeutic Research, 17, 987-1000.
Aggarwal. N., Goindi, S. (2012). Preparation and evaluation of antifungal efficacy of griseofulvin loaded
deformable membranevesicles in optimized guinea pig model of Microsporum canis - dermatophytosis.
International Journal of Pharmaceutics, 437(1-2), 277-287.
Akhtar, N., Verma, A., Pathak, K. (2015). Topical delivery of drugs for the effective treatment of fungal
infections of skin. Current Pharmaceutical Design, 21(20), 2892-2913.
Akhtar, N., Varma, A., Pathak, K. (2016). Ethosomes as vesicles for effective transdermal delivery: From
bench to clinical implementation. Current Clinical Pharmacology, 11(3), 168-190.
Akombaetwa, N., Ilangala, A. B., Thom, L., Memvanga, P. B., Witika, B. A., Buya, A. B. (2023). Current
advances in lipid nanosystems intended for topical and transdermal drug delivery applications.
Pharmaceutics, 15(2), 656.
Anselmann, R. (2001). Nanoparticles and nanolayers in commercial applications. Journal of Nanoparticle
Research, 3, 329-336.
BeautyGlimpse (2023, August 15) How To Use Onion For Skin Care? Also Know The Benefits And Side
Effects. Retrieved from the BeautyGlimpse website: [Link]
use/.
Bozzuto, G., Molinari, A. (2015). Liposomes as nanomedical devices. International Journal of Nanomedicine,
10, 975-999.
178 Ashima Ahuja, Yogesh Murti and Meenakshi Bajpai

Burchacka, E., Potaczek, P., Paduszyński, P., Karłowicz-Bodalska, K., Han, T., Han, S. (2016). New effective
azelaic acid liposomal gel formulation of enhanced pharmaceutical bioavailability. Biomedicine &
Pharmacotherapy, 83, 771-775.
Chaiyana, W., Anuchapreeda, S., Punyoyai, C., Neimkhum, W., Lee, K. H., Lin, W. C., Lue, S. C., Viernstein,
H., Mueller, M. (2019). Ocimum sanctum linn. as a natural source of skin anti-ageing compounds.
Industrial Crops and Products, 127, 217-224.
Chigurupati, S., Mughal, M. R., Okun, E., Das, S., Kumar, A., McCaffery, M., Seal, S., Mattson, M. P. (2013).
Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial
cells in cutaneous wound healing. Biomaterials. 34, 2194-2201.
Choudhury, H., Pandey, M., Hua, C. K. (2017). An update on natural compounds in the remedy of diabetes
mellitus: A systematic review. Journal of Traditional and Complementary Medicine, 8(3), 361-376.
Dehdashtian, A., Stringer, T. P., Warren, A. J., Mu, E. W., Amirlak, B., Shahabi, L. (2018). Anatomy and
Physiology of the Skin. In: Riker, A. (eds.) In Melanoma: A Modern Multidisciplinary Approach.
Springer, Cham. pp. 15-26.
Duarah, S., Durai, R. D., Narayanan, V. B. (2017). Nanoparticlein-gel system for delivery of vitamin C for
topical application. Drug Delivery and Translational Research, 7(5), 750-760.
Ezzat, S. M., Salama, M. M., ElMeshad, A. N., Teaima, M. H., Rashad, L. A. (2016). HPLC–DAD–MS/MS
profiling of standardized rosemary extract and enhancement of its anti-wrinkle activity by encapsulation
in elastic nanovesicles. Archives of Pharmacal Research, 39(7), 912-925.
Goyal, R., Macri, L. K., Kaplan, H. M. Kohn, J. (2016). Nanoparticles and nanofibers for topical drug delivery.
Journal of Control Release, 28(240), 77-92.
Huang, Y., Yu, F., Park, Y. S., Wang, J., Shin, M. C., Chung, H. S., Yang, V. C. (2010). Co-administration of
protein drugs with gold nanoparticles to enable percutaneous delivery. Biomaterials, 31, 9086-9091.
Jeon, H. S., Seo, J. E., Kim, M. S., Kang, M. H., Oh, D. H., Jeon, S. O., Seong, H. J., Choi, Y. W., Lee, S.
(2013). A retinyl palmitate-loaded solid lipid nanoparticle system: effect of surface modification with
dicetyl phosphate on skin permeation in vitro and anti-wrinkle effect in vivo. International Journal of
Pharmaceutics, 452, 311-320.
Jøraholmen, M. W., Johannessen, M., Gravningen, K., Puolakkainen, M., Acharya, G., Basnet, P., Škalko-
Basnet, N. (2020). Liposomes-in-hydrogel delivery system enhances the potential of resveratrol in
combating vaginal chlamydia infection. Pharmaceutics, 12(1203), 1-14.
Jose, J., Charyulu, R. N. (2016). Prolonged drug delivery system of an antifungal drug by association with
polyamidoamine dendrimers. International Journal of Pharmaceutical Investigation, 2016, 6(2), 123-127.
Khan, N. Mukhtar, H. (2007). Tea polyphenols for health promotion. Life Sciences, 8(7), 519-533.
Kumar, K. S., Bhowmik, D., Chiranjib., Biswajit. (2010). Aloe vera: A potential herb and its medicinal
importance. Journal of Chemical and Pharmaceutical Research, 2, 21-29.
Kumar, S., Swarankar, V., Sharma, S., Baldi, A. (2012). Herbal cosmetics: Used for skin and hair. Inventi
Rapid: Cosmeceuticals, 4, 3-7.
Kwan, S. H., Ismail, M. N. (2020). Discovery of Channa striata extracts as regenerative medicine in promoting
wound healing and scarless skin regeneration. Natural Product Journal, 10(1), 1-8.
Liu, M., Wen, J., Sharma, M. (2020). Solid lipid nanoparticles for topical drug delivery: Mechanisms, dosage
form perspectives, and translational status. Current Pharmaceutical Design, 26(27), 3203-3217.
Ma, Z., Wang, X., Li, C. (2000). Strategies of drug delivery for deep fungal infection: A review.
Pharmaceutical Nanotechnology, 8(5), 372-390.
Marin, S., Vlasceanu, G. M., Tiplea, R. E., Bucur, I. R., Lemnaru, M., Marin, M. M., Grumezescu, A. M.
(2015). Applications and toxicity of silver nanoparticles: A recent review. Current Topics in Medicinal
Chemistry, 15, 1596-1604.
Mignani, S., El Kazzouli, S., Bousmina, M., Majoral, J. P. (2013). Expand classical drug administration ways
by emerging routes using dendrimer drug delivery systems: A concise overview. Advanced Drug Delivery
Reviews, 65, 1316-1330.
Mohamed, S. A., Hargest, R. (2022). Surgical anatomy of the skin. Surgery, 40:1-7.
Nami, S., Aghebati-Maleki, A., Aghebati-Maleki, L. (2021). Current applications and prospects of
nanoparticles for antifungal drug delivery. EXCLI Journal, 20, 562-584.
 Lipid-Based Nanoparticles for Topical and Transdermal Drug Delivery 179

