Carbohydrate Polymers 333 (2024) 121985

Contents lists available at ScienceDirect

Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol

Review

Application of sodium sulfobutylether-β-cyclodextrin based

on encapsulation
Jiaqi Huang a, b, 1, Xiaofeng Wang b, 1, Ting Huang a, b, Yang Yang a, b, Jiasheng Tu a, Jian Zou b,
Huiying Yang b, *, Rui Yang b, *
a
Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, China
b
National Institutes for Food and Drug Control, National Key Laboratory for Quality Control of Pharmaceutical Excipients, Beijing 100050, China

A R T I C L E I N F O A B S T R A C T

Keywords: Sodium Sulfobutylether-β-cyclodextrin (SBE-β-CD) is a derivative of β-cyclodextrin, characterized by its stereo

Sodium Sulfobutylether-β-cyclodextrin structure, which closely resembles a truncated cone with a hydrophobic internal cavity. The solubility of
SBE-β-CD insoluble substances within the hydrophobic cavity is significantly enhanced, reducing contact between the guest
Inclusion
and the environment. Consequently, SBE-β-CD is frequently employed as a co-solvent and stabilizer. As the
Protection
Enantioseparation
research progresses, it has been observed that the inclusion of SBE-β-CD is reversible and competitive. Besides,
Dyes some inclusion complexes undergo distinct physicochemical property alterations compared to the guests.
Additionally, certain guests exhibit varying inclusions with SBE-β-CD at different concentrations. These features
have contributed to the expanding applications. SBE-β-CD finds widespread application in pharmaceutics as a
protective agent and pKa regulator, in pharmaceutical analysis as a chiral substance separator, and in biomedical
engineering for encapsulating dyes and modifying sensors. The article will elaborate in detail on the physico­
chemical properties of SBE-β-CD, encapsulation principles, and factors influencing the formation of inclusion
complexes. Furthermore, the review focuses on the application of SBE-β-CD through encapsulation in pharma­
ceutics, pharmaceutical analysis, and biomedical engineering. Finally, the prospects and potential applications of
SBE-β-CD are discussed.

1. Introduction exhibit a unique three-dimensional structure resembling a hollow

truncated cone (refer to Fig. 1). This characteristic structure features
Cyclodextrins (CDs), cyclic oligosaccharides containing 6–12 glucose hydrophobic cavities, enabling the formation of inclusion complexes
units, are produced through enzymatic action by cyclodextrin gluco­ with various guest substances (Crini, 2014; Xing Ma & Zhao, 2015).
syltransferases (Saenger, 1980; Uekama, 1981). Among the various Among these CDs, β-CD is the most commonly utilized, primarily
types of CDs, the most extensively studied ones are α-, β-, and γ-CD, because of its cost-effectiveness. Highly esteemed for the enhancement
which consist of 6, 7, and 8 glucopyranose molecules, respectively. They of solubility, particularly when forming inclusion complexes with poorly

Abbreviations: CD, Cyclodextrin; SBE-β-CD, Sodium Sulfobutylether-β-cyclodextrin; HP-β-CD, Hydroxypropyl-β-cyclodextrin; DS, Degree of substitution; C, Car­
bon; SOR, Sorafenib; QM, Quantum chemistry; MD, Molecular dynamics; QSAR, Docking and quantitative structure activity relationship; QSPR, Quantitative
structure–property relationship; QSAR, Quantitative structure–activity relationship; DFT, Density functional theory; pKa, Acid dissociation constant; pH, Potential of
hydrogen; CPZ, Chlorpromazine; 3D, Three dimension; SG+, The protonated form of haematogenin; SGOH, The neutral form of haematogenin; SGR, Sanguinarine;
CS, Chitosan; NP, Nanoparticle; IDE, Idebenone; HA, Hyaluronic acid; SC-40230, bisdiamine; HCl, Hydrochloric acid; CE, Capillary electrophoresis; SBECDIL, Ionic
liquid chiral selector based on sulfobutylether-β-cyclodextrin; HPLC, High-performance liquid chromatography; CPE, Chlorpheniramine; AIE, Aggregation-induced
emission; ACQ, Aggregation-caused quenching; AOH+, Acridine orange; TO, Thiazole orange; DAPI, 4′, 6-Diamidino-2-phenylindole; AuO, Auramine-O; PMA, 1-
Pyrenemethyl amine; BBR, Cationic dye berberine; TPE-Py, Tetraphenylene pyridine; BDZ, BODIPY-benzimidazole conjugate dye; AMCA, Aminomethyl coumarinic
acid; BY40, C.I. Basic Yellow 40; PhB, Ethyl phthalate; P-BrNp, Naphthylpyridinium-acrylamide copolymers; CL, chemiluminescence; PSS, Polymer polystyrene
sulfonate; BDD, Boron-doped diamond; GO, Glucose oxidase; Pty, Polytyrosamine.
* Corresponding authors.
E-mail addresses: [email protected] (H. Yang), [email protected] (R. Yang).
1
Authors who contributed equally to this work.

