Send Orders for Reprints to reprints@benthamscience.

net 1431

Anti-Cancer Agents in Medicinal Chemistry, 2020, 20, 1431-1446

REVIEW ARTICLE
ISSN: 1871-5206
eISSN: 1875-5992

Impact
Factor:
2.04

Synthesis and Applications of Hydrogels in Cancer Therapy

The journal for in-depth reviews and high quality research
papers on Anti-Cancer Agents

Anchal Singhal1,*, Niharika Sinha2, Pratibha Kumari3 and Manoushikha Purkayastha3

1
Department of Chemistry, St. Joseph's College (Autonomous), Bangalore-560027, India; 2Department of Chemistry, Gautam Buddha
University, Noida, India; 3Department of Chemistry, Deshbandhu College, University of Delhi, New Delhi, India

Abstract: Hydrogels are water-insoluble, hydrophilic, cross-linked, three-dimensional networks of polymer

Anti-Cancer Agents in Medicinal Chemistry

chains having the ability to swell and absorb water but do not dissolve in it, that comprise the major difference
ARTICLE HISTORY
between gels and hydrogels. The mechanical strength, physical integrity and solubility are offered by the
crosslinks. The different applications of hydrogels can be derived based on the methods of their synthesis, re-
Received: March 23, 2019 sponse to different stimuli, and their different kinds. Hydrogels are highly biocompatible and have properties
Revised: November 10, 2019
Accepted: December 04, 2019 similar to human tissues that make it suitable to be used in various biomedical applications, including drug de-
livery and tissue engineering. The role of hydrogels in cancer therapy is highly emerging in recent years. In the
DOI:
10.2174/1871521409666200120094048
present review, we highlighted different methods of synthesis of hydrogels and their classification based on
different parameters. Distinctive applications of hydrogels in the treatment of cancer are also discussed.

Keywords: Hydrogels, biocompatible, polymers, cancer therapy, drug discovery, tissue engineering.

1. INTRODUCTION 2.1. Chemical Crosslinking

Hydrogels were first discovered in 1960 by Lim and Wichterle 2.1.1. Chemical Crosslinking by Free Radical Polymerization
[1]. These are cross-linked three-dimensional (3-D) network struc-
tures that possess the ability to absorb large amounts of water or Free radical polymerization comprises the chain growth
biological fluid without dissolving and are also known as aquagel method, which involves three steps viz., initiation, propagation and
[2]. Hydrogels are highly compatible with the human biological termination. Chemical crosslinking by free radical involves two
system due to their high water content. The water molecules are steps (i) polymerization of suitable hydrophilic polymers, (ii)
associated with the three-dimensional (3-D) network which forms a crosslinking of the polymeric chain by crosslinking agents such as
quasi-organized structure [3]. This 3-D network of hydrogels is glutaraldehyde [6], methacrylic groups [7], etc. The most studied
maintained through the elasticity of the solid. Dried hydrogels (xe- hydrogel example of this category is poly(2-hydroxyethyl
rogels) absorb water and the amount of water absorbed decides methacrylate) which is synthesized by the polymerization of 2-
their sizes. A compound must contain a minimum 10% of water to hydroxyethyl methacrylate which is further crosslinked in the pres-
behave like a hydrogel. A hydrogel is also often referred to as su- ence of crosslinking agent i.e., ethylene glycol dimethacrylate [8].
perabsorbent, if the weight of water absorbed exceeds 95% [4]. Since then, several hydrogels have been synthesized by modifying
monomer derivatives and crosslinking agents to enhance the char-
Due to their high water content, they undergo physical and acteristic properties of hydrogels. The majority of stimuli-
chemical changes in the presence of external stimuli such as pH, responsive hydrogels were synthesized by using this very conven-
temperature, magnetic or electric field, chemical substances, etc. tional method of the synthesis of polymers. In these polymers, a
and hence find numerous applications in different areas such as change in swelling of hydrogels occurs in presence of external
medicine, biotechnology, bioengineering and others. Herein, we stimuli such as a change in pH [9], temperature, UV-light, electric
present the synthesis, classification strategies and different uses of and magnetic fields, solvent and chelating species as well as inter-
hydrogels, especially in cancer therapy. nal stimuli such as CO 2, glucose, DNA, proteins, enzymes, anti-
gens/antibodies, etc.
2. PREPARATION/SYNTHESIS METHODS OF
HYDROGEL 2.1.2. Crosslinking by Complementary Functional Group via
Chemical Reactions
Different polymerization methods could be utilized for the syn-
thesis of the cross-linked polymeric chains that make up hydrogels. Polymers, having certain hydrophilic functional groups, such as
The properties of hydrogel depend on the arrangement and extent of –OH, –CONH–, –CONH2–, and –SO3H facilitate hydrogels to ab-
cross-linking of polymeric chains. On a broad scale, the synthesis sorb water and hence act as a potential material for their synthesis.
of the hydrogel can be summarized into two categories namely The reaction of polymeric chains having a specific functional group
chemical and physical methods respectively [5]. The schematic with complementary reactive functional groups such as an amine-
representation of synthetic strategies of hydrogels is shown in carboxylic acid or an isocyanate-OH/NH reaction or by Schiff base
Schemes 1 and 2. is used to form a covalent linkage. For example, hyaluronic acid
hydrogels were obtained by the derivatization of hyaluronic acid
with adipic dihydrazide followed by crosslinking with a macromo-
*Address correspondence to this author at the Department of Chemistry, St. lecular crosslinker. These gels are enzymatically degradable with
Joseph's College (Autonomous), Bangalore-560027, India; hyaluronidase and therefore have the potential to act as a delivery
E-mail: [email protected] matrix for sustained release of drugs at wound sites [10].

1875-5992/20 $65.00+.00 © 2020 Bentham Science Publishers

1432 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.



           

            

    

        
     
       
      

       

    !
  

                  

     

Scheme 1. Synthetic strategies of hydrogels.

However, a hydrogel formed by crosslinking by addition reac- which further combines to form covalent crosslinking. High radia-
tion is preferable as it does not form any by-products and hence this tion crosslinking in the presence of oxygen (particularly in solution
method can be easily applied for an in situ formation of a hydrogel. phase) is specifically important in the formation of natural hydro-
For example, polysaccharides can be crosslinked with a variety of gels as it enhances the mechanical and thermal properties of these
reagents such as 1,6-hexamethylenediisocyanate, divinyl sulfone, or hydrogels [20, 21]. Rimdusit et al., comparatively studied the prop-
1, 6-hexane dibromide and many others by addition reaction [11]. erties of chemical and radiation-induced crosslinking of methylcel-
Crosslinking of Poly(Ethylene Glycol) (PEG) derivatives can be lulose [22]. Studies have shown that the degree of swelling of the
achieved by Michael-type addition with di- or trifunctional prote- radiation-induced crosslinked hydrogel is more than the chemically
ase-sensitive peptides [12], multifunctional PEG thiols [13], thiol- crosslinked hydrogels, though increasing the dose of radiation
modified chitosan [14] and other reagents. The network properties clearly decreases the degree of swelling. Mechanistically, on expo-
of hydrogel can be tuned by varying the concentration of the dis- sure to high energy radiation, water molecules dissociate to gener-
solved polymer and the amount of crosslinking agent. ate hydroxyl groups that attack polymer chains to give rise to the
formation of micro-radicals. These micro-radicals recombine on
2.1.3. Crosslinking by Condensation Reaction different chains and result in the formation of a covalent-
The formation of hydrogel crosslinked by condensation reac- crosslinked structure [23]. Examples of some polymers which are
tions can be done by applying the same methodology used for the generally crosslinked through high energy irradiation are
synthesis of condensation polymer between hydroxyl groups or poly(acrylic acid) [24], poly(ethylene glycol) [25], poly(vinyl alco-
amines with carboxylic acids [15]. Condensation reaction involving hol) [26], Poly(Vinyl Methyl Ether) (PVME) [27], and PNIPAAm
the formation of carbon-nitrogen double bond is studied most as it hydrogels [28]. Hydrogel properties such as swelling ratio and per-
requires milder condition, as well as the only byproduct form in the meability mainly depends upon the contents of polymers used and
reaction is water. The stability of the hydrogel crosslinked by the irradiation dose [29, 30].
formation of the C=N bond can be altered by varying the substrate, 2.1.5. Crosslinking Using Enzymes and Peptides
as well as the catalyst, used in the reaction [16]. Kalow and group
synthesized the photoresponsive hydrogel by crosslinking thiol with Chemical crosslinking using chemical reagent as a crosslinker
boronic acid forming a boronic ester [17]. N,N-(3- may produce some of the other side effects, so as the crosslinking
dimethylaminopropyl)-N-ethyl carbodiimide was used as a reagent involving high radiations. Enzymes/peptides crosslinked hydrogels
to synthesize gelatin-based hydrogel by Feijen et al. [18]. Yoshida are highly biocompatible with better pharmacokinetics and their
et al. [19] prepared temperature-responsive hydrogels using NI- degradation evidently produces no toxicity to the biological envi-
PAAm copolymers with poly(amino acid)s as a side-chain group ronment as well as their degradation rate can be monitored by vary-
and activated ester groups. These hydrogels easily get crosslinked ing the substrate and concentration of crosslinker [31]. Zhu et al.,
with the degradable poly(amino acid) chains upon merely mixing synthesized a series of pH-sensitive hydrogels crosslinked by pep-
the copolymer aqueous solutions. tide-based bis-acrylate showing enhanced drug delivery properties
in antibacterial wound dressing applications [32]. Broguiere and
2.1.4. Crosslinking by High Energy Irradiation group synthesized the hydrogel crosslinked by bacterial ligase en-
High-energy radiations, such as gamma (γ) and electron beam, zyme i.e., sortase A. The studies reveal that enzyme sortase A has
can be used to polymerize unsaturated compounds without the use some of the better applications such as faster gelation, better
of crosslinker. High radiation introduces crosslinking without the crosslinking for 3D-culture and tissue engineering applications, as
addition of any chemical reagent, but by the formation of radicals compared to transglutaminase activated factor XIII [33, 34]. Other
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1433

O H
O H
O H
O H

O H
Hydrogen bonding N
OH H
Ionic interaction COOH H2N
COOH H2N
COOH H2N

Condensation reaction

Protein/enzyme Initiator I
Protein/enzyme crosslinking
linker Free-radical
Linker

Radiations
Crystallization
g/a/UV
X-rays

Scheme 2. Synthesis of hydrogels through different methods.

enzymes which are studied and reported in the synthesis of molecules [45] but can also be used as a matrix for the encapsula-
crosslinked hydrogels are Transglutaminase (TG) [35], peroxidases tion of living cells and for the release of proteins [46]. Crosslinking
[36], tyrosinase [37], phosphopantetheinyl transferase [38], lysyl through ionic interaction is widely studied in the synthesis of in situ
oxidase [39], plasma amine oxidase [40], phosphatases [41] and gelling hydrogels as this interaction gives the advantage of biodeg-
recently dual enzyme viz., HRP & tyrosinase [42]. Enzymatic radation in extracellular fluids which bind competitively with the
crosslinking requires milder conditions such as neutral pH, in an gel components and as a result, decross-linking of network occurs.
aqueous medium and at moderate temperature entailing that they In addition to this, ionic interaction is also used to crosslink mi-
can also be used to develop in situ hydrogels. Thi et al., synthesized croparticle or nanoparticle gels. This approach can be applied for
in situ hydrogels crosslinked with dual enzymes, where Horseradish the peptides having opposite charge, which predominantly forms
Peroxidase (HRP) and Tyrosinase (Tyr) were used. In situ formation of the β-sheet structure and further forms hydrogel [47].
hydrogel carries a promising range of biomedical applications.
2.2.2. Crosslinking with Hydrogen Bonding
2.2. Physical Crosslinking Hydrogen bonding interactions can also be used to form physi-
The synthesis of the hydrogel by physical crosslinking has cally crosslinked gel-like structures. Mixtures of two or more natu-
gained significant attention in recent years. Physically crosslinked ral polymers can display rheological synergism, i.e., the polymer
hydrogel does not require a linking agent as compared to chemical blends are gel-like as compared to their constituent polymer indi-
crosslinking methods. Crosslinking agents not only affect the pro- viduals. Such types of interactions can be seen in Poly(Acrylic
bity of the substances, but they may also produce some toxic effects Acid) (PAAc) and Poly(Methacrylic Acid) (PMAAc) where the
naturally. Different methods involved in the synthesis of physically polymers forming hydrogel are held together by hydrogen bonds
crosslinked hydrogels are as follows: between the oxygen of the PEG and the carboxylic group of PAAc
or PMAAc [48]. Water content, as well as mechanical properties of
2.2.1. Crosslinking by Ionic Interaction the hydrogel, can be modulated by varying solvent and altering the
temperature. Taking advantage of these properties, Zhang et al.
The synthesis of hydrogel through crosslinking by ionic interaction synthesized tough and stiff poly(1-vinylimidazole-co-methacrylic
can be achieved in two ways (i) between a polymer and an oppositely acid) (P(VI-co-MAAc)) hydrogels [49]. Chang et al. synthesized the
charged small molecule as a linker, and (ii) between two polymers dual crosslinked hydrogel with high toughness due to the synergic effect
of opposite charge. Ionic crosslinking hydrogels are said to be sen- of hydrophobic alkyl chain and hydrogen bonding of ureidopyrimidone
sitive for pH change at room temperature [43, 44]. Drug delivery in moiety of poly(ureidopyrimidone methacrylate-co-stearyl acrylate-
the case of acidic pH in hydrogel crosslinked by ionic interactions co-acrylic acid) [P(UPyMA-co-SA-co-AA)] [50].
is faster as compared to the ionic crosslinked hydrogel in basic pH.
Alginate and chitosan are well-known examples of anionic and 2.2.3. Crosslinking by Crystallization
cationic polymers respectively that can be crosslinked by ionic
interactions. Ionic crosslinked hydrogels due to their biocompatibil- The crystallization of polymers is another method to form
ity and ease of gelation not only make them easily encapsulate bio- physically crosslinked gels. For example, when PVA aqueous solu-
1434 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