Nasir, A. (2010). Nanotechnology and dermatology: Part II-risks of nanotechnology. Clinics in Dermatology,
28, 581-588.
Nene, S., Shah, S., Rangaraj, N., Mehra, N. K., Singh, P. K., Srivastava, S. (2021). Lipid based nanocarriers:
A novel paradigm for topical antifungal therapy. Journal of Drug Delivery Science and Technology, 62,
102397.
Pandit, J., Garg, M., Jain, N. K. (2014). Miconazole nitrate bearing ultraflexible liposomes for the treatment of
fungal infection. Journal of Liposome Research, 24(2), 163-169.
Raahulan, S., Sanapalli, B. K. R., Karri, V. V. S. R. (2019). Paclitaxel loaded transferosomal vesicular drug
delivery for the treatment of melanoma skin cancers. International Journal of Research in Pharmaceutical
Sciences, 10(4), 2891-2897.
Rajeswari, R., Umadevi, M., Rahale, C. S., Puspha. R., Kumar, S., Bhowmik, D. (2012). Aloe vera: The miracle
plant its medicinal and traditional uses in India. Journal of Pharmacogosy and Phytochemistry, 1(4), 118-
124.
Sathish, D., Shayeda, Rao, Y. M. (2011). Acne and its treatment options - A review. Current Drug Delivery,
8(6), 634-639.
Scientific Committee on Consumer Safety (SCCS) (2012, September 25) Opinion on Zinc Oxide (Nano Form).
Retrieved from the Scientific Committee on Consumer Safety website: [Link]
scientific-opinion-on-nano-form-zinc-oxide-available-for-comment/ Scientific Committee on Consumer
Safety (SCCS) (2013, December 12) Opinion on Carbon Black (Nano Form). Retrieved from the
Scientific Committee on Consumer Safety website:.[Link]
consumer_safety/docs/sccs_o_144.pdf
Scientific Committee on Consumer Safety (SCCS) (2018, January 19) Opinion on Titanium Dioxide (Nano
Form) as UV-Filter in Sprays. Retrieved from the Scientific Committee on Consumer Safety website:
[Link]
01aa75ed71a1.0001.01/DOC_1
Serafini, M. R., Guimaraes, A. G., Quintans-Júnior, L. J., Nunes, P. S., Matos, I. G., Saravanan, S., Araujo, A.
A. (2014). Recent patents on medicinal plants/natural products as a therapeutic approach to wounds and
burns healing. Recent Patents Biotechnology, 8(3), 231-239.
Singh, V., Verma, R., Kaushik, D., Mittal, V. (2020). Recent patents on phytoconstituents-based formulations
for the treatment of acne infection: A review. Recent Patents on Anti-Infective Drug Discovery, 15(2),
119-136.
Tang, S., Chen, J., Cannon, J., Cao, Z., Baker J. R., Wang, S. (2021). Dendrimer-based posaconazole
nanoplatform for antifungal therapy. Drug Delivery, 28(1), 2150-2159.
Tiwari, M., Dubey, V., Lahiri, A. (2020). Comparative study of various herbal cosmetics: A survey. Asian
Journal Pharmaceutical and Clinical Research, 13(10), 31-34.
Venugopal, J., Prabhakaran, M. P., Low, S., Choon, A. T., Zhang, Y. Z., Deepika, G. (2008). Nanotechnology
for nanomedicine and delivery of drugs. Current Pharmaceutical Design, 14, 2184-2200.
Yadav, N., Aggarwal, R., Targhotra, M., Sahoo, P. K., Chauhan, M. K. (2021). Natural and nanotechnology
based treatment: an alternative approach to psoriasis. Current Nanomedicine, 11(1), 21-39.
Yu, Z., Lv, H., Han, G., Ma, K. (2016). Ethosomes loaded with cryptotanshinone for acne treatment through
topical gel formulation. PLoS One, 11(7), e0159967.
Zeb, A., Arif, S. T., Malik, M., Shah, F. A., Din, F. U., Qureshi, O. S., Lee, E. S., Lee, G. Y., Kim, J. K. (2019).
Potential of nanoparticulate carriers for improved drug delivery via skin, Journal of Pharmaceutical
Investigation, 49, 485-517.
Chapter 13

Synergy of Nanotechnology and Genetic Therapies:

Lipid Nanocarriers for RNA and DNA Delivery

Isha Goyal1
Ridhi Bajaj1
Manish Kumar Jheengar2
and Rajan Swami1,
1
Chitkara College of Pharmacy, Chitkara University, Punjab, India
2
School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi

Abstract

Genetic mutations can render cancer cells resistant to existing chemotherapy drugs, thereby
driving the need for novel chemotherapy agents. However, the emergence of multidrug
resistance further complicates the scenario. Gene therapy has demonstrated effectiveness
not only in reducing tumor size but also in mitigating multidrug resistance, ultimately
rendering the cancer cells more responsive to chemotherapy. Indigenous fragility of genetic
material renders them incapable of being used as it is for delivery. Besides, systemic and
cytoplasmic enzymes responsible for the lysis of DNA and RNA material make it even
harder to deliver neurotherapeutics to the target site, i.e., cytoplasm or nucleus. The
synergy between nucleic acid therapies and nanotechnology has opened the door to
groundbreaking strategies in the realm of molecular medicine. This book chapter explores
the dynamic interface of RNA and DNA therapies with lipidic nanoparticles, showcasing
their potential to revolutionize the landscape of targeted drug delivery.

Keywords: lipidic nanoparticles, nanoparticles, gene delivery, shRNA, DNA

Abbreviations

NPs Nanoparticles
DNA Deoxyribonucleic acid
RNA Ribonucleic acid
LNPs Lipidic Nanoparticles
mRNA Mitochondrial mRNA


Corresponding Author’s Email: drrjnswami@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
182 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

shRNA Short hairpin RNA

MDR Multi drug resistance
EPR Enhanced Permeability and Retention
SLNs Solid lipid nanoparticles
SDDS Smart drug delivery systems
CDDS Control drug delivery systems
DSPE 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine
DOPE dioleoylphosphatidylethanolamine
siRNA Small interfering RNA

Introduction

Advancements in our comprehension of diseases’ molecular and genetic foundations have

catalysed the transition from conventional chemical therapeutics to a new therapeutic paradigm
grounded in biological genetic material. This emerging domain, termed “gene therapy,” is
focused on the cautious introduction of therapeutic or functional gene copies into specific
cellular targets within an individual. The primary objective of gene therapy is to rectify or
replace defective genetic sequences. This entails either the replacement of malfunctioning
genes with healthy equivalents or the introduction of novel genetic elements with the purpose
of ameliorating or positively modulating the clinical trajectory of a particular medical
condition. It can also repair damaged DNA, prevent metastasis, and offer customized treatments
based on a patient’s unique genetic profile. While gene therapy is still under investigation, its
potential for more effective and less toxic cancer treatments is significant, but the field is
continually evolving with ongoing research and clinical trials (Andrade López et al., 2023).
This year, the Nobel prize in chemistry was awarded to Katalin Karikó, and Drew Weissman,
in recognition of their groundbreaking discoveries in the field of nucleoside base modifications.
Their pioneering work has paved the way for the development of highly effective mRNA
vaccines against COVID-19. These modifications hold promise for correcting gene mutations
and have opened up innovative possibilities in the development of more targeted and effective
gene therapy approaches. This achievement is significant not only in the context of addressing
the global pandemic but also has broader implications for our understanding of gene mutations
and innovative approaches in chemotherapy (de Lima Barbosa, 2023). Cancer, according to
early cancer evolution theories like those by Nowell and Vogelstein, happens when certain
changes (mutations) in pertinent genes, responsible for controlling the crucial functions of the
cells especially related to apoptosis and proliferation, are accumulated and passed on and cause
the growth of dominant cancer cells (germline mutations). These mutations make one cancer
cell different from the other and so does one type of cancer cells with another type. This
tendency marked them to be ‘heterogenous’ in nature and this heterogeneous nature marked
them hard to treat with just one medicine targeting one specific gene mutation. It’s a big
challenge for personalized cancer treatment. Sometimes, even if a drug works well at first, the
cancer can come back later. This happens because some groups of cells in the tumor are not
affected by the drug, developing multi-drug resistance (MDR) leading to no or subtherapeutic
effect, which subsequently leads to failure of therapy (Jiao et al., 2018). Besides, the idea of
using multiple drugs at the same time (co-administered drug delivery) helps to target cancer
 Synergy of Nanotechnology and Genetic Therapies 183