https://doi.org/10.1016/j.carbpol.2024.121985
Received 8 January 2024; Received in revised form 6 February 2024; Accepted 23 February 2024
Available online 24 February 2024
0144-8617/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-
nc/4.0/).
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

water-soluble drugs, β-CD plays a crucial role (Brewster & Loftsson, characteristics of the substance. Modified CDs exhibit lower hemolysis
2007; T. Loftsson & Brewster, 1996; Thorsteinn Loftsson & Duchene, compared to β-CD (Rajewski et al., 1995), significantly enhancing
2007; Strickley, 2004; Williams et al., 2013). β-CD is recognized as a safe biosafety. Variations in DS lead to differing hemolytic activity, with the
excipient for oral administration (Irie & Uekama, 1997; Rajewski & order of hemolytic activity for SBE-β-CDs being SBE7-β-CD < SBE4-β-CD
Stella, 1996). However, in non-gastrointestinal administration, the use ≪ SBE1-β-CD (Thompson, 1997). Alterations in DS also yield differences
of β-CD is linked to potential risks of significant hemolysis and neph­ in osmotic effects, subsequently impacting drug absorption. The osmo­
rotoxicity (Frank, Gray, & Weaver, 1976; Perrin, Field, Hansen, Mufson, lality of SBE-β-CDs is notably higher than that of HP-β-CD and increases
& Torosian, 1978; V. J. Stella & He, 2008), attributed to the formation of with higher DS (Proniuk & Blanchard, 2001; Zannou, Streng, & Stella,
cholesterol complexes. Furthermore, with a low water solubility of 2001). Moreover, the hygroscopicity of SBE-β-CD is influenced by DS. At
merely 1.85 % (Del Valle, 2004), β-CD tends to form crystalline in­ 95 % relative humidity, the order of hygroscopicity is SBE7-β-CD > SBE4-
clusions, making it unsuitable for drugs with limited apparent solubility. β-CD > SBE5-β-CD (Jain & Adeyeye, 2001). Altering DS also leads to
In response to the drawbacks of β-CD, such as its nephrotoxicity, he­ changes in binding constants, enthalpies, and entropies (Das, Ghate, &
molysis potential, and poor water solubility, researchers have developed Lewis, 2019). According to Zia, SBE1-β-CD with fewer substituents ex­
various derivatives of β-CD (Albers & Muller, 1995; Hedges, 1998; hibits similar complexation behavior to β-CD, while SBE-β-CD with
Rezanka, 2016, 2019; Uekama, Hirayama, & Irie, 1998). These de­ higher substituent levels displays different complexation behavior. With
rivatives include hydroxypropyl-β-cyclodextrin (HP-β-CD) (S. Q. Liu, increasing substituents, side chain mobility decreases, rendering the
Fan, Jia, & Pan, 1997), sodium sulfobutylether-β-cyclodextrin (SBE- molecular structure more ordered and less flexible. This difference may
β-CD), among others. This paper primarily focuses on SBE-β-CD. be attributed to the formation of extended side chain cavities (V. Zia,
SBE-β-CD is an anionic cyclodextrin derivative with high water sol­ Vander Velde, & Stella, 2014).
ubility. The substitution of sulfobutyl for the hydroxyl group at the 2, 3, The solubility of insoluble substances is significantly increased upon
or 6 positions of β-CD results in the generation of SBE-β-CDs with entering the hydrophobic cavity of SBE-β-CD. Simultaneously, the con­
varying degrees of substitution (DS) (refer to Fig. 1) (V. Stella & tact between the guest and the surrounding environment is reduced.
Rajewski, n.d.; V. J. Stella, Rajewski, Rajewski, Stella, & Stella, n.d.). Therefore, SBE-β-CD is widely used as a stabilizer and co-solvent.
The primary hydroxyl group at position 6 in β-CD is the most nucleo­ Further studies revealed that the encapsulation by SBE-β-CD is revers­
philic, the secondary hydroxyl group at position 2 is the most acidic, and ible and competitive. Additionally, certain inclusion complexes exhibit
the secondary hydroxyl group at position 3 is the most sterically hin­ different physicochemical properties than the contrasting guests.
dered. In weakly basic aqueous conditions, the secondary hydroxyl Moreover, some guests are encapsulated with SBE-β-CD in varying forms
group at carbon 2 (C2) exhibits higher reactivity than the primary hy­ at different concentrations. These features contribute to expanding the
droxyl group at carbon 6 (C6). Conversely, under highly alkaline con­ application range of SBE-β-CD. The paper will delve into the principles
ditions, the opposite is observed. In both scenarios, modifying the of SBE-β-CD encapsulation, explore the factors influencing complex
hydroxyl group at the carbon 3 (C3) position is notably challenging, formation, and provide an overview of their applications in pharma­
typically necessitating adjustments after substantial reactions involving ceutics, pharmaceutical analysis, and biomedical engineering based on
the C6 and C2 hydroxyl groups (Jindrich, Pitha, & Lindberg, 1995). encapsulation. Finally, insights into potential future developments in
In addition to the substitution site, DS significantly influences the this field will be offered.
physical and chemical properties of SBE-β-CD. DS of SBE-β-CD quantifies
the number of active hydroxyl groups on each CD that have been
substituted with sulfobutyl groups. DS exerts multifaceted effects on the