tion is stored at room temperature, the hydrogel of low mechanical Table 1. Classification of hydrogels based on different parameters.
strength is formed while a strong and highly elastic hydrogel is
formed when the same solution undergoes the freeze-thawing proc- S. No. Based On Classification Refs.
ess. The nature of gel forms depends upon the concentration, tem-
perature, time of freezing and the number of freezing cycles. BSA 1. Origin Natural [57]
protein-loaded PVA gel can also be obtained by dissolving BSA in Synthetic
an aqueous solution of PVA through freeze-thawing crystallization 2. Electrical Charge Neutral [58]
[51]. The preparation of dextran hydrogels and microspheres, based Ionic
on physical crosslinking using the crystallization technique, has Ampholytic
also been reported.
Zwitterionic
2.2.4. Crosslinking by Stereocomplex Formation 3. Ability to Swell Low [59]
Stereo-complexation is a synergistic interaction between poly- Medium
mer chains or small molecules of the same chemical composition, High
having different stereochemistry. Stereo-complex formation occurs Superabsorbent
due to the interaction between polymers having different tacticities 4. Crosslinking Physical [60]
or configurations. A well-known example of stereo-complexation Chemical
comprises the interaction between poly-lactic acid blocks with L-
and D-stereochemistry [52]. Hydrogel formation by isotactic 5. Composition Homopolymer [61]
PMMA and syndiotactic PPMA can be achieved by crosslinking Copolymer
through stereocomplexation [53]. Stereo-complex crosslinked hy- Multipolymer
drogel formation can occur by the blends of triblock copolymers of 6. Configuration Amorphous [62, 63]
PLLA–PEG–PLLA and PDLA–PEG–PDLA [54]. The major ad- Semi-crystalline
vantage of this system is that a hydrogel can be easily formed upon Crystalline
dissolving each product in water and mixing the solution. One sig-
nificant limitation of stereo-complexation is, however, the relatively
restricted range of polymer compositions that can be used. methyl/ethyl in their structure that forms hydrogen bonds with wa-
ter molecules. These hydrogels rupture cancer cells in a specific
2.2.5. Crosslinking by Amphiphilic Graft/Block Polymer range of temperature depending upon the type of tumor cells and
the polymer from which the hydrogel is prepared. Hydrogels com-
Hydrophobic interactions play an important role in designing
prising the hydrophobic amino acid residues L-valine and L-
physically crosslinked gels. Amphiphilic block and graft copoly- phenylalanine incorporated with magnetic nanoparticles have been
mers can self-assemble in water to form organized structures such
used for target-specific delivery of Doxorubicin (DOX), which is a
as polymeric micelles and hydrogels, in which the hydrophobic
well-known anti-cancer drug. The release of DOX with these gels
segments of the polymers are aggregated. Poloxamer (PX) is a as the carrier was controlled by temperature [66].
polymer which shows the thermo-reversible property in aqueous
solutions. PX consists of hydrophilic Poly (Ethylene Oxide) (PEO) Generally, thermoresponsive hydrogels can be classified ac-
and hydrophobic Poly(Propylene Oxide) (PPO) blocks arranged in cording to their either Lower Critical Solution Temperature (LCST)
a tri-block structure as PEO–PPO–PEO. The gelation of PX de- or Upper Critical Solution Temperature (UCST) properties. Almost
pends upon both temperature and concentration and the total gelling all the applications of these hydrogels depend upon the tempera-
process [55]. PX exists as a monomer in solution but as the concen- ture-responsive sudden change at LCST. Increased temperature
tration of PX increases, spherical micelles start to build up. Fur- leads to rupture of hydrogen bonding, van der Waals interactions
thermore, an increase in the PX concentration leads to a tightly among the polymer-polymer or polymer-solvent and hence these
packed system with a gel consistency [56]. forces dominate at LCST that led to a change in solubility and
hence the effect [67]. Recently, Qian et al., reported the synthesis of
3. CLASSIFICATION OF HYDROGELS gold nanorods-doped thermosensitive hydrogel that can be used for
the prevention of post reoccurrence of breast cancer. The doped-
Hydrogels can be broadly classified into various types based on hydrogel was loaded with doxorubicin and with the use of Near
different parameters, which are shown in Table 1 [57-63]. Infra-Red (NIR) laser and photothermal effects of gold nanorods,
Hydrogels are usually called smart hydrogels as they can adjust the drug was triggered to be released that induced the contraction of
very easily with environmental conditions. They respond to differ- a thermo-responsive hydrogel. Hence, this hybrid hydrogel finds
ent stimuli such as ionic strength, pH, magnetic, electric, enzy- great potential in the treatment of breast cancer reoccurrence [68].
matic, thermal, and different chemical setting. These conditional
changes are governed by the presence of types of functional groups 3.2. pH-Responsive Hydrogels
attached to hydrogels and various fundamental forces such as ionic pH-responsive hydrogels comprise polyelectrolytes that contain
and hydrophobic interactions, van der Waals forces and hydrogen the ionizable groups such as weak acids or weak bases with a pH
bonding, which make them interact within or between different range of 3-10 in their structure. Any change in pH is associated
hydrogel moieties (Fig. 1). with either acceptance or donation of electrons of the groups at-
The different stimuli-responsive hydrogels are discussed below: tached to the polymer chains. These groups can be any functional
moiety such as carboxylate, aldehyde, amine, ester, nitrate, etc. The
3.1. Thermoresponsive Hydrogels acidic groups release protons at high pH, while the basic groups
accept protons at low pH. The change in the electronic structure of
Temperature plays an important role in determining the proper- polymeric gels due to a change in environmental pH leads to swel-
ties of hydrogels based on the equilibrium between hydrophilic and ling or de-swelling, and other changes in solubility, structural con-
hydrophobic moieties present in them [64]. A very small tempera- formation and surface reactivity of these pH-responsive hydrogels
ture change can shift the original equilibrium and hence bring a [69]. Owing to these ubiquitous properties, these kinds of hydrogels
change in their properties [65]. These are generally aqueous mono- find great potential in various applications such as the delivery of
meric or polymeric gels having more hydrophobic groups such as insulin [70], cancer treatment [71], and delivery of drugs in the
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1435

   #  
    
   
  
 
   
 

       

 

     
    
 
 
     

 

   !

Fig. (1). Fundamental forces that control the behavior of stimuli-responsive polymeric hydrogels.

different body parts through injectable hydrogels [72-74]. The suc- efficient carriers for drug delivery. The light-triggered hydrogels
cess of these applications of pH-responsive hydrogels is based on can be categorized into three types namely 1) exhibiting photother-
the fact that there is a wide pH range in the gastrointestinal tract of mal effect, 2) up-converting nanoparticles and 3) two-photon ab-
the human body and some specific regions of tumors as well that sorption. Near Infra-Red (NIR) responsive hydrogels exert a pho-
stimulate the response to environmental stimuli for drug delivery tothermal effect upon irradiation with NIR light that leads to in-
systems. The most commonly formulated pH-controlled polymeric creased temperature and triggers the release of drug at target site.
gels include Poly(Acrylic Acid) (PAA), Poly(Methacrylic Acid) These drug carrier hydrogels also exert cytotoxic effects on the
(PMAA) and poly(N, N’-dimethyl aminoethyl methacrylamide) tumor cells due to increased temperature and hence synergize the
(PDEAEMA) [75]. Lee et al. formulated a PAA-based polymeric therapeutic effect [81]. Two-photon absorption in the NIR range
hydrogel that can efficiently deliver the doxorubicin in the body for exerts higher excitation and better penetration of drugs and hence
the treatment of breast cancer. The release of drug was triggered at overcomes the drawback of poor penetration of UV-Vis range drug
reduced pH that led the stimuli-responsive hydrogel to collapse the delivery systems. Fourniols et al. [82] synthesized light-stimulated
vesicle and hence inhibits the tumor growth [76]. Recently, Jay- Temozolomide (TMZ)-loaded hydrogel and studied its efficiency in
mond et al., synthesized a chitosan-based hydrogel grafted with treating brain tumors. The TMZ-loaded hydrogel has been observed
graphene oxide and PMAA. This gel showed the highest efficiency to photopolymerize very quickly upon irradiation with a UV light
of drug release at pH 4 and hence studied for the potential use in the that triggered the release of TMZ (drug) at the tumor site. The de-
treatment of breast cancer [77]. The sponge-like pH-responsive creased tumor weight using this light-sensitive hydrogel proved its
nature of PDEAEMA imparts the properties of anti-cancer thera- potential application in cancer treatment. According to a report,
peutic release. Recently, Chen et al. reported the synthesis of novel Zhang et al. prepared an ABA-type triblock copolymer hydrogel
polymeric micelle as pentablock-[poly(ethyleneglycol)-b-(poly(2- loaded with gold nanorods, which generates photothermal effect
(diethylamino)ethylmethacrylate)-b-poly(hydroxy ethyl methacry- upon irradiation with NIR light and hence triggers the site-specific
late)-g-folic acid)2] [PEG-b-(PDEAEMA-b-PHEMA-g-FA)2] that release of the drug while undergoing gel–sol transition [83].
acts as an efficient drug carrier for anticancer therapy [78]. It has
Photodegradable hydrogels have also been prepared by incorpo-
been shown that at a reduced pH of 5, the amino groups get proto-
rating three different photocleavable groups into the backbone of
nated that trigger the highest release of doxorubicin compared to a
PEG macromers [84]. Photo-crosslinked hydrogels can be easily
higher pH range. Zhang and colleagues synthesized a series of pH-
synthesized through photopolymerization and exert a great effect on
responsive hydrogels with hydrazone linkage via conjugating PEG
cancer treatment, biosensing, tissue engineering and other biomedi-
onto a farnesylthiosalicylate derivative FTS-hydrazide (FTS-H).
cal applications [85, 86].
These micelles undergo hydrolysis at acidic conditions and hence
trigger FTS-H to exert its chemotherapeutic effect [79]. Similarly, 3.4. Glucose Sensitive Hydrogels
Kang and his group used imine linkage to synthesize pH-responsive
methoxy poly(ethylene glycol)-4β-aminopodophyllotoxin (mPEG- The unique properties of hydrogels to undergo a change in
NPOD-I) that exerts its action of drug release into carcinoma cells swelling characteristics in the presence of glucose make it suitable
at pH 4 and 5 [80]. Hence pH-controlled hydrogels are quite capa- for various applications including cancer treatment, diabetes treat-
ble of drug release in response to environmental stimuli. ment [87], etc. Glucose-sensitive systems based on glucose-
responsive hydrogels have a wide range of features that make them
3.3. Light- and Chemical-Responsive Hydrogels capable of insulin delivery such as fast response to glucose concen-
tration, abrupt contraction and relaxation due to pH changes along
Light is one of the promising external stimuli to bring about with easy synthetic approaches [88]. These glucose-sensitive hy-
changes in properties of hydrogels upon irradiation and makes them drogels act as ‘synthetic pancreas’ and deliver the metered dose of
1436 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

Drug Delivery +

Adipose
Hydrogel Cartilage
Tissue Engineering Bone, etc

Contact Lens

Agriculture Water storage granules

Biosensor

Scheme 3. Different applications of hydrogels.

insulin for closed-loop therapy [89]. Insulin tends to form amyloid fields such as medicine, materials science, nanotechnology and
fibrils and possesses limited stability that may lead to oral delivery other industrial applications. They are of ubiquitous interest to drug
of insulin through injections even more lethal [90]. The use of acid- delivery systems [98] because of their resemblance to natural tis-
labile polymers such as polyesters in the synthesis of glucose- sues as water comprises the greatest constituent of the human body.
stimulated hydrogels offers another advantage as these materials The various applications of hydrogels (not limited to) are shown in
biodegrade quite rapidly on sensing the elevated concentration of Scheme 3.
glucose and hence triggers the drug release at target-site [91].
Hydrogels are mainly used for cancer treatments. Cancer is one
Hence, the synthesis of smart hydrogels with glucose-sensitivity
of the fatal diseases in the world and results in a large number of
finds great potential in therapeutics [92, 93].
deaths per year. Many types of cancers remain incurable due to its
complex nature [99]. It reduces the quality of life and life expec-
3.5. Ultrasound Sensitive Hydrogels
tancy. Metastasis and abnormal cell growth are the two main char-
Ultrasound sensitive hydrogels offer a digital drug release sys- acteristics of cancer development which leads to cancer recurrence
tem that can be accelerated and switched back as desired. These and proves to be the most important reason for mortality. Hydrogels
ultrasound-responsive polymeric hydrogels get disrupted on the based drug delivery systems, stimuli-responsive hydrogels, etc.
application of ultrasound and trigger the sustainable release of the have improved chemotherapy results and post-operative problems.
drug at the target site. Mooney et al. [94] demonstrated the applica- Hydrogels are quite efficient in the release of drugs at target and
tion of these smart polymeric gels for the digital release of the drug hence result in better clinical outcomes with even low concentration
upon triggered by ultrasound to reduce the growth of breast cancer of the drug. Hydrogels are also capable to release two or more
cells. Hydrogels containing a metal-organic framework also offer drugs at different targets simultaneously in the body [100]. The
advantages of the site-specific release of the drug as ultrasound different applications of hydrogels mainly depend upon their types,
energy penetrates deeply in the tissues and leads to disruption of structure etc. The different kinds of hydrogels are represented in
these covalently bonded polymeric gels [95]. Pillay and coworkers Table 2 [101-107].
proved that pH- and thermal-responsive polymeric hydrogels con- The different kinds of hydrogels and their applications are
taining polymethacrylates and polyethylene oxide/polypropylene briefly discussed below:
oxide co-block or triblock groups show a successful contribution to
chemotherapy upon irradiation with ultrasound energy. The highly 4.1. Chitosan Based Hydrogels
intense ultrasound stimulates the physical alterations in the polym-
eric structure of hydrogels that triggers the site-specific release of a Chitosan-based hydrogels offer potential applications in the
chemotherapeutic drug and hence offers an interesting drug deliv- drug delivery system for cancer therapy due to their low immuno-
ery system for cancer therapy [96]. genicity, eco-friendliness and biocompatibility with biological sys-
tems. De-Paz et al. studied the effect of chitosan concentration and
4. APPLICATIONS OF HYDROGELS AGAINST CANCER dispersion composition including the degree of cross-linking on the
delivery of diclofenac sodium (DCNa) loaded on chitosan-based
Owing to unique properties of absorbing and desorbing water in hydrogel and found these systems quite effective for tailor-made
different conditions [97], hydrogels find great potential in different controlled drug release [108]. Liu et al. developed the in situ formu-
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1437

Table 2. Types of hydrogels.