cell’s faulty mechanism effectively but that has been linked with elevated toxicity due to toxic
potential of associated drugs. Hence, researchers needed another area which could be used to
catch cancer from the roots i.e., genetic level. For the same, researchers find refuge in gene
therapy. Where, the complex state of cancer is changed by introducing genetic materials, like
genes, DNA, oligonucleotides, or RNA, into either cancerous or normal cells. In regular
treatments, modifications are related to how cells work by changing their proteins. However,
in gene therapy, this can be achieved by altering how specific genes are used, which then brings
about the desired changes in cell behaviour (Cross et al., 2006). Currently, there are 22
approved gene therapy products, including imlygic, luxturna, zolgensma, spinraza, patisiran,
and others (FDA). Recently world has witnessed tectonic shifts in the use of biological therapies
including gene therapy over conventional small-drug delivery. Researchers have many reasons
to advocate this shift. When we look at gene therapy broadly, we have two important parts: the
genetic “drugs” (sometimes called “passengers”) that can fix problems, and the carriers of these
drugs (like vehicles) that can take the fixes to the right place on the map inside the body where
they’re needed. While delivering genes in naked form There are many hurdles in the path to
conceptualise gene therapy for clinical use. That includes the fragile nature of the gene having
delicate nucleotide strands that break apart (called gene smearing) by the action of harsh
mechanical stirring, instrument stress or even by the action of harsh aprotic solvent
(denaturation) (Swami et al., 2013; Torchilin, 2014). Besides stability of the genetic material is
always compromised in the presence of enzymes such as DNAase, and RNAase in the
physiological systems making it difficult to deliver in naked form. Furthermore, the anionic
nature of the gene makes it difficult to internalise into the cell(Yin et al., 2014). Furthermore,
for gene therapy to be effective, delivered genetic material must continue to be expressed in
target cells over an extended period, posing a significant challenge. Other than these regulatory
concerns finding the correct dosage regimen is also a few of the concerns in effective gene
therapy (Torchilin, 2014). Hence, gene needs the assistance of a gene delivery vehicle for
cellular delivery of cargo, which includes viral vehicles, or non-viral gene delivery systems.
Viruses make obvious starting points for vector development, owing to their natural inherited
virulence to internalise in the cells to transfer their genetic materials for causing infection. Viral
vector genomes undergo modifications, including the deliberate removal of certain regions, to
disrupt their replication and enhance safety. However, this approach presents challenges,
notably heightened immunogenicity, triggering an inflammatory response that can lead to
transduced tissue degeneration, as well as concerns about toxin production, potential mortality,
insertional mutagenesis, and limitations in transgenic capacity size. This compromises further
exploration. However, evolutions in the area of viruses helped to make new viral capsids
without immunogenic factors. However, owing to these probable side effects, researchers are
not finding non-viral delivery domains (Gottesman et al., 2002). Non-viral gene delivery
methods mainly rely on using physical or chemical techniques to insert external genetic
material into specific cells. For instance, one common method is electroporation, where short
electrical pulses create temporary openings in cell membranes, enabling DNA to get inside.
Another approach involves using tiny fatty bubbles called liposomes or lipid nanoparticles
(NPs) to wrap and safeguard the genetic material, making it easier for it to enter the cells. These
methods provide versatile ways to transport genes without needing viruses, which is safer and
more adaptable for various applications in science and medicine. In addition to electroporation,
other methods such as nuceofection, sonoporation, jet gun, and gene gun exist. However, these
mechanical approaches may lack patient compliance and industrial scalability. As a result,
184 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

researchers are exploring newer technologies, such as nanotechnology, in non-viral delivery

for enhanced efficiency and broader applicability.

Navigating the Synergy of Nucleic Acid Therapies and Nanotechnology

Nucleic acid therapies and nanotechnology are indeed two rapidly advancing fields with
profound implications for the future of medicine. Nucleic acid therapies include the application
of nucleic acids, specifically DNA and RNA, as therapeutic agents for the treatment or
prevention of diseases. These therapies harness the fundamental genetic information contained
within nucleic acids to address various medical conditions, including genetic disorders,
infectious diseases, and even cancer (Gewirtz et al., 1998). Nanotechnology enables targeted
drug delivery systems, such as NPs coated with therapeutic agents, which can enhance drug
efficacy while minimizing side effects. These NPs can be engineered to specifically target
diseased cells or tissues, thereby improving drug delivery precision (Qiu et al., 2023). NPs
provide the polymeric, lipidic, and metallic NPs and nanocarriers for efficient gene delivery
(Figure 1).

Figure 1. Various nanotechnology-based delivery systems used for gene delivery.

Nanotechnology has a specific use in managing cancer illness. In essence, there are three
primary approaches to creating nano-carriers for effective gene delivery i.e., Passive Targeting,
Active targeting, and Smart delivery. The term “passive targeting” refers to the accumulation
 Synergy of Nanotechnology and Genetic Therapies 185

of NPs that do not have any specific disease-targeting elements. The extent of accumulation
depends on their inherent physical and chemical properties, such as size, shape, charge, and
flexibility, as well as the unique characteristics of the tumor, such as its abnormal blood vessel
development due to angiogenesis. This abnormal vascular structure promotes the leakage of
NPs into the tumor microenvironment, leading to a higher concentration within the tumor
compared to the bloodstream because tumors lack lymphatic drainage. This phenomenon is
known as the “Enhanced Permeability and Retention” (EPR) effect, a concept introduced by
Hiroshi Maeda and his colleagues in 1986. An alternative strategy involves “active targeting,”
which explores the use of ligands or molecules that specifically bind to receptors overexpressed
on the tumor’s surface. This approach can also involve using smart materials that respond to
specific triggers like pH, enzymes, or temperature to release drugs selectively within the tumor.
In the following sections, we will provide a comprehensive overview of various categories of
nanotherapeutic interventions for co-delivering treatments in cancer management. Another
approach, known as “smart delivery,” capitalizes on the dynamic nature of living processes that
respond to the specific conditions within the tumor. This strategy involves adapting to tumor
physiology, such as altering the delivery system’s viscosity in response to the tumor
microenvironment such as the tumor’s acidic pH, or modifying the release kinetics based on
the tumor’s hypoxic (low oxygen) state. By intelligently responding to the tumor’s environment
and needs, smart delivery systems aim to enhance the precision and effectiveness of drug
delivery in the treatment of cancer.