Fig. 1. The structure of β-CDs (a), SBE-β-CD (DS = x + y + z) (b. c), and SBE7-β-CDs (d).

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J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

2. Principle of SBE-β-CD encapsulation The encapsulation of SBE-β-CD is characterized by competitiveness,

selectivity, and reversibility. Meanwhile, certain physical and chemical
Encapsulation is defined as the reliance of guest molecules on hy­ properties of certain guests change the formation of inclusion com­
drophobic interactions (Bayat, Homami, Monzavi, & Talei Bavil Olyai, plexes. Besides, the concentration of the host and guest influences
2022; Flores et al., 2015; Khomutov, Sidorov, Dovbnya, & Donova, encapsulation for some guests, thereby altering the aggregation state.
2002; Y. Liu, Han, & Chen, 2002; Miskolczy, Megyesi, & Biczók, 2022). These characteristics contribute significantly to expanding its applica­
Charge interaction between the two species plays a significant role in tions in the medical field.
this process (Chakraborty, Chittela, Jonnalgadda, & Pal, 2022; Varnai,
Malanga, Sohajda, & Beni, 2022; Vahid Zia, 1998). Hydrogen bonding 2.1. Research methods
(Jafari, Raissi, & Hashemzadeh, 2022; L. Liu & Guo, 2002), Van der
Waals forces (Oo, Kerdpol, Mahalapbutr, & Rungrotmongkol, 2022), The encapsulation of SBE-β-CD is reversible, with research primarily
and other interactions with the cavities of the host molecule also focused on calculating binding constants (Baghel & Banjare, 2023;
contribute to the encapsulation process. Cyclodextrins dissolved in Eggers et al., 2023). Binding constants, also referred to as formation and
water act as host molecules capable of accommodating suitable guest complex stabilization constants, serve as equilibrium constants for the
molecules (Wankar et al., 2020). formation of complexes and are frequently used to describe the affinity
SBE-β-CD, a derivative of β-CD, features not only a round plateau- of the guest to the host. A stronger affinity and easier binding to SBE-
shaped hydrophobic inner cavity but also the branched sulfobutyl β-CD is associated with larger binding constants (Brewster & Loftsson,
chains that extend this hydrophobic cavity, aiding in the encapsulation 2007; Fielding, 2000; Houk, Leach, Kim, & Zhang, 2003; Rekharsky
of drug molecules (refer to Fig. 2). Aman et al. employed molecular et al., 2007; Turnbull & Daranas, 2003).
dynamics to model the inclusion complexes of Sorafenib with HP-β-CD, The binding constants of complexes at the molecular level can be
γ-CD, and SBE7-β-CD, which revealed that SBE7-β-CD exhibited superior studied using many techniques, commonly used are fluorescence spec­
encapsulation efficiency for SOR compared to other CDs (Aman et al., troscopy (Rajamohan, Viswalingam, Lee, Prabu, & Sivakumar, 2023),
2023). Chakraborty et al. discovered that the binding constants of a ultraviolet and visible spectrum absorption spectroscopy (Martinez-
styrene-based fluorescent probe to SBE-β-CD were significantly higher Guerra et al., 2022), circular dichroism (Kraszni, Agh, Horvath, Mirza­
than those observed for β-CD. This difference is likely attributable to the hosseini, & Horvath, 2023), electron magnetic resonance spectroscopy
robust electrostatic interactions between the cationic guest and the (Neculae et al., 2022), Taylor dispersion analysis (Santos, Ribeiro, &
polyanionic body, as well as the extended hydrophobic interaction re­ Esteso, 2019), affinity capillary electrophoresis (Sursyakova, Levdan­
gion provided by the sulfobutylether group (Chakraborty, Ray, Singh, & sky, & Rubaylo, 2022), isothermal calorimetry (Peluso et al., 2023) and
Pal, 2019). infrared spectroscopy (Rajamohan et al., 2022). In a study conducted by
The inclusion process of SBE-β-CD is reversible and exhibits selec­ Yuanli et al. in 2023, it was observed that the binding constants obtained