S. No. Hydrogel Description Refs.

1. Chitosan It is a natural cationic copolymer. It is hydrophilic in nature and is degradable via human enzymes resulting in [101]
biocompatibility and biodegradability enabling it to be used as a biological device.
2. Gelatin It is a natural polymer. It is biodegradable, biocompatible and has a low coagulation activity towards platelets, which [102]
makes it suitable for biomedical applications.
3. DNA They are made up of DNA. During the gelation process, the biological components can be encapsulated. [103]
4. Nanoparticles They are sub-micron sized particles, which in combination with hydrogels, offer a wide range of applications in the [104]
biomedical field.
5. Photodegradable These are used for the capture and release of the cells. [105]
6. Supramolecular It consists of noncovalent bonds and forms a macromolecular polymer. [106]
7. Magnetic-PNIPA They are formed by incorporating magnetic particles in cross-linked polymer gels. [107]

lation of chitosan-based hydrogel that shows efficient use in drug or enzyme ligation and DNA hybridization have been used to syn-
delivery and regenerative medicine [109]. Chitosan is used to pre- thesize a variety of DNA hydrogels by crosslinking cationic polye-
pare hydrogels to be used as drug carriers. Being a natural product, lectrolytes with differently sequenced DNA models such as single-
chitosan is a renewable pharmaceutic adjuvant with good biocom- stranded DNA, branched double-stranded DNA and has shown
patibility. Therefore, it has a strong potential for application as a reduced side effects with improved chemotherapy [116]. The hy-
drug carrier [109]. In situ formation of these chitosan-based hydro- drated nature of DNA hydrogels and their resemblance to the natu-
gels can be categorized as in situ phase separation and in situ cova- ral micro-environment of the cells promote their use as tissue scaf-
lent cross-linking methods. In the phase separation method, a folds in regenerative medicine. The degradation of AuNP-DNA
change in solubility of polymer comes into effect on varying the pH, hydrogels loaded with doxorubicin triggered by different stimuli
temperature and other external factors or by the removal of solvent. such as temperature, pH and ionic interactions leads to site-specific
Various secondary forces, including intermolecular/intramolecular, sustained drug release and hence shows great potential in the drug
hydrogen bonding, van der Waals forces and electrostatic associa- delivery system. The AuNPs present in the hydrogels help in the
tion, are employed for the in situ formation of chitosan-based hy- rapid clearance of toxins and reduce the long-term toxicity of the
drogels. In the covalent linking technique of in situ formation of the system [117].
hydrogel, the chemical linkage between different polymer chains
provides support for the synthesis of the 3-D gel matrix. Zhang et al. 4.4. Nanoparticles-Based Hydrogels
[110] used the chitosan-based thermo-responsive polyethylene glycol
hydrogel (PCgel) for in vitro testing of breast cancer therapy. The The basis of tumor-targeting drug delivery systems using
PCgel undergoes a transition from solution to gel state at physio- nanoparticles is their ability to passively or actively accumulate in
logical conditions and hence offers implantation without using sur- the desired tissues or cells. The nanoparticle-based hydrogels are
gical techniques and hence finds great potential in clinical applications. responsive to various physical as well as chemical conditions such
as pH response [118], temperature response [119], enzymatic re-
4.2. Gelatin Based Hydrogels sponse [120], and antigen response [121]. The innovative hybrid
nanoparticle-hydrogels have shown enhanced potential in the site-
Gelatin hydrogels act as multifunctional biomaterials for their specific controlled drug release over a long period of time without
potential use in clinical applications. Partial chemical and thermal harming the healthy tissues in the treatment of the brain tumor.
degradation of collagen results in the production of gelatin that can These nanogels have also been quite useful in diagnostic and imag-
be easily stabilized by a covalent net point. Gelatin hydrogels cross- ing applications. Hence, these nanopolymeric structures find prom-
linked with Lysine Diisocyanate (LDI) ethyl ester have shown ising strategies for the diagnosis and treatment of glioblastoma and
promising results in in vitro interaction with arterial endothelial other kinds of brain cells [122].
cells and mesenchymal stem cells. Pietzsch et al. reported the use of
gelatin hydrogels in in vivo tissue interaction and preclinical imag- 4.5. Photodegradable Hydrogels
ing in mice experiments [111]. Degradation of gelatin hydrogels A photodegradable hydrogel is generally PEG-coated which
leads to the penetration of fluid into the particles due to its hydro- consists of PEG cross-linked by photolabile moieties. It first cap-
philic nature that promotes the diffusion-controlled site-specific tures cancer cells, isolates and then releases desired anti-cancer
release of the drug. The paclitaxel-loaded gelatin particles represent drugs in the presence of light [123]. The photodegradable hydrogels
a rapid release that can be used for the treatment of bladder cancer, undergo degradation to release the desired group of cells from the
etc. [112]. A photothermal gelatin hydrogel containing the PEI– cultured/captured surface for downstream analysis and hence allow
Ppy-NC is used for plastic surgery, orthopedics, etc. [113]. According the detection of the cells depending upon their function that offers
to a report, BC/gelatin scaffolds have been used to seed the human advantages in gene expression studies and re-cultivation. Photode-
breast cancer cell line to investigate their potential in 3D cells in vitro gradable hydrogels cross-linked with coumarin or o-nitrobenzyl
culture. It has been shown that triple-negative receptor expression derivatives lead to the real-time assessment of chemical or physical
was retained in MDA-MD-231 cells cultured in BC/gelatin scaffolds properties of materials and hence offer spatiotemporally patterning
thus proving the efficient use of gelatin hydrogels as in vitro culture of biological signals in hydrogel matrix to tailor patient-specific
scaffolds for tumor cells [114]. delivery of drugs and other therapeutic regimens [124].

4.3. DNA Hydrogels 4.6. Supramolecular Hydrogels

DNA-based hydrogels offer a perfect biomaterial for various Due to the natural source of supramolecular hydrogels, they are
applications, including drug delivery, tissue engineering, biosens- biocompatible in nature. Different modifications and formulations
ing, etc. [115]. Different techniques such as enzyme polymerization have been done to make supramolecular hydrogels an ideal choice
1438 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

for drug delivery systems [125]. Recently, Wu et al. synthesized system, the drug-containing core is coated with a hydrogel mem-
injectable supramolecular hydrogel by cross-linking methoxy- brane. The concentration of the drug is higher in the center to allow
poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(ethylene imine a constant release rate and the gradient created between the drug in
copolymer and α-cyclodextrin (α-CD) with targeted folic acid the hydrogel and the surrounding environment leads to diffusion of
group (MPEG-PCL-PEI-FA) for sustained codelivery of che- active components from the high concentration through the hydro-
motherapeutic drug Paclitaxel (PTX) and Nurr77 gene that results gel to the lower one. Chemical delivery and environmental delivery
in inhibiting the growth of folate receptor and hence inhibits the are also opted according to the need. There are different routes of
tumor growth [126]. In another report, Wu et al. described the syn- administration of drugs in the body. Different types of hydrogels
thesis of MPEG-PCL-PEI-α-CD supramolecular hydrogel that can have several applications in drug delivery [137]. Polysaccharides
form stable polyplexes with anionic DNA for effective on-demand hydrogels have been specifically designed for the colon region of
gene delivery and assists in effective shrinkage of therapeutic resis- the GI (gastrointestinal) tract due to the presence of a high concen-
tance tumor [127]. tration of polysaccharidase enzymes in this region. Hence, different
kinds of hydrogels can be used for treating different parts of the
4.7. Magnetic-PNIPA body, depending upon the requirement and surrounding conditions.
For example, guar gum hydrogel cross-linked with glutaraldehyde
Magnetic-poly(N-isopropylacrylamide) gels are used in mag- has been used for the sustained delivery of Ibuprofen to colon
netic hyperthermia treatment of cancer [128]. Ferromagnetic and [138]. Due to the tenability of hydrogels, these are used to treat skin
superparamagnetic particles are introduced into the tumor tissue cancer. Conventionally, Paclitaxel (PTX) was administered intrave-
under the magnetic field which leads to the rupture of cancer cells nously to treat skin cancer. PTX could not differentiate between
[129]. Cancer therapeutic drug-loaded magnetic thermo-hydrogels healthy cells and cancer cells, and hence it has several side effects
raise the temperature of the system under the effect of the magnetic that may even result in death. Several approaches have been devel-
field thus exposing the cells to a temperature above the physiologi- oped where the researchers have encapsulated the drug PTX in
cal condition and lead to a large change in volume in these gels that hydrogels, which is used for melanoma cancers [139]. Peppa et al.
triggers the site-specific release of anti-cancer drugs [130]. Re- reported the synthesis of a pH-sensitive hydrogel comprising
cently, Zhang et al. reported the synthesis of the magnetic su- poly(methylacryl-graft-ethylene glycol) p(MMA-g-EG) in conjuga-
pramolecular hydrogel by crosslinking the α-CD with copolymer tion with PMMA nanoparticles and tested the release of encapsu-
substrates on the surface of PEGylated iron oxide nanoparticles and lated drug within this hydrogel by a change in pH from the stomach
used it in breast cancer mice model for the prevention of the reoc- to the small intestine. This gel system was also tested as a model for
currence of tumor. These hydrogels possess a magnetocaloric liq- colon and GI cancer cells. The cytocompatibility of the polymeric
uid-conformal property that undergoes sol-gel transition upon trig- network offers this hydrogel to act as a chemotherapeutic drug car-
gered by an alternating current magnetic field that allows the target- rier for cancer treatment [140]. Zhu et al. reported the synthesis of
specific release of chemotherapeutic drugs [131]. the supramolecular polymeric drug having the hydrogel as a precur-
sor to enhance the drug loading capacity and avoid the burst release
5. DIFFERENT APPROACHES TO USE HYDROGELS IN of the drug. They first synthesized the supramolecular polymeric
CANCER TREATMENT moiety in the form of polyaldehyde dextran modified with β-
5.1. Drug-Delivery Systems cyclodextrin (PAD-CD) and molecular prodrug as adamantane-
modified doxorubicin (AD-DOX) and linked them together using
Hydrogels are often called ‘smart gels’ or ‘intelligent gels, due host-guest interaction between AD and CD. This prodrug was fur-
to their ability to perceive the external stimuli and respond accord- ther reacted with carboxymethyl chitosan to produce injectable
ing to their physical and chemical properties that trigger the drug DOX-loaded supramolecular hydrogel. The degradation behavior of
release. Hydrogels offer a very interesting solution in reaching a this modified hydrogel was investigated under different pH condi-
sustained and targeted release of pharmaceuticals, both increasing tions for drug release to prevent the growth of the tumor [141].
the effect of the drug itself and lowering side effects at the same
time and hence comprise an ideal class of materials for biomedical Cisplatin (CDDP) has attracted researchers for its significant
applications such as drug screening, drug delivery, biosensing and use in cancer treatment. CDDP-bearing chondroitin sulfate nano-
tissue engineering [98, 132-134]. Hydrogel-based drug delivery gels (CS-Nanogels) are formulated using metal-ligand chelation and
systems can be used in various ways for epidermal, oral, ocular, then cross-linked with Poly(Ethylene Glycol)-Poly(β-Aminoester
rectal, and subcutaneous applications [135]. Hydrogels can be Urethane) (PEG-PAEU) hydrogels. These bioresorbable nanogels
loaded with drugs either through direct mixing of polymer (to be degrade under the influence of a change in temperature and pH and
used to make hydrogel), drug cross-linker and initiator (if needed) hence trigger the cancer cell-specific release of CDDP [142]. Sev-
within the matrix, or pre-formed hydrogel can be mixed with drug eral strategies have been formulated for effective drug release using
solution [136]. Different forces such as interactions between poly- hydrogels. Hydrogel-based hydrophobic drug delivery is quite dif-
mer-polymer, polymer-solvent and other factors including the na- ficult due to the incompatible interaction of the hydrophobic drug
ture of the solvent, cross-linking density of polymeric material exert with the hydrophilic hydrogel network. Hence, different techniques
an effect on the drug loading as well as swelling behavior of the have been employed to improve hydrophobic drug loading onto
hydrogel. The drug can be released from the hydrogel through vari- hydrogels. One of the methods involves the loading of the hydro-
ous ways including response in swelling, diffusion, chemically phobic drug on the hydrogel using appropriate solvent through
mediated and presence of external stimuli. In a swelling-controlled which drug binds to the hydrogel through different intermolecular
release mechanism, the drug-loaded hydrogel swells once it comes and hydrogen bond forces [143]. Recrystallization of the drug can
into contact with bio-fluid. The swelling beyond the limit leads to be avoided this way while exposure of hydrogels to water leads to
the release of drug molecules with the relaxation of polymeric enhanced release of the hydrophobic drug. Another approach is the
compounds. This process is also referred to as Case II transport. It incorporation of hydrophobic sites. This method introduces binding
is known as ‘anomalous transport’ if this approach is combined sites for hydrophobic drugs and condenses the bulk dimensions of
with diffusion. The diffusion-controlled drug release can be repre- the gel. This leads to a reduction in pore size with slow-release
sented by two different devices, i.e. matrix or reservoir devices. In through diffusion control. In this technique, more hydrophobic side
the matrix system, the drug is dissolved uniformly throughout the chains can be attached to the main polymeric moieties that bring out
3-D structure of the hydrogel and drug release occurs through the the hydrophobic domain in the hydrogel network and allow the
macromolecular pores of the water-filled hydrogel. In the reservoir effective binding of the hydrophobic drug to the hydrogel. Octyl-
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1439