Lipidic Non-Viral Gene Delivery

In nanotechnology dominion, lipidic NPs (LNPs) are the only class of NPs that could be able
to overcome the clinical troubles to reach the pharmaceutical market. Hence, the researchers
have worked hard to synergise the use of lipidic NPs in gene delivery. LNPs offer scalability
thanks to well-established manufacturing processes and can be readily adapted by adding
targeting molecules. Depending upon the vast array of lipids, the LNPs can be divided into two
major parts, vesicle-based and matrix-based. A detailed representation of the type of lipidic
drug delivery is presented in Figure 1. Despite many types of gene delivery, lipoplexes are the
most general NPs used for gene delivery encompassing polyionic attraction-based NPs in
between anionic genes with cationic lipids. Subsequently, numerous polymers and newer
polymeric nanotherapeutics have been employed in combination with oppositely charged lipids
to form complexes with conjugated genes. Additionally, vesicular systems, such as liposomes,
have been investigated for the co-delivery of genes and drugs. Advanced liposomal structures
offer a significant advantage over traditional gene delivery methods by utilizing two distinct
mechanisms for targeting, resulting in a more effective reduction of tumors. Other lipid-based
NPs include matrix systems like solid lipid NPs (SLNs), oil-incorporated nanostructured lipidic
nanocarriers (NLCs), Liposomes etc., will be discussed in greater detail in the subsequent
sections of this chapter. Figure 2. illustrates various lipidic nanoparticles used for gene delivery
with their advantages and disadvantages.
Toxicity is the primary concern, which limits the exploration of drug delivery. Being from
a synthetic origin, they tend to show higher toxicity. Subsequently, this could happen due to
the biocompatible nature of the lipids. The biocompatibility of lipids plays a pivotal role in their
186 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

suitability for various biomedical applications. Due to their natural presence within the human
body, lipids often demonstrate a remarkable level of biocompatibility, reducing the likelihood
of adverse reactions or toxicity when they are employed in medical contexts. Moreover,
researchers can modify and tailor lipids to further enhance their biocompatibility, ensuring their
safety and effectiveness in delivering therapeutic agents or genetic materials. The capacity of
lipids to form stable and biocompatible structures, such as lipid NPs and liposomes, has
significantly advanced the field of nanomedicine, offering a versatile platform for delivering
treatments while minimizing any harm to the body’s natural processes.

Figure 2. Various lipidic nanoparticles explored for gene delivery.

Synergy between Lipidic NPs and Nucleic Acid Therapy

Passive and Active Targeting

Passive targeting involves the use of physicochemical and pharmacological factors to ensure
that a drug or drug-carrier system remains focused on a particular treatment site for
maintenance purposes (Öztürk et al., 2018). Passive targeting takes advantage of specific
changes in the cancer vasculature. These modifications, along with the specific shape of the
nanoparticle formulations, enable them to cross these permeable junctions, allowing their
gradual and selective build-up at the tumor site. This phenomenon is known as the EPR effect
(Clemons et al., 2018). The use of passive drug targeting strategies enables the development of
targeted nano-carrier systems loaded with chemotherapy drugs, resulting in an enhanced
therapeutic profile while minimizing toxic effects. The passive targeting approach has
significant therapeutic potential and is less toxic; however, this is affected by the variability of
the EPR effect between and within different tumors, as well as the physical constraints
 Synergy of Nanotechnology and Genetic Therapies 187

associated with it (Rosenblum et al., 2018). Han et al prepared a nanocage system based on
upconversion NPs. This system provided protection for the siRNA, prevented its degradation
by the nuclease in organisms, and selectively delivered siRNAs to tumor sites. The nanoparticle
system demonstrated tumor-suppressive effects using passive targeting in the treatment of lung
tumors, the use of tumor-targeting up-conversion nanoparticle nanocages resulted in consistent
changes in body weight and higher tumor inhibition ratios (Han et al., 2022). For example, in
a study, Jyotsana et al. have used LNPs for delivery of RNA interference (RNAi)-based
therapeutics (siRNA) using lipidic NPs against driver BCR-ABL fusion oncogene to target
human chronic myeloid leukemia (CML) cells in vivo. The study demonstrated the prepared
cationic LNPs’ role in delivering 100% content to cancer cells in a non-toxic manner (Jyotsana
et al., 2019). Although we found many data related to passive targeting before 2015, that old
data will not do justice with this updated chapter. However, there are instances where multiple
drugs were co-delivered with genes to substantiate the supportive gene therapy with drugs. To
improve the efficiency of breast cancer treatment and reduce side effects, researchers co-loaded
paclitaxel (PTX), crizotinib (CRI), and Bcl-xL siRNA into cationic liposomes (CTL). These
liposomes leverage the EPR effect in breast cancer. The resulting CRI-PTX-CTL had specific
characteristics with a particle size of approximately 138.63 nm and a zeta potential of about
50.90 mV. In vitro, release studies revealed simultaneous release of CRI and PTX from the
liposomes. Cellular experiments demonstrated synergistic effects of CRI and PTX, effective
uptake of these compounds, and successful inhibition of Bcl-xL expression by CTL-siRNA.
This study underscores the potential of CRI-PTX-CTL-siRNA as a promising delivery system
for breast cancer treatment (Li et al., 2022). Lipids have also been used to decrease the toxicity
issues of the polymers by conjugating genes with the combination of lipids and polymers. This
assembly on the one hand helps to decrease the toxicity of the polymer on the other helps in
making the system biocompatible. Monirinasab et al. conjugated siRNA with polylectic acid
(PLA)-polyethylene glycol (PEG)-PLA copolymer with lipids. The resultant NPs were able to
internalise into the MCF7 cell and able to downregulate the cancerous IGF-1R gene (70% ± 3)
(Asadi et al., 2018). Similar research was also reported by Thanki et al (Thanki et al., 2019).
Active targeting is important to deliver drugs, genes, and theranostics to specific sites of interest
while bypassing normal tissues. This approach increases therapeutic efficacy while minimizing
side effects (Attia et al., 2019). Strategies for active targeting to specific sites can be classified
into three types: targeting tumor cells, vascular targeting, and targeting subcellular organelles
(Yang et al., 2016). Active targeting involves the use of one or more targeting moieties attached
to the surface of the nanoparticle. These fragments specifically interact with antigens or
receptors that are either uniquely expressed or highly expressed on tumor cells compared to
normal tissues (Pearce et al., 2019). Using molecular recognition processes, the coupling of a
homing moiety, such as a ligand or monoclonal antibody, can achieve drug delivery to
pathological sites or enable crossing biological barriers through active targeting (Kumari et al.,
2016). Active targeting serves as a complementary approach to EPR-based passive targeting,
aiming to enhance the accumulation and retention of nanomedicines in tumors (Shi et al., 2020).
Holistic explorations were also carried out in the case of LNPs for gene therapy. The subsequent
sections of the chapter illustrate the research undertaken in the area of LNPs which are
conjugated or coated with the ligands having affinity for the receptors overexpressed on tumor
cells. As with other targeting domains, folic acid is also explored to maximize gene delivery.
Kabilova et al., prepared a folate-containing liposome conjugate using PEG as a linker. They
introduced a polycationic lipid, 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-
188 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

tetraazahexacosan, to enhance the fusogenic properties of the liposomes. Additionally,