modified carboxymethylpullulan is one such example of the success toxic degradation products [156]. Therefore, some new challenges
of this technique [144]. Bhashkar et al. developed a different emerged for the choice of biomaterials and this need was accom-
method including transdermal delivery of poorly water-soluble plished by the development of hydrogels as wound dressings [157].
compounds using Nanostructured Lipid Carrier (NLC) and SLN
occupied hydrogel systems to release antihypertensive nitrendipine 5.2.2. Cardiac Repair
[145]. Eckert et al. [146] employed a new technique for the use of The diffusion of nutrients, oxygen, and cells toward the dam-
hydrogel spacers in the dose-escalated radiotherapy for the treat- aged myocardium takes place through 3D hydrogel networks [158].
ment of prostate cancer. Patients undergoing dose-escalated radio- Nowadays, these hydrogel networks are in a huge trend to generate
therapy having T1-2N0M0 prostate cancer were experimented with heart tissue. These networks are also used to encapsulate angio-
hydrogel spacers. The rectal toxicity was reduced with the use of genic biomolecule such as VEGF, bFGF, PDGF, etc. or chemokines
hydrogel injections in the dose-escalated radiotherapy of prostate such as stromal-derived factor-1 to stimulate the expression of an-
cancer [147]. giogenic genes [159]. Luciferase-expressing cardiac stem cells
(CSC-Luc2) were encapsulated into a multimodal hydrogel-based
5.2. Tissue Engineering encapsulation consisted of a poly(ethylene glycol) network cross-
Hydrogels find an important application in tissue engineering linked with bioactive peptides functionalized with Gd(III).
by providing suitable scaffold material due to their resemblance to Crosslinking was done through the inclusion of a Heparin-Binding
Peptide (HBP) sequence in the cross-linker design which resulted in
the extracellular matrix of biological tissues. They can be used as a
a gel and showed mechanical properties resembling those of cardiac
carrier for the delivery of therapeutics or other bioactive materials
tissue [160]. iPSC-derived cardiomyocytes can also be delivered by
and for filling vacant space in the body. The 3-D structural network
a self-adhesive hydrogel for heart repair [161]. Thus, natural mate-
of hydrogels can also be used to provide support to the cells for
rials were also initiated in cardiac tissue engineering applications
organ replacement.
which included fibrin, collagen, peptides, glutathione, chitosan
Hydrogels provide an efficient scaffold in target-specific drug polyurethane, alginate, sericin, decellularized extracellular matrix
delivery, as, otherwise, local delivery of the drug may result in products, silk fibroin and synthetic materials such as hydroxyethyl
toxic effects on other normal tissues and a high dose of drug is also cellulose, Polyethylene Glycol (PEG), poly(glycerol sebacate)
required due to non-specific uptake by other tissues and enzymatic ureido-pyrimidinone, poly(lactic-co-glycolic acid) and poly(N-
degradation of the drug in other parts of the body while reaching isopropylacrylamide) (pNIPAM) [162].
required site. Chitosan and alginate as natural hydrogels and 5.2.3. Bone Repair
Poly(Vinyl Alcohol) (PVC), Poly(Ethylene Oxide) (PEO) and
Poly(Propylene Fumarate) (PPF) as synthetic hydrogels are com- Hydrogels have emerged as potential alternatives for bone re-
mon scaffolds used in tissue engineering. Another important appli- pair. They also possess the potential to sustain the delivery of vari-
cation of hydrogel scaffold includes the production of different ous biomolecules for bone fracture healing. There are various con-
types of tissues such as bone, fat, cartilage, muscle, neurons and ditions that must be fulfilled or maintained in order to regenerate
liver. Initially, Langer and Vacanti [148] demonstrated the require- bone tissue through hydrogel scaffolds. Some of those conditions
ments and clinical applications of hydrogel scaffolds in cartilage, such as cell survival, biocompatibility, effective mass transport,
nerve, blood vessel, skin, bone, cornea, several organs including mechanical stimulation, biodegradability and proliferation must be
liver and kidney, etc. Afterwards, various studies of injectable hy- maintained. The hydrogels used for bone replacement are made up
drogels in tissue engineering have been reported worldwide. The of a wide range of inorganic hydroxyapatite and organic collagen
stimuli-responsive, multifunctional and hybrid injectable hydrogels fibers or composite materials which consist of collagen, chitosan
are under development for tissue repair and regeneration [149, 150]. (Cs) added to Hyaluronic Acid (HA), collagen-like polypeptide,
poly(Pro-Hyp-Gly), PLLA, PLGA and PCL, polycaprolactone and
Different kinds of hydrogels are used for different applications. chitosan alginate, PEG, collagen and agarose/chitosan [163], so-
For example, cartilage engineering and nerve grafting can be best dium alginate (Alg), Polyacrylic Acid (PAA) and Demineralized
obtained by utilizing alginate hydrogel scaffolds as compared to Bone Matrix (DBM) [164]. The ex vivo use of autologous cells is
other hydrogels, while collagen hydrogels find the best suit for the basis of bone tissue engineering, which are seeded into osteo-
grafting large blood vessels [151, 152]. Chitosan and chitin-based conductive scaffolds and implanted into bone defects. Mesenchy-
hydrogels are widely used as biological adhesives in surgical appli- mal Stem Cells (MSCs) are the most useful cell source as they have
cations. These hydrogels are quite effective in sealing the small self-renewing capacity and support bone regeneration on implanta-
wounds in a way to let go off body fluids and air and hence enhance tion [165]. There are different cells which emerged as new options
the healing properties [153, 154]. The different applications of hy- for cartilage regeneration such as multipotent Articular Cartilage-
drogels in various tissue engineering techniques are described below: Resident Chondroprogenitor Cells (ACPCs) [166]. There are vari-
ous methods which are used to employ hydrogels for bone tissue
5.2.1. Wound Dressings
engineering such as chemical-crosslinking [167], ionizing irradia-
The artificial synthetic fibers and gauzes are the traditional tion [168], physical crosslinking [169], using nitrate salts, and en-
dressings and they fail sometimes for infectious wounds. They may zymatic-crosslinking. In spite of a wide range of applications of
get attached to wounds that cause damage to epithelial tissue, bleed- hydrogels in bone tissue engineering, they have some limitations as
ing and pain on dressing replacement. Nowadays, the wound dress- well. These are due to their poor mechanical properties and poor
ings replace the functions of damaged skin and promote both performance under load-bearing conditions. Currently, injectable
wound healing and skin healing. Hydrogel dressings are used to methacrylate-based bone defect fillers have high compression
decrease the risk of wound adhesion and they also promote wound strengths than cancellous bone. To improve the applicability of
healing. Hydrogels have various advantages as compared to sepa- hydrogels, they are made porous as it enhances their cell viability,
rating materials. They are permeable to various substances such as proliferation, and migration.
oxygen, nutrients and waste [155]. Hydrogel-based bio-adhesives
5.2.4. Skin Repair
are used to copy the physicochemical properties of the extracellular
matrix. They have some increased microbial properties and de- The development of new wound dressings includes hydrogels
creased adhesion to adjacent tissue which improves the treatment of for skin regeneration. The wound healing process is promoted by in
chronic wounds. The normal healing process may be interrupted by situ thermo-responsive injectable self-healing hydrogel dressings
1440 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

DRUG HYDROGEL

Scheme 4. Hydrogel assisted drug delivery at the target site inside the human body.

with anti-infection and antioxidative properties, a body temperature interactions. Living sensors are mainly living cell-polymeric net-
sol-gel transition, and the appropriate adhesiveness, swelling ratios, works having a blend of hydrogels with microorganisms and living
biocompatibility and conductivity. These hydrogels have various cells. As microorganisms are quite capable to detect a wide range of
advantages such as they flow freely as injectable liquids before chemical moieties at a wide range of temperatures and pH, they act
administration and only the gel under physiological conditions as an ideal material for biosensing applications. Molecular interac-
[170]. There is a wide range of hydrogels that are developed for tions encompass various strategies, out of which the most common
skin wound dressings. Some of them are very frequently used such include the interaction of enzymes with substrates. There is a wide
as multifunctional materials, including silk sericin, chitosan, colla- range of hydrogel matrices-embedded enzyme-substrate-based bio-
gen, pullulan, agarose [171], and pectin, poloxamers, hyaluronic sensors that find the application in the detection of amino acids,
acid, peptides [172], honey and carboxylic acid residues [173]. The urea, organic-soluble alcohols, ammonia, hydrogen peroxide, glu-
conductive polymer polyaniline was used to form an injectable cose, etc. Glucose-sensitive hydrogels mentioned in Section 3.1.4 is
antibacterial/antioxidant electroactive hydrogel for wound dressing one such example of the application of hydrogels in biosensing
and it possesses self-healing and adhesive properties [174]. The techniques. Another example of molecular interactions-based bio-
poor mechanical properties in terms of thermostability can be over- sensors includes antibody-antigen sensors. Different antigens (or
come by physical and chemical crosslinking [175]. antibodies) embedded on the transducer to antibodies (or antigens)
get recognition through immunochemical reactions and hence spe-
5.3. Biosensors cific signals are produced that depend upon the analyte concentra-
tion [178].
Biosensors can be defined as compounds or devices that help in
the recognition or analysis of biological information. Biosensors are 6. ADVANTAGES OF HYDROGELS OVER
gaining significant attention for their use in home diagnostics, test- CONVENTIONAL THERAPEUTIC METHODS
ing biological phenomenon and environmental sensing. The impor-
tant component of biosensors includes the presence of bioactive Cancer is a deadly disease caused by the exponential growth of
compounds such as tissues, enzymes, living cells or antibodies, abnormal cells, which can further invade other body cells. The main
which shows high specificity towards one function without any causative agents of the disease include chemical or toxic compound
interference/response to other constituents present in the system. exposures, harmful ionizing radiation, some pathogens, an envi-
Hydrogel scaffolds find their use in the protection of these active ronmental pollutant, stress, physical inactivity and human genetics.
biocomponents in the form of immobilization matrices to preserve Principal cancer treatment includes surgery, radiotherapy, and che-
their specificity and avoid unwanted interaction with cells or other motherapy. Traditional chemotherapeutic agents work by interfer-
biological molecules. The bioactive components can be linked to ing with the cell division (mitosis), restricting the rapid growth of
the biosensing system through encapsulation into membranes, en- cancerous cells. Although chemotherapy is one of the most com-
trapment into the matrix, physical adsorption and covalent bonding mon approaches for cancer treatment, it possesses certain limita-
[176, 177]. The hydrogel-based sensors undergo a change in vol- tions and side effects, which restrict its efficacy. Chemotherapeutic
ume upon interaction with the analyte and triggered by the target drugs severely affect normal healthy cells and tissues as they do not
component that results in specific recognition and hence can be differentiate between a normal cell and cancer cell. Secondly, a
used as a potential component in biosensing applications. Depend- very small percentage of the drug reaches tumor areas leading to
ing upon the nature of the analyte, the sensing component can be insufficient bio-accessibility and hence a higher dose is required of
categorized into two groups namely living sensors and molecular the respective chemotherapeutics drugs. The major concern of
chemotherapy is its adverse effect on different body organs and
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1441

motherapy is its adverse effect on different body organs and healthy CONSENT FOR PUBLICATION
cells leading to several side effects on the body such as anemia, low
WBCs count, fatigue, hair loss, loss of appetite, nausea, etc. There- Not applicable.
fore, more advanced techniques of chemotherapy are highly desir-
able to achieve sustained and target-specific release of therapeutics FUNDING

with minimal adverse effects on healthy cells. None.

The localized drug delivery system has been widely researched
in the past few years and has been proved to be a better alternative CONFLICT OF INTEREST
for conventional chemotherapy with abilities to control drug release The authors declare no conflict of interest, financial or other-
in the targeted area. There are several potential materials such as wise.
polymers, lipids, polymeric hydrogels, inorganic carriers, and bio-
macromolecular scaffolds that efficiently act as drug carriers with ACKNOWLEDGEMENTS
site-specificity and enhanced therapeutic efficacy. The use of hy-
drogels offers various advantages such as improved stability of the The authors thank the University of Delhi, India, for providing
drug embedded/linked in the hydrogel moiety that imparts en- necessary facilities to carry out this work.
hanced anticancer activity, controlled drug release at the tumor-
specific site, minimized drug loss, reduced toxicity, averted the REFERENCES
need for frequent administrations, diminished subsequent side ef- [1] Wichterle, O.; Lim, D. Hydrophilic gels for biological use. Nature,
fects and minimized cost of therapy. The hydrogel assisted drug 1960, 185, 117-118.
delivery at the target site inside the human body is shown in http://dx.doi.org/10.1038/185117a0
Scheme 4. [2] Paleos, G.A. Pittsburgh Plastics Manufacturing; Buttler: PA, 2012.
[3] Hoare, T.R.; Kohane, D.S. Hydrogels in drug delivery: Progress
Hydrogel based drug delivery system, specifically, is a very and challenges. Polymer (Guildf.), 2008, 49, 1993-2007.
important tool in this direction and this may be attributed to its in http://dx.doi.org/10.1016/j.polymer.2008.01.027
situ gelation. Various kinds of macromolecules, including DNA, [4] Narayanaswamy, R.; Torchilin, V.P. Hydrogels and their applica-
proteins, and hydrophilic/hydrophobic drugs, can be embedded in tions in targeted drug delivery. Molecules, 2019, 24(3), 603-623.
hydrogel moieties. Docetaxel (DTX), a conventional chemothera- http://dx.doi.org/10.3390/molecules24030603 PMID: 30744011
[5] Akhtar, M.F.; Hanif, M.; Ranjha, N.M. Methods of synthesis of
peutic drug used for the treatment of lung cancer, shows adverse hydrogels … A review. Saudi Pharm. J., 2016, 24(5), 554-559.
hematological effects, including neutropenia and anemia and is http://dx.doi.org/10.1016/j.jsps.2015.03.022 PMID: 27752227
cytotoxic in nature. Whereas PLGA-PEGPLGA copolymer-based [6] Aly, A.S. Self-dissolving chitosan. I. Preparation and characterisa-
localized carrier for DTX shows promising results by attaining tion and evaluation for drug delivery system. Angew Macromol.
prolonged exposure of the drug to the specific area as well as also Chem., 1998, 259, 33-38.
lowers toxicity [179]. MRI monitoring is one of the important http://dx.doi.org/10.1002/(SICI)1522-
means for the detection of cancer disease. Poly (organophos- 9505(19981001)259:1<13::AID-APMC13>3.0.CO;2-T
[7] Martin, B.D.; Linhardt, R.J.; Dordick, J.S. Highly swelling hydro-
phazene)-based magnetic and thermo-sensitive injectable hydrogel
gels from ordered galactose-based polyacrylates. Biomaterials,
associated with MRI-monitoring has been developed and used as an 1998, 19(1-3), 69-76.
efficient and biodegradable imaging platform for anti-cancerous http://dx.doi.org/10.1016/S0142-9612(97)00184-1 PMID: 9678852
drugs [180]. [8] Rizwan, M.; Yahya, R.; Hassan, A.; Yar, M.; Azzahari, A.D.; Sel-
vanathan, V.; Sonsudin, F.; Abouloula, C.N. pH sensitive hydro-
Paclitaxel (PTX) is one of the most common chemotherapeutic gels in drug delivery: Brief history, properties, swelling, and re-
drugs used for the treatment of different kinds of cancer, such as lease mechanism. Mater. Selection Appl. Polym., 2017, 9(137), 1-
ovarian, breast, colon and lung cancer. Since the drug is hydropho- 37.
bic in nature, several organic formulations are used to increase its [9] Sahooa, P.; Leonga, K.H.; Nyamathullaa, S.; Onukib, Y.; Takaya-
solubility that results in various side effects, including bone marrow mac, K.; Chunga, L.Y. Optimization of pH-responsive car-
suppression, allergic reactions, hair loss, numbness, muscle pains, boxymethylated iota-carrageenan/chitosan nanoparticles for oral
severe lung inflammation and diarrhea [181]. Thermo-sensitive insulin delivery using response surface methodology. React. Funct.
Polym., 2017, 119, 145-155.
chitosan-based hydrogel cross-linked with non-ionic surfactant http://dx.doi.org/10.1016/j.reactfunctpolym.2017.08.014
vesicles (niosomes) having PTX drug loaded on its surface provides [10] Xu, X.; Jha, A.K.; Harrington, D.A.; Farach-Carson, M.C.; Jia, X.
a great alternative as it exhibits antibacterial, biocompatible, biode- Hyaluronic acid-based hydrogels: From a natural polysaccharide to
gradable, and muco-adhesive properties. Hence, hydrogels provide complex networks. Soft Matter, 2012, 8(12), 3280-3294.
an innovative means for their use in cancer detection, treatment, http://dx.doi.org/10.1039/c2sm06463d PMID: 22419946
and prevention of the post-operative reoccurrence of cancer cells [11] Coviello, T.; Grassi, M.; Rambone, G.; Santucci, E.; Carafa, M.;
along with their other uses in biotechnology and regenerative Murtas, E.; Riccieri, F.M.; Alhaique, F. Novel hydrogel system
medicine. from scleroglucan: synthesis and characterization. J. Control. Re-
lease, 1999, 60(2-3), 367-378.
http://dx.doi.org/10.1016/S0168-3659(99)00091-7 PMID:
CONCLUSION 10425341
[12] Kim, J.; Kong, Y.P.; Niedzielski, S.M.; Singh, R.K.; Putnam, A.J.;
A detailed description of hydrogels is represented in this review
Shikanov, A. Charaecterization of the cross linking kinetics of
based on their classification, synthetic methods and applications. multi-arm poly(ethylene glycol) hydrogels formed via Michael-
Different varieties of hydrogels are discussed here, along with their type addition. Soft Matter, 2016, 12(7), 2076-2085.
mode of action in therapeutics. It is noted here that hydrogels play http://dx.doi.org/10.1039/C5SM02668G PMID: 26750719
an important role in cancer therapy with aid to drug encapsulation [13] Darling, N.J.; Hung, Y.S.; Sharma, S.; Segura, T. Controlling the
and its delivery at the target site that maximizes the use of initial kinetics of thiol-maleimide Michael-type addition gelation kinetics
drug concentration taken and reduces the side effects at other or- for the generation of homogenous poly(ethylene glycol) hydrogels.
gans of the body. Hydrogels find an efficient way of their applica- Biomaterials, 2016, 101, 199-206.
http://dx.doi.org/10.1016/j.biomaterials.2016.05.053 PMID:
tions in different areas including diagnosis, imaging platforms, 27289380
cancer treatment, surgical operations, tissue regeneration, biosen- [14] Teng, D.Y.; Wu, Z.M.; Zhang, X.; Wang, Y.X.; Zheng, C.; Wang,
sors and biotechnology. Z.; Li, C.X. Synthesis and characterization of in situ cross-linked
1442 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