dioleoylphosphatidylethanolamine (DOPE) was added to further increase Fusogenicity The
prepared formulations resulted in 3-4 fold higher internalization of siRNA targeting MDR1
mRNA. In vivo, studies demonstrated an approximately 18% increase in intratumor titer due to
efficient downregulation of p-glycoprotein expression (to 40% of the control) in the tumor
(Kabilova et al., 2018). While Li et al. aimed to enhance efficacy through the co-delivery of
chemotherapeutic drugs with gene delivery, they tagged liposomes with folic acid and
encapsulated them with ursolic acid for this purpose. The encapsulated tagged liposomes were
further complexed with Bmi1 siRNA. The prepared formulation successfully led to significant
tumor reduction (Li et al., 2019). on the other side, Tong et al. utilised a dual targeting strategy
for cervical cancer targeting. The liposomes were complexed with siRNA Bcl-2 and tagged
with folic acid and hyaluronic acid for dual targeting. The results were promising and showed
remarkably high transfection in tumor cells leading to inhibition of the cancer-causing gene
Bcl-2 causing apoptosis (Tong et al., 2020). Transferrin is a protein that has been extensively
used in active targeting of gene delivery. Many researchers have utilised it in single or dual
targeting. Ilarduya et al. documented that transferrin-lipoplexes enhance gene delivery in the
presence of serum, improving expression in primary cells, HepG2, and 3T3-L1 adipocytes.
They protect DNA from degradation and are prepared efficiently with protamine sulfate. In
vivo, protamine-Tf-lipoplexes achieve significant gene expression in various tissues following
intravenous administration (De Ilarduya et al., 2002). Similarly, to overcome the BBB
limitations, liposomal NPs engineered with transferrin and penetratin (Pen) were used to deliver
the nerve growth factor (NGF) gene to treat Alzheimer’s disease (AD). In vitro and in vivo
studies demonstrated the effectiveness of these dual-modified liposomes in crossing the BBB,
increasing NGF expression in neuronal cells, and reducing toxic Aβ peptides in APP/PS1 mice.
This approach shows promise for AD treatment through NGF gene therapy, stimulating cell
proliferation and enhancing synaptic markers (Rodrigues et al., 2020). Another similar work
documented by Wu et al demonstrated the use of PEG to make stealth liposomes for long-
circulating liposomes DNA complexes NPs in the blood by bypassing clearance and
recognition from RES uptake. Besides surface modification with Transferrin helps in targeting
the NPs in the brain by crossing BBB. The lipoplex ratio (DOTAP (cationic lipid): DNA Ratio)
was found to be pertinent in stabilising the DNA (Wu et al., 2020). The targeting ability of the
transferrin was further advanced using dual targeting using two different ligands
simultaneously, liposomal NPs with dual surface modifications using cell-penetrating peptide
(PFVYLI or R9F2), and transferrin ligands were prepared. These NPs demonstrated higher in
vitro transfection efficiency than single-modified ones. R9F2Tf-liposomes effectively crossed
the BBB and transfected primary neurons in vitro, as well as reached the brain parenchyma in
mice (6.6%) without causing damage. This dual-modification strategy of targeting transferrin
receptors and enhancing cell penetration proves effective for brain-targeted gene delivery (dos
Santos Rodrigues et al., 2020a). similarly, Rodrigues and colleagues. The group prepared a
dual-functionalized liposome system, Cell-penetrating peptide (CPP)-transferrin-liposome for
efficient brain gene delivery by crossing the BBB. Three different CPPs (penetration
accelerating sequence–R8, Kaposi fibroblast growth factor (kFGF), melittin) were compared
for enhancing transfection efficiency. These modified liposomes effectively penetrated BBB in
an in vitro model, leading to the successful transfection of primary neurons. In vivo, kFGF-
Transferrin-liposomes demonstrated superior BBB penetration and brain distribution after
intravenous administration, suggesting the potential of this strategy for brain-targeted gene
 Synergy of Nanotechnology and Genetic Therapies 189

delivery (dos Santos Rodrigues et al., 2020b). Wei et al., devised a strategy consisting of
selective transferrin coating to create blood-brain barrier (BBB)-permeable and targeted
vesicles for potent RNA interference (RNAi) therapy of brain metastatic breast cancer. They
developed transferrin-functionalized chimeric polymersomes carrying small interfering RNA
(siRNA) against Polo-like kinase 1 (Tf@TBP-CPs-siPLK1) for the treatment of brain
metastatic triple-negative breast cancer (TNBC) in MDA-MB 231 cells. Transferrin facilitated
efficient penetration of the BBB and displayed high specificity towards MDA-MB 231 cells.
As a result, Tf@TBP-CPs-siPLK1 effectively inhibited tumor progression. This selective
transferrin coating is a powerful approach for RNAi therapy in brain metastatic breast cancer
(Wei et al., 2021). In another study, Hagino et al., have created GALA-modified lipid NPs for
targeted delivery of plasmid DNA into the lungs, aiming to treat lung cancer. When plasmid
DNA was encapsulated in double-coated LNPs, transfection activity in the lungs was
significantly improved. In summary, the optimized double-coated GALA (GALA peptide)-
MEND (multifunctional envelope-type nanodevice) described in this study demonstrates
highly efficient and selective delivery and expression of plasmid DNA in the lungs by assisting
dual functions one in targeting the cancers second by enhancing the endosomal escape of the
cargo which ease in cytoplasmic delivery of the cargo. Furthermore, the double-coating strategy
significantly increases the efficiency of gene expression at the intracellular level. The optimized
double-coated GALA-MEND holds great potential to treat lung cancer (Hagino et al., 2021).
Few researchers have used co-delivery of gene and chemotherapeutic drugs simultaneously
using a targeting ligand. Zhang et al., delivered docetaxel and GRP78 siRNA using 1,2-
Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)/DOPA (dioleoyl phosphatidic acid)
lipoplex NPs for the management of castration-resistant prostate cancer. Cell adhesion peptides
like arginine-glycine-aspartic acid (RGD) peptide was used as targeting moiety to channelise
the movement of the NPs. The possible synergy between DTXL and GRP78 siRNA enhances
cell cycle progression, apoptosis, and autophagy, potentially increasing DTXL’s cell-killing
effect. This research has promising clinical applications (Zhang et al., 2019). Hepatocellular
carcinoma (HCC) is a widespread and severe cancer, often resistant to chemotherapy. A study
reported by Kim et al., explored a combination therapy approach using hepatoma-targeting
ligand-based liposomes to co-deliver curcumin and PTTG1 siRNA for enhanced anticancer
effects. The liposomes effectively loaded curcumin and siPTTG1, accumulated at tumor sites,
entered HCC cells and displayed greater cytotoxicity to cancer cells compared to non-targeted
liposomes. This dual-treatment approach effectively inhibited tumor growth and showed
promise for improving HCC treatment (Kim et al., 2023). Another group has worked on similar
lines and was able to deliver docetaxel with SIRT 1 shRNA using amino acid-lipid based
biosurfactant coated dendrimers. The biosurfactants in aggreplexes help to reduce the toxicity
of the cationic dendrimers by balancing the charge and also assist in increasing the hydrophobic
drug encapsulation by multiple folds. Inhibitory concentration when half of the concentration
of cells were dead (IC50) was found to be ~3.2 folds lower in the case of aggreplexes as
compared to naïve counterparts (Malavia et al., 2021). Although active targeting is very
effective in transferring the content to the required tumor cites but immature release of cargo
before reaching desired sites. For this purpose, smart drug delivery strategies were used.
190 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