hydrogel based on self-assembly of thiol-modified chitosan with [32] Zhu, J.; Han, H.; Ye, T.T.; Li, F.X.; Wang, X.L.; Yu, J.Y.; Wu,
PEG diacrylate using Michael type addition. Polymer (Guildf.), D.Q. Biodegradable and pH sensitive peptide based hydrogel as
2010, 51, 639-646. controlled release system for antibacterial wound dressing applica-
http://dx.doi.org/10.1016/j.polymer.2009.12.003 tion. Molecules, 2018, 23(12), 3383-3397.
[15] Khan, S.; Ullah, A.; Ullah, K.; Rehman, N. Insight into hydrogels. http://dx.doi.org/10.3390/molecules23123383 PMID: 30572689
Des. Monomers Polym., 2016, 19(5), 456-478. [33] Broguiere, N.; Formica, F.A.; Barreto, G.; Zenobi-Wong, M. Sor-
http://dx.doi.org/10.1080/15685551.2016.1169380 tase A as a cross-linking enzyme in tissue engineering. Acta Bio-
[16] Zhang, Z.; He, C.; Chen, X. Hydrogels based on pH-responsive mater., 2018, 77, 182-190.
reversible carbon–nitrogen double-bond linkages for biomedical http://dx.doi.org/10.1016/j.actbio.2018.07.020 PMID: 30006315
applications. Mater. Chem. Front., 2018, 2, 1765-1778. [34] Arkenberg, M.R.; Moore, D.M.; Lin, C.C. Dynamic control of
http://dx.doi.org/10.1039/C8QM00317C hydrogel crosslinking via sortase-mediated reversible transpeptida-
[17] Accardo, J.V.; Kalow, J.A. Reversibly tuning hydrogel stiffness tion. Acta Biomater., 2019, 83, 83-95.
through photocontrolled dynamic covalent crosslinks. Chem. Sci. http://dx.doi.org/10.1016/j.actbio.2018.11.011 PMID: 30415064
(Camb.), 2018, 9(27), 5987-5993. [35] Yung, C.W.; Wu, L.Q.; Tullman, J.A.; Payne, G.F.; Bentley, W.E.;
http://dx.doi.org/10.1039/C8SC02093K PMID: 30079213 Barbari, T.A. Transglutaminase crosslinked gelatin as a tissue en-
[18] Kuijpers, A.J.; van Wachem, P.B.; van Luyn, M.J.; Engbers, G.H.; gineering scaffold. J. Biomed. Mater. Res. A, 2007, 83(4), 1039-
Krijgsveld, J.; Zaat, S.A.; Dankert, J.; Feijen, J. In vivo and in vitro 1046. http://dx.doi.org/10.1002/jbm.a.31431 PMID: 17584898
release of lysozyme from cross-linked gelatin hydrogels: A model [36] Kim, K.S.; Park, S.J.; Yang, J.A.; Jeon, J.H.; Bhang, S.H.; Kim,
system for the delivery of antibacterial proteins from prosthetic B.S.; Hahn, S.K. Injectable hyaluronic acid-tyramine hydrogels for
heart valves. J. Control. Release, 2000, 67(2-3), 323-336. the treatment of rheumatoid arthritis. Acta Biomater., 2011, 7(2),
http://dx.doi.org/10.1016/S0168-3659(00)00221-2 PMID: 666-674.
10825564 http://dx.doi.org/10.1016/j.actbio.2010.09.030 PMID: 20883838
[19] Yoshida, T.; Aoyagi, T.; Kokufuta, E.; Okano, T. Newly designed [37] Roberts, J.J.; Naudiyal, P.; Lim, K.S.; Poole-Warren, L.A.; Mar-
hydrogel with both sensitive thermoresponse and biodegradability. tens, P.J. A comparative study of enzyme initiators for crosslinking
J. Polym. Sci. A Polym. Chem., 2003, 41, 779-787. phenol-functionalized hydrogels for cell encapsulation. Biomater.
http://dx.doi.org/10.1002/pola.10595 Res., 2016, 20, 30.
[20] Wan Ishak, W.H.; Ahmad, I.; Ramli, S.; Mohd Amin, M.C.I. http://dx.doi.org/10.1186/s40824-016-0077-z PMID: 27713832
Gamma irradiation-assisted synthesis of cellulose nanocrystal- [38] Mosiewicz, K.A.; Johnsson, K.; Lutolf, M.P. Phosphopantetheinyl
reinforced gelatin hydrogels. Nanomaterials (Basel), 2018, 8(10), transferase-catalyzed formation of bioactive hydrogels for tissue
749-762. engineering. J. Am. Chem. Soc., 2010, 132(17), 5972-5974.
http://dx.doi.org/10.3390/nano8100749 PMID: 30241416 http://dx.doi.org/10.1021/ja9098164 PMID: 20373804
[21] Wisotzki, E.I.; Hennes, M.; Schuldt, C.; Engert, F.; Knolle, W.; [39] Elbjeirami, W.M.; Yonter, E.O.; Starcher, B.C.; West, J.L. Enhanc-
Decker, U.; Kas, J.A.; Zink, M.; Mayr, S.G. Tailoring the material ing mechanical properties of tissue-engineered constructs via lysyl
properties of gelatin hydrogels by high energy electron irradiation. oxidase crosslinking activity. J. Biomed. Mater. Res. A, 2003,
J. Mater. Chem. B Mater. Biol. Med., 2014, 2, 4297-4309. 66(3), 513-521.
http://dx.doi.org/10.1039/C4TB00429A http://dx.doi.org/10.1002/jbm.a.10021 PMID: 12918034
[22] Rimdusit, S.; Somsaeng, K.; Kewsuwan, P.; Jubsilp, C.; Tipti- [40] Bakota, E.L.; Aulisa, L.; Galler, K.M.; Hartgerink, J.D. Enzymatic
pakorn, S. Comparison of gamma radiation crosslinking and cross-linking of a nanofibrous peptide hydrogel. Biomacro-
chemical crosslinking on properties of methylcellulose hydrogel. molecules, 2011, 12(1), 82-87.
Eng. J. (N.Y.), 2012, 6(4), 15-28. http://dx.doi.org/10.1021/bm1010195 PMID: 21133404
http://dx.doi.org/10.4186/ej.2012.16.4.15 [41] Teixeira, L.S.; Feijen, J.; van Blitterswijk, C.A.; Dijkstra, P.J.;
[23] Peppas, N.A.; Mikos, A.G. Preparation methods and structure of Karperien, M. Enzyme-catalyzed crosslinkable hydrogels: Emerg-
hydrogels. In: Hydrogels in Medicine and Pharmacy; Peppas, N.A., ing strategies for tissue engineering. Biomaterials, 2012, 33(5),
Ed.; CRC Press: Boca Raton, FL, 1986, Vol. I, pp. 1-27. 1281-1290. http://dx.doi.org/10.1016/j.biomaterials.2011.10.067
[24] Peppas, N.A.; Merrill, E.W. Hydrogels as swollen elastic networks. PMID: 22118821
J. Appl. Polym. Sci., 1977, 21, 1763-1770. [42] Thi, P.L.; Lee, Y.; Nguyen, D.H. Park, K.D. In situ forming gelatin
http://dx.doi.org/10.1002/app.1977.070210704 hydrogels by dual-enzymatic cross-linking for enhanced tissue ad-
[25] Stringer, J.L.; Peppas, N.A. Diffusion of small molecular weight hesiveness. J. Mater. Chem. B Mater. Biol. Med., 2017, 5, 757-764.
drugs in radiation-crosslinked poly (ethylene oxide) hydrogels. J. http://dx.doi.org/10.1039/C6TB02179D
Control. Release, 1996, 42, 195-202. [43] Buwalda, S.J.; Boere, K.W.; Dijkstra, P.J.; Feijen, J.; Vermonden,
http://dx.doi.org/10.1016/0168-3659(96)01457-5 T.; Hennink, W.E. Hydrogels in a historical perspective: From sim-
[26] Jabbari, E.; Nozari, S. Swelling behavior of acrylic acid hydrogels ple networks to smart materials. J. Control. Release, 2014, 190,
prepared by γ-radiation crosslinking of polyacrylic acid in aqueous 254-273.
solution. Eur. Polym. J., 2000, 36, 2685-2692. http://dx.doi.org/10.1016/j.jconrel.2014.03.052 PMID: 24746623
http://dx.doi.org/10.1016/S0014-3057(00)00044-6 [44] Banerjee, S.L.; Khamrai, M.; Kundu, P.P.; Singha, N.K. Synthesis
[27] Kishi, R.; Ichijo, H.; Hirasa, O. Thermo-responsive devices using of self-healable and pH responsive hydrogel based on an ionic
poly(vinyl methyl ether) hydrogels. J. Intell. Mater. Syst. Struct., polymer/clay nanocomposite. RSC Advances, 2016, 6, 81654-
1993, 4, 533-537. 81665.
http://dx.doi.org/10.1177/1045389X9300400413 http://dx.doi.org/10.1039/C6RA01074A
[28] Kishi, R.; Hirasa, O.; Ichijo, H. Fast responsive poly(N- [45] Pérez-Luna, V.H.; González-Reynoso, O. Encapsulation of bio-
sopropylacrylamide) hydrogels prepared by γ-ray irradiation. Po- logical agents in hydrogels for therapeutic applications. Gels, 2018,
lym. Gels Netw., 1997, 5, 145-151. 4(3), 61.
http://dx.doi.org/10.1016/S0966-7822(96)00037-8 http://dx.doi.org/10.3390/gels4030061 PMID: 30674837
[29] Moerkerke, R.; Meeussen, F.; Koningsveld, R. Phase transitions in [46] Wee, S.; Gombotz, W.R. Protein release from alginate matrices.
swollen networks. 3. Swelling behavior of radiation crosslinked Adv. Drug Deliv. Rev., 1998, 31(3), 267-285.
poly (vinyl methyl ether) in water. Macromolecules, 1998, 31, http://dx.doi.org/10.1016/S0169-409X(97)00124-5 PMID:
2223-2229. 10837629
http://dx.doi.org/10.1021/ma971512+ [47] Chen, P. Self-assembly of ionic-complementary peptides: A phys-
[30] Arndt, K.F.; Schmidt, T.; Reichelt, R. Thermo-sensitive poly (vinyl icochemical viewpoint. Colloids Surf Physicochem Eng Aspects,
methyl ether) micro-gel formed by high energy radiation. Polymer 2005, 261, 3-24.
(Guildf.), 2001, 42, 6785-6791. http://dx.doi.org/10.1016/j.colsurfa.2004.12.048
http://dx.doi.org/10.1016/S0032-3861(01)00164-1 [48] Eagland, D.; Crowther, N.J.; Butler, C.J. Complexation between
[31] Guo, K.; Chu, C.C. Synthesis of biodegradable amino-acid-based polyoxyethylene and polymethacrylic acid-The importance of the
poly(ester amide)s and poly(ether ester amide)s with pendant func- molar mass of polyoxyethylene. Eur. Polym. J., 1994, 30, 767-773.
tional groups. J. Appl. Polym. Sci., 2010, 117, 3386-3394. http://dx.doi.org/10.1016/0014-3057(94)90003-5
http://dx.doi.org/10.1002/app.32080
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1443

[49] Zhang, X.N.; Wang, Y.J.; Sun, S.; Hou, L.; Wu, P.; Wu, Z.L.; [66] Casolaro, M.; Casolaro, I.; Bottari, S. Long-term doxorubicin re-
Zheng, Q. A tough and stiff hydrogel with tunable water content lease from multiple stimuli-responsive hydrogels based on a-
and mechanical properties based on the synergistic effect of hydro- amino-acid residues Eur. J. Pharmaceut. Biopharmaceut., 2014,
gen bonding and hydrophobic interaction. Macromolecules, 2018, 88(2), 424-433.
51(20), 8136-8146. http://dx.doi.org/10.1016/j.ejpb.2014.06.005
http://dx.doi.org/10.1021/acs.macromol.8b01496 [67] Norouzi, M.; Nazari, B.; Miller, D.W. Injectable hydrogel-based
[50] Chang, X.; Geng, Y.; Cao, H.; Zhou, J.; Tian, Y.; Shan, G.; Bao, drug delivery systems for local cancer therapy. Drug Discov. To-
Y.; Wu, Z.L.; Pan, P. Dual-crosslink physical hydrogels with high day, 2016, 21(11), 1835-1849.
toughness based on synergistic hydrogen bonding and hydrophobic http://dx.doi.org/10.1016/j.drudis.2016.07.006 PMID: 27423369
interactions. Macromol. Rapid Commun., 2018, 39(14), 1700806- [68] Qu, Y.; Chu, B.Y.; Peng, J.R.; Liao, J.F.; Qi, T.T.; Shi, K.; Zhang,
1700813. X.N.; Wei, Y.Q.; Qian, Z.Y. A biodegradable thermo-responsive
http://dx.doi.org/10.1002/marc.201700806 hybrid hydrogel: therapeutic applications in preventing the post-
[51] Meenakshi; Ahuja, M. Metronidazole loaded carboxymethyl tama- operative reocurrence of breast cancer. NPG Asia Mater., 2015, 7,
rind kernel polysaccharide-polyvinyl alcohol cryogels: Preparation e207.
and characterization. Int. J. Biol. Macromol., 2015, 72, 931-938. http://dx.doi.org/10.1038/am.2015.83
http://dx.doi.org/10.1016/j.ijbiomac.2014.09.040 PMID: 25301698 [69] Alsuraifi, A.; Curtis, A.; Lamprou, D.A.; Hoskins, C. Stimuli re-
[52] Stenekes, R.J.H.; Talsma, H.; Hennink, W.E. Formation of dextran sponsive polymeric systems for cancer therapy. Pharmaceutics,
hydrogels by crystallization. Biomaterials, 2001, 22(13), 1891- 2018, 10(3), 136-153.
1898. http://dx.doi.org/10.3390/pharmaceutics10030136 PMID:
http://dx.doi.org/10.1016/S0142-9612(00)00375-6 PMID: 30131473
11396895 [70] Qi, X.; Wei, W.; Li, J.; Zuo, G.; Pan, X.; Su, T.; Zhang, J.; Dong,
[53] Tsuji, H. Poly(lactide) stereocomplexes: Formation, structure, W. Salecan-based pH-sensitive hydrogels for insulin delivery. Mol.
properties, degradation, and applications. Macromol. Biosci., 2005, Pharm., 2017, 14(2), 431-440.
5(7), 569-597. http://dx.doi.org/10.1021/acs.molpharmaceut.6b00875 PMID:
http://dx.doi.org/10.1002/mabi.200500062 PMID: 15997437 28055215
[54] Slager, J.; Glandnikoff, M.; Domb, A.J. Stereocomplexes, based on [71] Ishak, R.A.; Awad, G.A.; Mortada, N.D.; Nour, S.A. Preparation,
biodegradable polymers and bioactive macromolecules. Macromol. in vitro and in vivo evaluation of stomach-specific metronidazole-
Symp., 2001, 175(1), 105-115. loaded alginate beads as local anti-Helicobacter pylori therapy. J.
http://dx.doi.org/10.1002/1521-3900(200110)175:1<105::AID- Control. Release, 2007, 119(2), 207-214.
MASY105>3.0.CO;2-C http://dx.doi.org/10.1016/j.jconrel.2007.02.012 PMID: 17412443
[55] Lim, D.W.; Park, T.G. Stereocomplex formation between enanti- [72] Krishnaiah, Y.S.R.; Satyanarayana, V.; Dinesh Kumar, B.;
omeric PLA–PEG–PLA triblock copolymers: Characterization and Karthikeyan, R.S. In vitro drug release studies on guar gum-based
use as protein-delivery microparticulate carriers. J. Appl. Polym. colon targeted oral drug delivery systems of 5-fluorouracil. Eur. J.
Sci., 2000, 75, 1615-1623. Pharm. Sci., 2002, 16(3), 185-192.
http://dx.doi.org/10.1002/(SICI)1097- http://dx.doi.org/10.1016/S0928-0987(02)00081-7 PMID:
4628(20000328)75:13<1615::AID-APP7>3.0.CO;2-L 12128173
[56] Escobar-Chávez, J.J.; López-Cervantes, M.; Naïk, A.; Kalia, Y.N.; [73] George, M.; Abraham, T.E. pH sensitive alginate-guar gum hydro-
Quintanar-Guerrero, D.; Ganem-Quintanar, A. Applications of gel for the controlled delivery of protein drugs. Int. J. Pharm.,
thermo-reversible pluronic F-127 gels in pharmaceutical formula- 2007, 335(1-2), 123-129.
tions. J. Pharm. Pharm. Sci., 2006, 9(3), 339-358. http://dx.doi.org/10.1016/j.ijpharm.2006.11.009 PMID: 17147980
PMID: 17207417 [74] Kim, M.S.; Park, K. Injectable hydrogel. In: Encyclopedia of
[57] Gyles, D.A.; Castro, L.D.; Silva, J.O.C., Jr; Ribeiro-Costa, R.M. A Nanotechnology, Bhushan, B.; Ed.; Springer; 2012, pp. 1091-1096.
review of the designs and prominent biomedical advances of natu- [75] Brannon-Peppas, L.; Peppas, N.A. Dynamic and equilibrium swel-
ral and synthetic hydrogel formulations. Eur. Polym. J., 2017, 88, ling behaviour of pH-sensitive hydrogels containing 2-
373-392. hydroxyethyl methacrylate. Biomaterials, 1990, 11(9), 635-644.
http://dx.doi.org/10.1016/j.eurpolymj.2017.01.027 http://dx.doi.org/10.1016/0142-9612(90)90021-H PMID: 2090297
[58] Ahmed, E.M. Hydrogel: Preparation, characterization, and applica- [76] Lee, S.M.; Ahn, R.W.; Chen, F.; Fought, A.J.; O’Halloran, T.V.;
tions: A review. J. Adv. Res., 2015, 6(2), 105-121. Cryns, V.L.; Nguyen, S.T. Biological evaluation of pH-responsive
http://dx.doi.org/10.1016/j.jare.2013.07.006 PMID: 25750745 polymer-caged nanobins for breast cancer therapy. ACS Nano,
[59] Wang, K.; Burban, J.; Cussler, E. Hydrogels as separation agents. 2010, 4(9), 4971-4978.
Responsive Gels: Volume Transitions II, 1993, 110, 67-79. http://dx.doi.org/10.1021/nn100560p PMID: 20738118
[60] Hacker, M.C.; Mikos, A.G. Synthetic Polymers. Principles Regen- [77] Abbasian, M.; Rodi, M.M.; Mahmoodzadeh, F.; Eskandani, M.;
erat. Med., 2011, 587-622. Jaymand, M. Chitosan-grafted-poly(methacrylic acid)/graphene ox-
[61] Yang, L.; Chu, J.S.; Fix, J.A. Colon-specific drug delivery: New ide nanocomposite as a pH-responsive de novo cancer chemother-
approaches and in vitro/in vivo evaluation. Int. J. Pharm., 2002, apy nanosystem. Int. J. Biol. Macromol, 2018, 118, 1871-1879.
235(1-2), 1-15. [78] Chen, Q.; Zheng, J.; Yuan, X.; Wang, J.; Zhang, L. Folic acid
http://dx.doi.org/10.1016/S0378-5173(02)00004-2 PMID: grafted and tertiary amino based pH-responsive pentablock polym-
11879735 eric micelles for targeting anticancer drug delivery. Mater. Sci.
[62] Kofinas, P.; Cohen, R.E. Development of methods for quantitative Eng. C, 2018, 82, 1-9.
characterization of network morphology in pharmaceutical hydro- http://dx.doi.org/10.1016/j.msec.2017.08.026 PMID: 29025636
gels. Biomaterials, 1997, 18(20), 1361-1369. [79] Zhang, X.; Huang, Y.; Ghazwani, M.; Zhang, P.; Li, J.; Thorne,
http://dx.doi.org/10.1016/S0142-9612(97)00077-X PMID: S.H.; Li, S. Tunable pH-responsive polymeric micelle for cancer
9363336 treatment. ACS Macro Lett., 2015, 4, 620-623.
[63] Pathmanathan, K.; Johari, G.P. Relaxation and crystallization of http://dx.doi.org/10.1021/acsmacrolett.5b00165
water in a hydrogel. J. Chem. Soc., Faraday Trans., 1994, 90(8), [80] Kang, Y.; Ha, W.; Liu, Y-Q.; Ma, Y.; Fan, M-M.; Ding, L-S.;
1143-1148. Zhang, S.; Li, B-J. pH-responsive polymer-drug conjugates as mul-
http://dx.doi.org/10.1039/ft9949001143 tifunctional micelles for cancer-drug delivery. Nanotechnology,
[64] Matsumoto, K.; Sakikawa, N.; Miyata, T. Thermo-responsive gels 2014, 25(33), 335101.
that absorb moisture and ooze water. Nat. Commun., 2018, 9(1), http://dx.doi.org/10.1088/0957-4484/25/33/335101 PMID:
2315-2321. 25073730
http://dx.doi.org/10.1038/s41467-018-04810-8 PMID: 29899417 [81] Raja, A.; Hayat, U.; Rasheed, T.; Bilal, M.; Iqbal, H.M.N. “Smart”
[65] Bajpai, A.K.; Shukla, S.K.; Bhanu, S.; Kankane, S. Responsive materials-based near-infrared light-responsive drug delivery sys-
polymers in controlled drug delivery. Prog. Polym. Sci., 2008, 33, tems for cancer treatment: A review. J. Mater. Sci. Technol., 2018,
1088-1118. 8(1), 1497-1509. http://dx.doi.org/10.1016/j.jmrt.2018.03.007
http://dx.doi.org/10.1016/j.progpolymsci.2008.07.005 [82] Fourniols, T.; Randolph, L.D.; Staub, A.; Vanvarenberg, K.;
Leprince, J.G.; Préat, V.; des Rieux, A.; Danhier, F. Temo-
1444 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