Smart Delivery

Smart drug delivery systems (SDDS) involve a process in which drugs are either not released
(or released extremely slowly) before reaching target tissues/organs and only at specific sites
of action, delivered at reasonable rates (Liu et al., 2016). SDDS can deliver drugs to specific
locations with low dosing frequency and spatial control, aiming to reduce the side effects
encountered in traditional drug delivery systems (CDDS) (Hossen et al., 2019). SDDS offer
advantages because they have the potential to overcome some of the physiological challenges
faced by traditional chemotherapeutics. These SDDS can selectively accumulate at the tumor
site, thereby achieving high therapeutic indices. Tumors have a few characteristic hallmarks
that were accumulated in the cell in the journey to become tumor cells. One of the hallmarks
of changing the tumor microenvironment in a way that supports the angiogenesis and flourishes
tumor cell division (low pH etc.) or by increasing inflammation using tumor-associated
macrophage polarisation. By taking advantage of these changes many researchers have
modulated the delivery system to make them target cancer in a more specific way. They may
also respond to double or multiple combinations of different stimuli. This extraordinary
adaptability has increased their importance as controlled drug delivery systems with site-
specific precision. Smart drug delivery can be utilised using multiple ways. But primarily the
exploration was carried out using the advantage of tumor microenvironment characteristics
such as acidic pH, hypoxic state, high temperature, redox potential, etc. The LNPs were
designed in a way that they deliver the gene only in the vicinity of the tumor where the
mentioned stimuli are present. Our group has worked on shRNA delivery using pH-sensitive
liposomes. We designed a specific and improved breast cancer therapy using pH-sensitive
liposomes for the co-delivery of SIRT1 shRNA and Docetaxel. DTX-lipoplexes were prepared
through solvent evaporation and rehydration methods. Extensive evaluation in vitro and in vivo
revealed that DTX-lipoplex demonstrated approximately threefold higher docetaxel
concentration within tumor cells, leading to a significant reduction in tumor burden compared
to non-pH-sensitive lipid transfection agents and clinical (Approximately 78%). In conclusion,
co-delivering docetaxel and SIRT1 shRNA within a single tumor-specific nano-platform has
the potential to enhance the therapeutic efficacy of current therapies (Kumar et al., 2020, Swami
et al., 2021). Sato et al., worked on the same line but used their own customized pH-sensitive
lipid YSK12-C4, for the preparation of liposomes. The structure activity relationship of the
lipids assisted in easy internalisation by escaping the endosomes, followed by a significant
reduction in IC50 values. In another study, siRNA delivery is a critical task as they tend to
aggregate in physiological conditions due to traditional ionizable lipids. To overcome this
challenge, we developed a new charge-reversible lipid called dioleoylglycerophosphate-
diethylenediamine conjugate (DOP-DEDA), capable of maintaining a consistent charge across
different pH levels, eliminating the need for PEG-conjugated lipids to ensure stability. DOP-
DEDA LNPs efficiently encapsulate siRNA targeting polo-like kinase 1 (PLK1), effectively
suppressing its expression. Notably, their interaction with biological membranes is pH-
dependent, and cellular uptake is boosted by apolipoprotein E3 (apoE3). This innovation makes
DOP-DEDA LNPs a reliable and potent siRNA delivery system with significant therapeutic
potential. Lipid-based “nano-Transformers” are engineered for efficient siRNA delivery in
cancer treatment. They adapt to the intracellular acidic environment, enabling siRNA release
into the cytoplasm with high loading efficiency and minimal cytotoxicity. Unlike traditional
carriers, they promote endosomal membrane fusion, leading to direct siRNA release. In vitro,
 Synergy of Nanotechnology and Genetic Therapies 191

they achieve up to 95% reduction in CDK1 mRNA, and in vivo, they inhibit tumor growth
without causing immunogenic responses, making them a promising next-gen siRNA delivery
system for enhanced efficacy and safety (He et al., 2018). Shobaki et al., manipulated the
function of TAM by LNPs consisting of pH sensitive lipids composed of siRNA (inhibiting M2
polarisation of TAM). It was selectively and efficiently taken up and demonstrated robust gene
silencing activity in tumor-associated macrophages (TAMs) within a human tumor xenograft
model in nude mice. siRNA delivery silenced the signal transducer and activator of
transcription 3 (STAT3) and hypoxia-inducible factor 1 α (HIF-1α) (Shobaki et al., 2020).

Challenges in Gene Delivery using LNPs

Lipid NPs used for gene delivery face several substantial challenges. Firstly, the process of
scaling up their production from laboratory-scale to larger quantities presents various
difficulties. Maintaining batch-to-batch consistency becomes critical to ensure that the NPs
perform reliably and effectively. Additionally, optimizing the manufacturing process is
essential not only to ensure consistent quality but also to make it cost-effective for potential
clinical and commercial use. Secondly, regulatory hurdles pose a significant barrier. These lipid
NPs are subject to rigorous oversight by regulatory bodies such as the FDA and EMA. To gain
approval for clinical use, extensive preclinical and clinical studies must be conducted to
demonstrate the safety and efficacy of the NPs. Initially, ethical clearance was the major
concern however existence of newer therapies in the market eased the clinical trials for
upcoming gene delivery. A few of the clinical trials completed or undergoing are presented in
Table 1. This regulatory process is intricate, time-consuming, and costly, making it particularly
challenging for smaller research groups and companies to navigate.

Table 1. Completed and active clinical trials in the field of gene delivery using lipids or other
delivery systems

Identifier Company Disease Vector/Gene Clinical trial

phase
NCT00003450 University of Texas Ovarian Cancer and Ad5CMV-p53 gene 1, Completed
Southwestern Medical Peritoneal Cavity
Center Cancer
NCT04911166 Houston Methodist Cancer Non-Small Cell Lung AdV-IL-12 1, Completed
Center Cancer
NCT00788307 Mayo Clinic Rochester Prostate cancer Ad5-CMV-NIS 1, Unknown
NCT02555397 Henry Ford Health System Prostate cancer Ad5-yCD/ 1, Completed
Detroi mutTKSR39rep-hIL12
NCT00004038 Fox Chase Cancer Center Breast Cancer Ad5CMV-p53 gene I, Completed
Philadelphia
NCT01455389 Genprex, Inc. Lung Cancer TUSC2 I/II Active
NCT02340117 SynderGene Therapeutics, Metastatic Pancreatic SGT-53 II recruiting
Inc. cancer
NCT0591356 M.D. Anderson Cancer Advanced malignant EphA2 siRNA I active
Solid Neoplasm

Thirdly, the interaction of these NPs with proteins is a complex and critical aspect. These
particles can form what’s known as a “protein corona” when they come into contact with
192 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

proteins in the biological environment, altering their surface properties and behaviour. This
interaction can lead to unpredictable changes in how they are distributed within the body and,
consequently, their therapeutic outcomes. Understanding and controlling these interactions are
essential to ensure the reliability, safety, and effectiveness of lipid nanoparticle formulations.
Similarly, PEG surface coating (PEG chain length and PEG amount) influences the carrier
intracellular internalization. In addition to these challenges, there are broader considerations
such as how the immune system responds to these NPs, the potential for unintended effects in
the body, and the development of resistance to gene therapy. To overcome these challenges, a
multidisciplinary approach involving experts in various fields such as materials science,
pharmacology, immunology, and regulatory affairs is crucial.

Conclusion

Gene delivery is a complex endeavour that demands advanced formulation techniques to

safeguard the delicate genetic material. NPs have revolutionized gene delivery systems,
offering numerous advantages such as scalability, biocompatibility, and tumorgenicity.
Researchers have employed lipid-based drug delivery systems through various approaches.
This includes directly complexing genes with cationic lipids to form lipoplexes or surface-
complexing genes with liposomes or lipid nanocarriers, utilizing the cavities or matrix of the
lipidic system to enable co-delivery of other drugs. To enhance targeting precision, the surfaces
of these lipid carriers have been further modified with single or multiple ligands to facilitate
binding to overexpressed receptors on cancer cells. A promising approach for cancer gene
delivery involves utilizing physiological markers or hallmarks specific to cancer cells as stimuli
for the controlled release of genes from carriers or to localise the vehicle in the tumor vicinity.
Despite significant research efforts, challenges persist due to regulatory issues, translating
research findings into practical applications in the industry, and concerns related to
immunogenicity and off-target effects of genes. Nevertheless, as research continues to advance,
there is optimism for a promising future in the field of gene delivery.