zolomide-loaded photopolymerizable PEG-DMA-based hydrogel [100] Sepantafar, M.; Maheronnaghsh, R.; Mohammadi, H.; Radmanesh,
for the treatment of glioblastoma. J. Control. Release, 2015, 210, F.; Hasani-Sadrabadi, M.M.; Ebrahimi, M.; Baharvand, H. Engi-
95-104. neered hydrogels in cancer therapy and diagnosis. Trends Biotech-
http://dx.doi.org/10.1016/j.jconrel.2015.05.272 PMID: 25982679 nol., 2017, 35(11), 1074-1087.
[83] Zhang, H.; Guo, S.S.; Fuand, Y.; Zhao, A. Near-infrared light- http://dx.doi.org/10.1016/j.tibtech.2017.06.015 PMID: 28734545
responsive hybrid hydrogel based on UCST triblock copolymer and [101] Ahmadi, F.; Oveisi, Z.; Samani, S.M.; Amoozgar, Z. Chitosan
gold nanorods. Polymers (Basel), 2018, 10(1), 9. based hydrogels: Characteristics and pharmaceutical applications.
http://dx.doi.org/10.3390/polym10010009 Res. Pharm. Sci., 2015, 10(1), 1-16.
[84] Griffin, D.R.; Kasko, A.M. Photo-selective delivery of model PMID: 26430453
therapeutics from hydrogels. ACS Macro Lett., 2012, 1(11), 1330- [102] Kuijpers, A.J.; Engbers, G.H.M.; Krijgsveld, J.; Zaat, S.A.; Dank-
1334. ert, J.; Feijen, J. Cross-linking and characterisation of gelatin ma-
http://dx.doi.org/10.1021/mz300366s PMID: 25285242 trices for biomedical applications. J. Biomater. Sci. Polym. Ed.,
[85] Azagarsamy, M.A.; Anseth, K.S. Wavelength-controlled photo- 2000, 11(3), 225-243.
cleavage for the orthogonal and sequential release of multiple pro- http://dx.doi.org/10.1163/156856200743670 PMID: 10841277
teins. Angew. Chem. Int. Ed. Engl., 2013, 52(51), 13803-13807. [103] Lee, J.B.; Peng, S.; Yang, D.; Roh, Y.H.; Funabashi, H.; Park, N.;
http://dx.doi.org/10.1002/anie.201308174 PMID: 24173699 Rice, E.J.; Chen, L.; Long, R.; Wu, M.; Luo, D. A mechanical
[86] Choi, J.R.; Yong, K.W.; Choi, J.Y.; Cowie, A.C. Recent advances metamaterial made from a DNA hydrogel. Nat. Nanotechnol.,
in photo-crosslinkable hydrogels for biomedical applications. Bio- 2012, 7(12), 816-820.
techniques, 2019, 66(1), 40-53. http://dx.doi.org/10.1038/nnano.2012.211 PMID: 23202472
http://dx.doi.org/10.2144/btn-2018-0083 PMID: 30730212 [104] Park, J.H.; Gu, L.; von Maltzahn, G.; Ruoslahti, E.; Bhatia, S.N.;
[87] Zhao, L.; Wang, L.; Zhang, Y.; Xiao, S.; Bi, F.; Zhao, J.; Gai, G.; Sailor, M.J. Biodegradable luminescent porous silicon nanoparti-
Ding, J. glucose oxidase-based glucose-sensitive drug delivery for cles for in vivo applications. Nat. Mater., 2009, 8(4), 331-336.
diabetes treatment. Polymers (Basel), 2017, 9(7), 255. http://dx.doi.org/10.1038/nmat2398 PMID: 19234444
http://dx.doi.org/10.3390/polym9070255 PMID: 30970930 [105] Tomatsu, I.; Peng, K.; Kros, A. Photoresponsive hydrogels for
[88] Peppas, N.A.; Bures, C.D. Glucose-Responsive Hydrogels, Ency- biomedical applications. Adv. Drug Deliv. Rev., 2011, 63(14-15),
clopedia of Biomaterials and Biomedical Engineering; Taylor & 1257-1266.
Francis: UK, 2006. http://dx.doi.org/10.1016/j.addr.2011.06.009 PMID: 21745509
[89] Bratlie, K.M.; York, R.L.; Invernale, M.A.; Langer, R.; Anderson, [106] Harada, A. Supramolecular Hydrogels, Encyclopedia of Polymeric
D.G. Materials for diabetes therapeutics. Adv. Healthc. Mater., Nanomaterials. Springer, 2014.
2012, 1(3), 267-284. [107] Ang, K.L.; Venkatraman, S.; Ramanujan, R.V. Magnetic PNIPA
http://dx.doi.org/10.1002/adhm.201200037 PMID: 23184741 hydrogels for hyperthermia applications in cancer therapy. Mater.
[90] Jiménez, J.L.; Nettleton, E.J.; Bouchard, M.; Robinson, C.V.; Dob- Sci. Eng. C, 2007, 27, 347-351.
son, C.M.; Saibil, H.R. The protofilament structure of insulin amy- [108] Iglesias, N.; Galbis, E.; Valencia, C.; De-Paz, M-V.; Galbis, J.A.
loid fibrils. Proc. Natl. Acad. Sci. USA, 2002, 99(14), 9196-9201. Reversible pH-sensitive chitosan-based hydrogels. Influence of
http://dx.doi.org/10.1073/pnas.142459399 PMID: 12093917 dispersion composition on rheological properties and sustained
[91] Hassan, C.M.; Doyle, F.J.; Peppas, N.A. Dynamic behavior of drug delivery. Polymers (Basel), 2018, 10(4), 392-309.
glucose-responsive poly(methacrylic acid-g-ethylene glycol) hy- http://dx.doi.org/10.3390/polym10040392 PMID: 30966427
drogels. Macromolecules, 1997, 30(20), 6166-6173. [109] Liu, L.; Gao, Q.; Lu, X.; Zhou, H. In situ forming hydrogels based
http://dx.doi.org/10.1021/ma970117g on chitosan for drug delivery and tissue regeneration. Asian J.
[92] Webber, M.J.; Anderson, D.G. Smart approaches to glucose- Pharma. Sci., 2016, 11, 673-683.
responsive drug delivery. J. Drug Target., 2015, 23(7-8), 651-655. http://dx.doi.org/10.1016/j.ajps.2016.07.001
http://dx.doi.org/10.3109/1061186X.2015.1055749 PMID: [110] Tsao, C-T.; Kievit, F.M.; Wang, K.; Erickson, A.E.; Ellenbogen,
26453161 R.G.; Zhang, M. Chitosan-based thermoreversible hydrogel as an in
[93] Matsumoto, A.; Tanaka, M.; Matsumoto, H.; Ochi, K.; Moro-Oka, vitro tumor microenvironment for testing breast cancer therapies.
Y.; Kuwata, H.; Yamada, H.; Shirakawa, I.; Miyazawa, T.; Ishii, Mol. Pharm., 2014, 11(7), 2134-2142.
H.; Kataoka, K.; Ogawa, Y.; Miyahara, Y.; Suganami, T. Synthetic http://dx.doi.org/10.1021/mp5002119 PMID: 24779767
“smart gel” provides glucose-responsive insulin delivery in diabetic [111] Tondera, C.; Hauser, S.; Krüger-Genge, A.; Jung, F.; Neffe, A.T.;
mice. Sci. Adv., 2017, 3(11), eaaq0723. Lendlein, A.; Klopfleisch, R.; Steinbach, J.; Neuber, C.; Pietzsch, J.
http://dx.doi.org/10.1126/sciadv.aaq0723 PMID: 29202033 Gelatin-based hydrogel degradation and tissue interaction in vivo:
[94] Huebsch, N.; Kearney, C.J.; Zhao, X.; Kim, J.; Cezar, C.A.; Suo, Insights from multimodal preclinical imaging in immunocompetent
Z.; Mooney, D.J. Ultrasound-triggered disruption and self-healing nude mice. Theranostics, 2016, 6(12), 2114-2128.
of reversibly cross-linked hydrogels for drug delivery and enhanced http://dx.doi.org/10.7150/thno.16614 PMID: 27698944
chemotherapy. Proc. Natl. Acad. Sci. USA, 2014, 111(27), 9762- [112] Kushibiki, T.; Matsumoto, K.; Nakamura, T.; Tabata, Y. Suppres-
9767. sion of tumor metastasis by NK4 plasmid DNA released from
http://dx.doi.org/10.1073/pnas.1405469111 PMID: 24961369 cationized gelatin. Gene Ther., 2004, 11(15), 1205-1214.
[95] Huang, W-C.; Ali, F.; Zhao, J.; Rhee, K.; Mou, C.; Bettinger, C.J. http://dx.doi.org/10.1038/sj.gt.3302285 PMID: 15103321
Ultrasound-mediated self-healing hydrogels based on tunable metal- [113] Satapathy, M.K.; Nyambat, B.; Chiang, C-W.; Chen, C-H.; Wong,
organic bonding. Biomacromolecules, 2017, 18(4), 1162-1171. P-C.; Ho, P-H.; Jheng, P-R.; Burnouf, T.C.-L.; Tsengand, E.-Y.;
http://dx.doi.org/10.1021/acs.biomac.6b01841 PMID: 28245355 Chuang, A. Gelatin hydrogel-containing nano-organic PEI–Ppy
[96] Zardad, A-Z.; Choonara, Y.E.; Du Toit, L.C.; Kumar, P.; Mabrouk, with a photothermal responsive effect for tissue engineering appli-
M.; Kondiah, P.P.D.; Pillay, V.M. A review of thermo- and ultra- cations. Molecules, 2018, 23, 1-17.
sound-responsive polymeric systems for delivery of chemothera- http://dx.doi.org/10.3390/molecules23061256
peutic agents. Polymers (Basel), 2016, 8(10), 359-380. [114] Wang, J.; Zhao, L.; Zhang, A.; Huang, Y.; Tavakoli, J.; Tang, Y.
http://dx.doi.org/10.3390/polym8100359 PMID: 30974645 Novel bacterial cellulose/gelatin hydrogels as 3D scaffolds for tu-
[97] Kowalski, G.; Kijowska, K.; Witczak, M.; Kuterasiński, Ł.; mor cell culture. Polymers (Basel), 2018, 10, 1-16.
Łukasiewicz, M. Synthesis and effect of structure on swelling [115] Shahbazi, M-A.; Ramos, T.B.; Santos, H.A. DNA hydrogel assem-
properties of hydrogels based on high methylated pectin and acrylic blies: bridging synthesis principles to biomedical applications. Adv.
polymers. Polymers (Basel), 2019, 11(1), 114-129. Ther., 2018, 1, 1800042-1800064.
http://dx.doi.org/10.3390/polym11010114 PMID: 30960098 http://dx.doi.org/10.1002/adtp.201800042
[98] Chai, Q.; Jiao, Y.; Yu, X. Hydrogels for biomedical applications: [116] Udomprasert, A.; Kangsamaksin, T. DNA origami applications in
Their characteristics and the mechanisms behind them. Gels, 2017, cancer therapy. Cancer Sci., 2017, 108(8), 1535-1543.
3(1), 1-15. [117] Song, J.; Hwang, S.; Im, K.; Hur, J.; Nam, J.; Hwang, S.; Ahn,
http://dx.doi.org/10.3390/gels3010006 PMID: 30920503 G.O.; Kim, S.; Park, N. Light-responsible DNA hydrogel-gold
[99] Fang, Y.; Tan, J.; Lim, S.; Soh, S. Rupturing cancer cells by the nanoparticle assembly forsynergistic cancer therapy. J. Mater.
expansion of functionalized stimuli-responsive hydrogels. Nature, Chem. B, 2015, 3, 1537-1543.
2018, 10, 1-9.
Synthesis and Applications of Hydrogels in Cancer Therapy Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 1445

[118] Yu, P.; Yu, H.; Guo, C.; Cui, Z.; Chen, X.; Yin, Q.; Zhang, P.; http://dx.doi.org/10.1016/j.jconrel.2011.09.098 PMID: 22001607
Yang, X.; Cui, H.; Li, Y. Reversal of doxorubicin resistance in [136] Peppas, N.A.; Bures, P.; Leobandung, W.; Ichikawa, H. Hydrogels
breast cancer by mitochondria-targeted pH-responsive micelles. in pharmaceutical formulations. Eur. J. Pharm. Biopharm., 2000,
Acta Biomater., 2015, 14, 115-124. 50(1), 27-46. http://dx.doi.org/10.1016/S0939-6411(00)00090-4
http://dx.doi.org/10.1016/j.actbio.2014.12.001 PMID: 25498306 PMID: 10840191
[119] Lv, S.N.; Cheng, C.J.; Song, Y.Y.; Zhao, Z.G. Temperature- [137] Li, J.; Mooney, D.J. Designing hydrogels for controlled drug deliv-
switched controlled release nanosystems based on molecular rec- ery. Nat. Rev. Mater., 2016, 1(12), 1-31.
ognition and polymer phase transition. RSC Advances, 2015, 5, http://dx.doi.org/10.1038/natrevmats.2016.71 PMID: 29657852
3248-3259. [138] Hovgaard, L.; Brondsted, H. Dextran hydrogels for colon-specific
http://dx.doi.org/10.1039/C4RA11075G drug delivery. J. Control. Release, 1995, 36, 159-166.
[120] Mi, Y.; Wolfram, J.; Mu, C.; Liu, X.; Blanco, E.; Shen, H.; Ferrari, http://dx.doi.org/10.1016/0168-3659(95)00049-E
M. Enzyme-responsive multistage vector for drug delivery to tumor [139] Vishnubhakthula, S.; Elupula, R.; Durán-Lara, E.F. Recent ad-
tissue. Pharmacol. Res., 2016, 113(Pt A), 92-99. vances in hydrogel-based drug delivery for melanoma cancer ther-
http://dx.doi.org/10.1016/j.phrs.2016.08.024 PMID: 27546164 apy: A mini review. J. Drug Deliv., 2017, 2017, 7275985.
[121] Ding, B.; Zhang, W.; Wu, X.; Wang, J.; Xie, C.; Huang, X.; Zhan, http://dx.doi.org/10.1155/2017/7275985 PMID: 28852576
S.; Zheng, Y.; Huang, Y.; Xu, N.; Ding, X.; Gao, S. DR5 mAb- [140] Schoener, C.A.; Hutson, H.N.; Peppas, N.A. pH-responsive hydro-
conjugated, DTIC-loaded immuno-nanoparticles effectively and gels with dispersed hydrophobic nanoparticles for the oral delivery
specifically kill malignant melanoma cells in vivo. Oncotarget, of chemotherapeutics. J. Biomed. Mater. Res. A, 2013, 101(8),
2016, 7(35), 57160-57170. 2229-2236.
http://dx.doi.org/10.18632/oncotarget.11014 PMID: 27494835 http://dx.doi.org/10.1002/jbm.a.34532 PMID: 23281185
[122] Basso, J.; Miranda, A.; Nunes, S.; Cova, T.; Sousa, J.; Vitorino, C.; [141] Xiong, L.; Luo, Q.; Wang, Y.; Li, X.; Shen, Z.; Zhu, W. An in-
Pais, A. Hydrogel-based drug delivery nanosystems for the treat- jectable drug-loaded hydrogel based on a supramolecular polym-
ment of brain tumors. Gels, 2018, 4(3), 62-90. eric prodrug. Chem. Commun. (Camb.), 2015, 51(78), 14644-
http://dx.doi.org/10.3390/gels4030062 PMID: 30674838 14647. http://dx.doi.org/10.1039/C5CC06025G PMID: 26290273
[123] Shin, D.S.; You, J.; Rahimian, A.; Vu, T.; Siltanen, C.; Ehsanipour, [142] Gil, M.S.; Thambi, T.; Phan, V.H.G.; Kim, S.H.; Lee, D.S. In-
A.; Stybayeva, G.; Sutcliffe, J.; Revzin, A. Photodegradable hydro- jectable hydrogels incorporating cancer cell-specific cisplatin re-
gels for capture, detection, and release of live cells. Angew. Chem. leasing nanogels for targeted drug delivery. J. Mater. Chem. B Ma-
Int. Ed. Engl., 2014, 53(31), 8221-8224. ter. Biol. Med., 2017, 5, 7140-7152.
http://dx.doi.org/10.1002/anie.201404323 PMID: 24931301 http://dx.doi.org/10.1039/C7TB00873B
[124] Liang, Y.; Li, L.; Scott, R.A.; Kiick, K.L. Polymeric biomaterials: [143] Zahedi, P.; Lee, P.I. Solid molecular dispersions of poorly water-
diverse functions enabled by advances in macromolecular chemis- soluble drugs in poly(2-hydroxyethyl methacrylate) hydrogels. Eur.
try. Macromolecules, 2017, 50(2), 483-502. J. Pharm. Biopharm., 2007, 65(3), 320-328.
http://dx.doi.org/10.1021/acs.macromol.6b02389 PMID: 29151616 http://dx.doi.org/10.1016/j.ejpb.2006.10.025 PMID: 17182231
[125] Saboktakin, M.R.; Tabatabaei, R.M. Supramolecular hydrogels as [144] Dulong, V.; Mocanu, G.; Le, D.C. A novel amphiphilic pH-
drug delivery systems. Int. J. Biol. Macromol., 2015, 75, 426-436. sensitive hydrogel based on pullulan. Colloid Polym. Sci., 2007,
http://dx.doi.org/10.1016/j.ijbiomac.2015.02.006 PMID: 25687476 285(10), 1085-1091.
[126] Liu, X.; Li, Z.; Loh, X.J.; Chen, K.; Li, Z.; Wu, Y-L. Targeted and http://dx.doi.org/10.1007/s00396-007-1655-3
sustained corelease of chemotherapeutics and gene by injectable [145] Bhaskar, K.; Krishna Mohan, C.; Lingam, M.; Jagan Mohan, S.;
supramolecular hydrogel for drug-resistant cancer therapy. Macro- Venkateswarlu, V.; Madhusudan Rao, Y.; Bhaskar, K.; Anbu, J.;
mol. Rapid Commun., 2019, 40(5), 1800117-1800125. Ravichandran, V. Development of SLN and NLC enriched hydro-
PMID: 29992700 gels for transdermal delivery of nitrendipine: In vitro and in vivo
[127] Liu, X.; Chen, X.; Chua, M.X.; Li, Z.; Loh, X.J.; Wu, Y-L. In- characteristics. Drug Dev. Ind. Pharm., 2009, 35(1), 98-113.
jectable supramolecular hydrogels as delivery agents of Bcl-2 con- http://dx.doi.org/10.1080/03639040802192822 PMID: 18665979
version gene for the effective shrinkage of therapeutic resistant tu- [146] Eckert, F.; Alloussi, S.; Paulsen, F.; Bamberg, M.; Zips, D.; Spill-
mors. Adv. Healthc. Mater., 2017, 6, 1700159-1700169. ner, P.; Gani, C.; Kramer, U.; Thorwarth, D.; Schilling, D.; Muller,
http://dx.doi.org/10.1002/adhm.201700159 A.C. Prospective evaluation of a hydrogel spacer for rectal separa-
[128] Zhang, J.; Huang, Q.; Du, J. Recent advances in magnetic hydro- tion in dose-escalated intensity-modulated radiotherapy for clini-
gels. Polym. Int., 2016, 65, 1365-1372. cally localized prostate cancer. BMC Cancer, 2013, 13, 1471-2407.
http://dx.doi.org/10.1002/pi.5170 http://dx.doi.org/10.1186/1471-2407-13-27
[129] Ramanujan, R.V.; Ang, K.L.; Venkatraman, S. Magnet-PNIPA [147] Vashist, A.; Vashist, A.; Gupta, Y.K.; Ahmad, S. Recent advances
hydrogels for bioengineering applications. J. Mater. Sci., 2009, 44, in hydrogel based drug delivery systems for the human body. J.
1381-1387. http://dx.doi.org/10.1007/s10853-006-1064-x Mater. Chem. B Mater. Biol. Med., 2014, 2, 147-166.
[130] Häring, M.; Schiller, J.; Mayr, J.; Grijalvo, S.; Eritja, R.; Díaz, http://dx.doi.org/10.1039/C3TB21016B
D.D. Magnetic gel composites for hyperthermia cancer therapy. [148] Langer, R.; Vacanti, J.P. Tissue engineering. Science, 1993,
Gels, 2015, 1(2), 135-161. 260(5110), 920-926.
http://dx.doi.org/10.3390/gels1020135 PMID: 30674170 http://dx.doi.org/10.1126/science.8493529 PMID: 8493529
[131] Wu, H.; Song, L.; Chen, L.; Zhang, W.; Chen, Y.; Zang, F.; Chen, [149] Ballios, B.G.; Cooke, M.J.; Donaldson, L.; Coles, B.L.; Morshead,
H.; Ma, M.; Gu, N.; Zhang, Y. Injectable magnetic supramolecular C.M.; van der Kooy, D.; Shoichet, M.S. A hyaluronan-based in-
hydrogel with magnetocaloric liquid-conformal property prevents jectable hydrogel improves the survival and integration of stem cell
post-operative recurrence in a breast cancer model. Acta Biomater., progeny following transplantation. Stem Cell Reports, 2015, 4(6),
2018, 74, 302-311. 1031-1045.
http://dx.doi.org/10.1016/j.actbio.2018.04.052 PMID: 29729897 http://dx.doi.org/10.1016/j.stemcr.2015.04.008 PMID: 25981414
[132] Chauhan, S.; Harikumar, S.L. Kanupriya, Hydrogels: A smart drug [150] Lee, J.H. Injectable hydrogels delivering therapeutic agents for
delivery system. Int. J. Res. Pharm. Chem., 2012, 2(3), 603-614. disease treatment and tissue engineering. Biomater. Res., 2018,
[133] Lee, J.M.; Park, D.Y.; Yang, L.; Kim, E-J.; Ahrberg, C.D.; Lee, K- 22(1), 27.
B.; Chung, B.G. Generation of uniform-sized multicellular tumor http://dx.doi.org/10.1186/s40824-018-0138-6 PMID: 30275970
spheroids using hydrogel microwells for advanced drug screening. [151] Drury, J.L.; Mooney, D.J. Hydrogels for tissue engineering: scaf-
Sci. Rep., 2018, 8(1), 17145. fold design variables and applications. Biomaterials, 2003, 24(24),
http://dx.doi.org/10.1038/s41598-018-35216-7 PMID: 30464248 4337-4351. http://dx.doi.org/10.1016/S0142-9612(03)00340-5
[134] Bregenzer, M.E.; Horst, E.N.; Mehta, P.; Novak, C.M.; Raghavan, PMID: 12922147
S.; Snyder, C.S.; Mehta, G. Integrated cancer tissue engineering [152] Li, X.; Fan, D. Smart collagen hydrogels based on 1-ethyl-3-
models for precision medicine. PLoS One, 2019, 14(5), e0216564. methylimidazolium acetate and microbial transglutaminase for po-
http://dx.doi.org/10.1371/journal.pone.0216564 PMID: 31075118 tential applications in tissue engineering and cancer therapy. ACS
[135] Bertrand, N.; Leroux, J.C. The journey of a drug-carrier in the Biomater. Sci. Eng., 2019, 5, 3523-3536.
body: an anatomo-physiological perspective. J. Control. Release, http://dx.doi.org/10.1021/acsbiomaterials.9b00393
2012, 161(2), 152-163.
1446 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 12 Singhal et al.