References

Andrade López, J. M., Pani, A. M., Wu, M., Gerhart, J., Lowe, C. J. (2023). Molecular characterization of
nervous system organization in the hemichordate acorn worm Saccoglossus kowalevskii. Plos Biology,
21(9), e3002242.
Asadi, H., Rostamizadeh, K., Esmaeilzadeh, A., Khodaei, M., and Fathi, M. (2018). Novel lipid-polymer hybrid
nanoparticles for siRNA delivery and IGF-1R gene silencing in breast cancer cells. Journal of Drug
Delivery Science and Technology, 48, 96-105.
Attia, M. F., Anton, N., Wallyn, J., Omran, Z., and Vandamme, T. F. (2019). An overview of active and passive
targeting strategies to improve the nanocarriers efficiency to tumour sites. Journal of Pharmacy and
Pharmacology, 71(8), 1185-1198.
Clemons, T. D., Singh, R., Sorolla, A., Chaudhari, N., Hubbard, A., Iyer, K. S. (2018). Distinction between
active and passive targeting of nanoparticles dictate their overall therapeutic efficacy. Langmuir, 34(50),
15343-15349.
Cross, D., Burmester, J. K., (2006). Gene therapy for cancer treatment: past, present and future. Clinical
medicine & research, 4(3), 218-227.
 Synergy of Nanotechnology and Genetic Therapies 193

De Ilarduya, C. T., Arangoa, M., Moreno-Aliaga, M., Düzgüneş, N. (2002). Enhanced gene delivery in vitro
and in vivo by improved transferrin-lipoplexes. Biochimica et Biophysica Acta (BBA)-Biomembranes,
1561(2), 209-221.
de Lima Barbosa, C. (2023). Medical Ethics in Nutrology. International Journal of Nutrology, 16(2).
dos Santos Rodrigues, B., Kanekiyo, T., and Singh, J. (2020a). In vitro and in vivo characterization of CPP and
transferrin modified liposomes encapsulating pDNA. Nanomedicine: Nanotechnology, Biology and
Medicine, 28, 102225.
dos Santos Rodrigues, B., Lakkadwala, S., Kanekiyo, T., Singh, J. Dual-modified liposome for targeted and
enhanced gene delivery into mice brain, in Journal of pharmacology and experimental therapeutics.
2020b. p. 354-365.
FDA, U., Approved Cellular and Gene Therapy Products.
Gewirtz, A. M., Sokol, D. L., Ratajczak, M. Z. (1998). Nucleic acid therapeutics: state of the art and future
prospects. Blood, The Journal of the American Society of Hematology, 92(3), 712-736.
Gottesman, M. M., Fojo, T., Bates, S. E. (2002). Multidrug resistance in cancer: role of ATP–dependent
transporters. Nature reviews cancer, 2(1), 48-58.
Hagino, Y., Khalil, I. A., Kimura, S., Kusumoto, K., Harashima, H. (2021). GALA-modified lipid nanoparticles
for the targeted delivery of plasmid DNA to the lungs. Molecular pharmaceutics, 18(3), 878-888.
Han, Y., Yang, Y., Sun, Q., Li, B., Yue, C., Liu, Y., de la Fuente, J. M., Cui, D. (2022). Dual-targeted lung
cancer therapy via inhalation delivery of UCNP-siRNA-AS1411 nanocages. Cancer Biology & Medicine,
19(7), 1047.
He, S., Fan, W., Wu, N., Zhu, J., Miao, Y., Miao, X., Li, F., Zhang, X., Gan, Y. (2018). Lipid-based liquid
crystalline nanoparticles facilitate cytosolic delivery of siRNA via structural transformation. Nano letters,
18(4), 2411-2419.
Hossen, S., Hossain, M. K., Basher, M. K., Mia, M. N. H., Rahman, M. T., Uddin, M. J. (2019). Smart
nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. Journal of
advanced research, 15, 1-18.
Jiao, Q., Bi, L., Ren, Y., Song, S., Wang, Q., Wang, Y, (2018). Advances in studies of tyrosine kinase inhibitors
and their acquired resistance. Molecular cancer, 17(1), 1-12.
Jyotsana, N., Sharma, A., Chaturvedi, A., Budida, R., Scherr, M., Kuchenbauer, F., Lindner, R., Noyan, F.,
Sühs, K., Stangel, M., Grote-Koska, D., Brand, K., Vornlocher, H., Eder, M., Thol, F., Ganser, A.,
Humphries, R. K., Ramsay, E., Cullis, P., Heuseret, M. (2019). Lipid nanoparticle-mediated siRNA
delivery for safe targeting of human CML in vivo. Annals of hematology, 98, 1905-1918.
Kabilova, T. O., Shmendel, E. V., Gladkikh, D. V., Chernolovskaya, E. L., Markov, O. V., Morozova, N. G.,
Maslov, M. A., Zenkova, M. A. (2018). Targeted delivery of nucleic acids into xenograft tumors mediated
by novel folate-equipped liposomes. European Journal of Pharmaceutics and Biopharmaceutics, 123, 59-
70.
Kim, M., Kim, S.-B., Kim, J., Kim, K.-S., Kim, D.-E. (2023). Co-delivery of curcumin and PTTG1 siRNA by
galactose receptor-targeted liposomes for enhanced anti-tumor effects in hepatocellular carcinoma.
Journal of Drug Delivery Science and Technology, 86, 104692.
Kumar, Y., Kuche, K., Swami, R., Katiyar, S. S., Chaudhari, D., Katare, P. B., Banerjee, S. K., Jain, S. (2020).
Exploring the potential of novel pH sensitive lipoplexes for tumor targeted gene delivery with reduced
toxicity. International Journal of Pharmaceutics, 573, 118889.
Kumari, P., Ghosh, B., Biswas, S. (2016). Nanocarriers for cancer-targeted drug delivery. Journal of drug
targeting, 24(3), 179-191.
Li, M., Li, S., Li, Y., Li, X., Yang, G., Li, M., Xie, Y., Su, W., Wu, J., Jia, L., Li, S., Ma, W., Li, H., Guo, N.,
Yu, P. (2022). Cationic liposomes co-deliver chemotherapeutics and siRNA for the treatment of breast
cancer. European Journal of Medicinal Chemistry, 233, 114198.
Li, W., Yan, R., Liu, Y., He, C., Zhang, X., Lu, Y., Khan, M. W., Xu, C., Yang, T., Xiang, G. (2019). Co-
delivery of Bmi1 small interfering RNA with ursolic acid by folate receptor-targeted cationic liposomes
enhances anti-tumor activity of ursolic acid in vitro and in vivo. Drug Delivery, 26(1), 794-802.
Liu, D., Yang, F., Xiong, F., Gu, N. (2016). The smart drug delivery system and its clinical potential.
Theranostics, 6(9), 1306.
194 Isha Goyal, Ridhi Bajaj, Manish Kumar Jheengar et al.

Malavia, N., Ghadi, R., Kuche, K., Date, T., Bhargavi, N., Chaudhari, D., Swami, R., Katare, P. B., Banerjee,
S. K., Jain, S. (2021). Green surfactant-dendrimer aggreplexes: An ingenious way to launch dual attack
on arch-enemy cancer. Colloids Surf B Biointerfaces, 204, 111821.
Öztürk, K., Eroğlu, H., Çalış, S. (2018). Novel advances in targeted drug delivery. Journal of drug targeting,
26(8), 633-642.
Pearce, A. K. O’Reilly, R. K., (2019). Insights into active targeting of nanoparticles in drug delivery: advances
in clinical studies and design considerations for cancer nanomedicine. Bioconjugate chemistry, 30(9),
2300-2311.
Qiu, C., Wu, Y., Shi, Q., Guo, Q., Zhang, J., Meng, Y., Wang, C., Xia, F., Wang, J., Xu, C. (2023). Advanced
strategies for nucleic acids and small-molecular drugs in combined anticancer therapy. International
Journal of Biological Sciences, 19(3), 789.
Rodrigues, B. D. S., Kanekiyo, T., Singh, J. (2020). Nerve growth factor gene delivery across the blood–brain
barrier to reduce beta amyloid accumulation in AD mice. Molecular Pharmaceutics, 17(6), 2054-2063.
Rosenblum, D., Joshi, N., Tao, W., Karp, J. M., Peer, D. (2018). Progress and challenges towards targeted
delivery of cancer therapeutics. Nature communications, 9(1), 1410.
Shi, Y., van der Meel, R., Chen, X., Lammers, T. (2020). The EPR effect and beyond: Strategies to improve
tumor targeting and cancer nanomedicine treatment efficacy. Theranostics, 10(17), 7921.
Shobaki, N., Sato, Y., Suzuki, Y., Okabe, N., Harashima, H. (2020). Manipulating the function of tumor-
associated macrophages by siRNA-loaded lipid nanoparticles for cancer immunotherapy. Journal of
Controlled Release, 325, 235-248.
Swami, R., Kumar, Y., Chaudhari, D., Katiyar, S. S., Kuche, K., Katare, P. B., Banerjee, S. K., Jain, S. (2021).
pH sensitive liposomes assisted specific and improved breast cancer therapy using co-delivery of SIRT1
shRNA and Docetaxel. Materials Science and Engineering: C, 120, 111664.
Swami, R., Singh, I., Khan, W., Ramakrishna, S. (2013). Diseases originate and terminate by genes: unraveling
nonviral gene delivery. Drug Deliv Transl Res, 3(6), 593-610.
Thanki, K., Zeng, X., Foged, C. (2019). Preparation, Characterization, and In Vitro Evaluation of Lipidoid–
Polymer Hybrid Nanoparticles for siRNA Delivery to the Cytosol. Nanotechnology for Nucleic Acid
Delivery: Methods and Protocols, 141-152.
Tong, Y., Wan, W.-j., Yang, H., Wang, Y., Wang, D.-d., Liu, Y., You, B.-g., Zhang, X.-n. (2020). Dual-
targeted cationic liposomes modified with hyaluronic acid and folic acid deliver siRNA Bcl-2 in the
treatment of cervical cancer. Research Square, Pre print.
Torchilin, V. P. (2014). Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nature
reviews Drug discovery, 13(11), 813-827.
Wei, Y., Sun, Y., Wei, J., Qiu, X. (2021). Selective transferrin coating as a facile strategy to fabricate BBB-
permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo. Journal
of controlled release, 337, 521-529.
Wu, S., Fu, J., Liu, D., Chen, D., Hu, H. (2020). The Blood–Brain Barrier Cell-Targeted Gene Delivery System
to Enhance Nerve Growth Factor Protein Secretion in the Brain. ACS Biomaterials Science &
Engineering, 6(11), 6207-6216.
Yang, Y., Yu, C. (2016). Advances in silica based nanoparticles for targeted cancer therapy. Nanomedicine:
Nanotechnology, Biology and Medicine, 12(2), 317-332.
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., Anderson, D. G. (2014). Non-viral vectors
for gene-based therapy. Nature Reviews Genetics, 15(8), 541-555.
Zhang, X., He, Z., Xiang, L., Li, L., Zhang, H., Lin, F., Cao, H. (2019). Codelivery of GRP78 siRNA and
docetaxel via RGD-PEG-DSPE/DOPA/CaP nanoparticles for the treatment of castration-resistant prostate
cancer. Drug Design, Development and Therapy, 1357-1372.
Chapter 14

Lipid Nanoparticles for Blood Brain Barrier

Hitesh Chopra1
Kavita Munjal2,
Vinod Kumar Gauttam3
Divya Dhawal Bhandari4
Sonia Arora5
Sonam Yadav6
and Mohamed Rahamathulla7
1Department of Biosciences, Saveetha School of Engineering,
Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
2Department of Pharmacy, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India
3Department of Pharmacognosy, Shiva Institute of Pharmacy, Bilaspur, Himachal Pradesh, India
4University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
5Chandigarh Group of Colleges Landran, Kharar, Punjab, India
6Shri Ramswaroop Memorial University, Lucknow Deva Road, Uttar Pradesh, India
7Department of Pharmaceutics, College of Pharmacy, King Khalid University, Alfaraa, Abha, Saudi Arabia

Abstract

Advancements in nanotechnology have profoundly transformed drug delivery, particularly

in addressing brain illnesses, where traditional approaches often face significant
challenges. This chapter explores the promising use of lipid-based nanocarriers to
overcome the delivery barrier to the brain, ensuring the effective therapeutic action of drugs
within the central nervous system (CNS). Lipid nanocarriers provide a versatile platform
for encapsulating various medicinal chemicals, enhancing their stability, targeting
specificity, and bioavailability. Examples of these nanocarriers include liposomes, solid
lipid nanoparticles, nanostructured lipids, and lipid-drug complexes. The text meticulously
examines the structural and chemical characteristics of different lipid nanocarriers and their
impact on the encapsulation and release kinetics of drugs. Lipid bilayers can accommodate
hydrophilic, hydrophobic, or amphiphilic drugs due to their adjustable properties, and
surface modification procedures enhance stability and prolong circulation time. The
chapter delves into preclinical and clinical research illustrating the effectiveness of lipid
nanocarriers in treating various neurological illnesses, including brain tumors, CNS-related
disorders such as Parkinson’s and Alzheimer’s, and neuroinflammatory ailments. The
conclusion of this chapter underscores the exceptional potential of lipid nanocarriers as a


Corresponding Author’s Email: kavitamunjal915@[Link].

In: Lipid Based Nanocarriers for Drug Delivery

Editors: Shikha Baghel Chauhan, Indu Singh, Ajmer Singh Grewal, Rajwinder Kaur
ISBN: 979-8-89113-920-6
© 2024 Nova Science Publishers, Inc.
196 Hitesh Chopra, Kavita Munjal, Vinod Kumar Gauttam et al.

flexible and successful method for enhancing brain medication delivery. The integration of
nanotechnology with lipid-based formulations lays the foundation for ongoing research and
advancement in the field of CNS treatments, presenting a novel approach to overcoming
the challenges associated with treating brain illnesses.

Keywords: lipid nanocarriers, blood-brain barrier, neurological illnesses, bioavailability,

release kinetics.

Abbreviations

BBB Blood-Brain Barrier

CNS Central Nervous System
DTX Docetaxel
Lipo-DOX Liposomal doxorubicin
DA Dopamine
SLNs Solid Lipid Nanoparticles

Introduction

The blood-brain barrier (BBB) is a crucial delivery control system in the human body, playing
a vital role in maintaining the delicate balance of the central nervous system (CNS) (Kadry et
al., 2020). It constitutes a complex system of meticulously regulated cellular and molecular