[153] Ono, K.; Saito, Y.; Yura, H.; Ishikawa, K.; Kurita, A.; Akaike, T.; http://dx.doi.org/10.1002/art.20269 PMID: 15146422
Ishihara, M. Photocrosslinkable chitosan as a biological adhesive. [167] Nurlidar, F.; Yamane, K.; Kobayashi, M.; Terada, K.; Ando, T.;
J. Biomed. Mater. Res., 2000, 49(2), 289-295. Tanihara, M. Calcium deposition in photocrosslinked poly(Pro-
http://dx.doi.org/10.1002/(SICI)1097-4636(200002)49:2<289::AID- Hyp-Gly) hydrogels encapsulated rat bone marrow stromal cells. J.
JBM18>3.0.CO;2-M PMID: 10571917 Tissue Eng. Regen. Med., 2018, 12(3), e1360-e1369.
[154] Zhao, X.; Kato, K.; Fukumoto, Y.; Nakamae, K. Synthesis of http://dx.doi.org/10.1002/term.2520 PMID: 28715113
bioadhesive hydrogels from chitin derivatives. Int. J. Adhes. Ad- [168] Kim, M.H.; Park, W.H. Chemically cross-linked silk fibroin hydro-
hes., 2001, 21(3), 227-232. gel with enhanced elastic properties, biodegradability, and biocom-
http://dx.doi.org/10.1016/S0143-7496(01)00003-3 patibility. Int. J. Nanomedicine, 2016, 11, 2967-2978.
[155] Annabi, N.; Rana, D.; Shirzaei Sani, E.; Portillo-Lara, R.; Gifford, PMID: 27382283
J.L.; Fares, M.M.; Mithieux, S.M.; Weiss, A.S. Engineering a [169] Kim, M.H.; Kim, B.S.; Lee, J.; Cho, D.; Kwon, O.H.; Park, W.H.
sprayable and elastic hydrogel adhesive with antimicrobial proper- Silk fibroin/hydroxyapatite composite hydrogel induced by
ties for wound healing. Biomaterials, 2017, 139, 229-243. gamma-ray irradiation for bone tissue engineering. Biomater. Res.,
http://dx.doi.org/10.1016/j.biomaterials.2017.05.011 PMID: 28579065 2017, 21(1), 12.
[156] Grip, J.; Engstad, R.E.; Skjæveland, I.; Škalko-Basnet, N.; Hol- http://dx.doi.org/10.1186/s40824-017-0098-2 PMID: 28652926
sæter, A.M. Sprayable carbopol hydrogel with soluble beta-1,3/1,6- [170] Miguel, S.P.; Ribeiro, M.P.; Brancal, H.; Coutinho, P.; Correia, I.J.
glucan as an active ingredient for wound healing - Development Thermoresponsive chitosan-agarose hydrogel for skin regeneration.
and in-vivo evaluation. Eur. J. Pharm. Sci., 2017, 107, 24-31. Carbohydr. Polym., 2014, 111, 366-373.
http://dx.doi.org/10.1016/j.ejps.2017.06.029 PMID: 28645493 http://dx.doi.org/10.1016/j.carbpol.2014.04.093 PMID: 25037363
[157] Moghadas, B.; Dashtimoghadam, E.; Mirzadeh, H.; Seidi, F.; [171] Buckley, C.T.; Thorpe, S.D.; O’Brien, F.J.; Robinson, A.J.; Kelly,
Hasani-Sadrabadi, M.M. Novel chitosan-based nanobiohybrid D.J. The effect of concentration, thermal history and cell seeding
membranes for wound dressing applications. RSC Advances, 2016, density on the initial mechanical properties of agarose hydrogels. J.
6(10), 7701-7711. http://dx.doi.org/10.1039/C5RA23875G Mech. Behav. Biomed. Mater., 2009, 2(5), 512-521.
[158] Gálvez-Montón, C.; Prat-Vidal, C.; Roura, S.; Soler-Botija, C.; http://dx.doi.org/10.1016/j.jmbbm.2008.12.007 PMID: 19627858
Bayes-Genis, A. Update: Innovation in cardiology (IV). Cardiac [172] Hashimoto, T.; Suzuki, Y.; Tanihara, M.; Kakimaru, Y.; Suzuki, K.
tissue engineering and the bioartificial heart. Rev. Esp. Cardiol. Development of alginate wound dressings linked with hybrid pep-
(Engl. Ed.), 2013, 66(5), 391-399. tides derived from laminin and elastin. Biomaterials, 2004, 25(7-8),
http://dx.doi.org/10.1016/j.rec.2012.11.012 PMID: 24775822 1407-1414. http://dx.doi.org/10.1016/j.biomaterials.2003.07.004
[159] Shu, Y.; Hao, T.; Yao, F.; Qian, Y.; Wang, Y.; Yang, B.; Li, J.; PMID: 14643615
Wang, C. RoY peptide-modified chitosan-based hydrogel to im- [173] An, Y-H.; Yu, S.J.; Kim, I.S.; Kim, S-H.; Moon, J-M.; Kim, S.L.;
prove angiogenesis and cardiac repair under hypoxia. ACS Appl. Choi, Y.H.; Choi, J.S.; Im, S.G.; Lee, K.E.; Hwang, N.S. Hydrogel
Mater. Interfaces, 2015, 7(12), 6505-6517. functionalized Janus membrane for skin regeneration. Adv.
http://dx.doi.org/10.1021/acsami.5b01234 PMID: 25756853 Healthc. Mater., 2017, 6(5), 1600795.
[160] Speidel, A.T.; Stuckey, D.J.; Chow, L.W.; Jackson, L.H.; Noseda, http://dx.doi.org/10.1002/adhm.201600795 PMID: 27995759
M.; Abreu Paiva, M.; Schneider, M.D.; Stevens, M.M. Multimodal [174] Zhao, X.; Wu, H.; Guo, B.; Dong, R.; Qiu, Y.; Ma, P.X. Antibacte-
hydrogel-based platform to deliver and monitor cardiac progeni- rial anti-oxidant electroactive injectable hydrogel as self-healing
tor/stem cell engraftment. ACS Cent. Sci., 2017, 3(4), 338-348. wound dressing with hemostasis and adhesiveness for cutaneous
http://dx.doi.org/10.1021/acscentsci.7b00039 PMID: 28470052 wound healing. Biomaterials, 2017, 122, 34-47.
[161] Wang, X.; Chun, Y.W.; Zhong, L.; Chiusa, M.; Balikov, D.A.; http://dx.doi.org/10.1016/j.biomaterials.2017.01.011 PMID: 28107663
Frist, A.Y.; Lim, C.C.; Maltais, S.; Bellan, L.; Hong, C.C.; Sung, [175] Li, X.; Su, X. Multifunctional smart hydrogels: Potential in tissue
H.J. A temperature-sensitive, self-adhesive hydrogel to deliver engineering and cancer therapy. J. Mater. Chem. B Mater. Biol.
iPSC-derived cardiomyocytes for heart repair. Int. J. Cardiol., Med., 2018, 6(29), 4714-4730.
2015, 190, 177-180. http://dx.doi.org/10.1039/C8TB01078A
http://dx.doi.org/10.1016/j.ijcard.2015.04.139 PMID: 25918074 [176] Koetting, M.C.; Peters, J.T.; Steichen, S.D.; Peppas, N.A. Stimu-
[162] Li, X.; Zhou, J.; Liu, Z.; Chen, J.; Lü, S.; Sun, H.; Li, J.; Lin, Q.; lus-responsive hydrogels: Theory, modern advances, and applica-
Yang, B.; Duan, C.; Xing, M.M.; Wang, C. A PNIPAAm-based tions. Mater. Sci. Eng. Rep., 2015, 93, 1-49.
thermosensitive hydrogel containing SWCNTs for stem cell trans- http://dx.doi.org/10.1016/j.mser.2015.04.001 PMID: 27134415
plantation in myocardial repair. Biomaterials, 2014, 35(22), 5679- [177] Mateescu, A.; Wang, Y.; Dostalek, J.; Jonas, U. Thin hydrogel
5688. http://dx.doi.org/10.1016/j.biomaterials.2014.03.067 PMID: films for optical biosensor applications. Membranes (Basel), 2012,
24746964 2(1), 40-69.
[163] Zhao, F.; Mc Garrigle, M.J.; Vaughan, T.J.; McNamara, L.M. In http://dx.doi.org/10.3390/membranes2010040 PMID: 24957962
silico study of bone tissue regeneration in an idealised porous hy- [178] Bahram, M.; Mohseni, N.; Moghtader, M. An introduction to hy-
drogel scaffold using a mechano-regulation algorithm. Biomech. drogels and some recent applications. In: Emerging Concepts in
Model. Mechanobiol., 2018, 17(1), 5-18. Analysis and Applications of Hydrogels, Majee, S.B.; Ed., InTech
http://dx.doi.org/10.1007/s10237-017-0941-3 PMID: 28779266 Open; 2016.
[164] Zheng, Y.; Huang, K.; You, X.; Huang, B.; Wu, J.; Gu, Z. Hybrid http://dx.doi.org/10.5772/64301
hydrogels with high strength and biocompatibility for bone regen- [179] Gao, Y.; Ren, F.; Ding, B.; Sun, N.; Liu, X.; Ding, X.; Gao, S. A
eration. Int. J. Biol. Macromol., 2017, 104(Pt A), 1143-1149. thermo-sensitive PLGA-PEG-PLGA hydrogel for sustained release
http://dx.doi.org/10.1016/j.ijbiomac.2017.07.017 PMID: 28687387 of docetaxel. J. Drug Target., 2011, 19(7), 516-527.
[165] Kon, E.; Muraglia, A.; Corsi, A.; Bianco, P.; Marcacci, M.; Martin, http://dx.doi.org/10.3109/1061186X.2010.519031 PMID:
I.; Boyde, A.; Ruspantini, I.; Chistolini, P.; Rocca, M.; Giardino, 20883085
R.; Cancedda, R.; Quarto, R. Autologous bone marrow stromal [180] Kim, J.I.; Kim, B.; Chun, C.; Lee, S.H.; Song, S-C. MRI-monitored
cells loaded onto porous hydroxyapatite ceramic accelerate bone long-term therapeutic hydrogel system for brain tumors without
repair in critical-size defects of sheep long bones. J. Biomed. Ma- surgical resection. Biomaterials, 2012, 33(19), 4836-4842.
ter. Res., 2000, 49(3), 328-337. http://dx.doi.org/10.1016/j.biomaterials.2012.03.048 PMID: 22483245
http://dx.doi.org/10.1002/(SICI)1097-4636(20000305)49:3<328:: [181] Gelderblom, H.; Verweij, J.; Nooter, K.; Sparreboom, A. Cremo-
AID-JBM5>3.0.CO;2-Q PMID: 10602065 phor EL: The drawbacks and advantages of vehicle selection for
[166] Alsalameh, S.; Amin, R.; Gemba, T.; Lotz, M. Identification of drug formulation. Eur. J. Cancer, 2001, 37(13), 1590-1598.
mesenchymal progenitor cells in normal and osteoarthritic human http://dx.doi.org/10.1016/S0959-8049(01)00171-X PMID: 11527683
articular cartilage. Arthritis Rheum., 2004, 50(5), 1522-1532.