tivity and competitiveness (Saokham, Muankaew, Jansook, & Loftsson, through affinity capillary electrophoresis were marginally lower
2018; Shimpi, Chauhan, & Shimpi, 2005; V. J. Stella, Rao, Zannou, & compared to those derived from the Taylor dispersion analysis proced­
Zia, 1999; J. Zhou, Jia, He, Li, & Cai, 2022). In the presence of multiple ure (Dai et al., 2023). It is important to emphasize that the method
guests in a solution, SBE-β-CD will preferentially bind to the substance employed for determining these binding constants may be influenced by
with higher affinity, forming an inclusion complex (refer to Fig. 3). aggregation. As a result, the experimental outcomes can exhibit de­
For certain guests, the formation of inclusions results in alterations in pendency on factors such as concentration and the specific method
specific physical and chemical properties (Yuen & Tam, 2010; D. Zhang employed (Thorsteinn Loftsson, Sigurdsson, & Jansook, 2023).
et al., 2019), contributing to an expansion of applications. In addition to experimentally measured binding constants, various
Additionally, inclusion formation for certain guests is concentration- computational approaches, such as quantum chemistry (QM) (L. Liu &
dependent (Fromming, Fridrich, & Mehnert, 1993), and the ratio of host Guo, 2004; Mazurek & Szeleszczuk, 2022; Pereva, Nikolova, Angelova,
to guest can control the aggregative state of these complexes (refer to Spassov, & Dudev, 2019), molecular dynamics (MD) (Jafari, Raissi, &
Fig. 4). When SBE-β-CD concentration is low, it is preferred that several Shahabi, 2022; Jitapunkul, Toochinda, & Lawtrakul, 2021; Suarez-Les­
guests form a complex with a single host molecule. When SBE-β-CD ton, Garrido, & Pineiro, 2022), quantitative structure–property (or ac­
concentrations are high, there is a greater tendency to form 1:1 inclusion tivity) relationship (QSPR or QSAR) (Abdolmaleki, Ghasemi, &
complexes. Ghasemi, 2017; Bayat et al., 2022; Ding et al., 2022; Jeschke & Cole,
2019; Yu, Xu, He, & Liang, 2023) are utilized to investigate host-guest
interactions through computer modeling. Alexei et al. developed a
QSPR model employing both Cubist and random forest methods,
achieving low error rates in predicted values in 2011. This model
accurately describes the formation of complexes and predicts the solu­
bilization effects of CDs (Merzlikine, Abramova, Kowsz, Thomas, &
Mano, 2011). Density Functional Theory (DFT) is another commonly
used method to investigate SBE-β-CD inclusion complexes (Jafari, Raissi,
& Hashemzadeh, 2022; Jafari, Raissi, Saberinasab, & Pasban, 2023;
Jafari, Raissi, & Shahabi, 2022). Seyfeddine et al. systematically per­
formed DFT calculations on CD-based complexes with boron-based ar­
omatic compounds, and the study results closely matched experimental
data (Rahali et al., 2022).
The currently available SBE-β-CD consists of a mixture of different DS
and substitution sites, which poses challenges for characterizing and
studying their physicochemical properties. To address this issue, com­
puter simulations are employed to construct 3D structures of SBE-β-CDs
with varying DS and investigate the influence of DS on encapsulation.
Fig. 2. The inclusion complex formed by the guest with SBE7− β-CD (part of the Bucur et al. utilized the AutoDock molecular modeling program to
guest is situated in the circular platform cavity, and part of it is in proximity to predict the molar ratio of SBE-β-CDs with different DS (DS = 1, 2, 3) in
the hydrophobic branch). forming complexes with insulin monomers, determining the

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J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

Fig. 3. Encapsulation of SBE-β-CD in the presence of two guests. (With a stronger affinity for the yellow guest compared to the blue guest).

Fig. 4. Encapsulation of SBE-β-CD in various ratios of host to guest.

conformation of these complexes and the intermolecular hydrogen aliphatic chain, the size of the aryl ring, the position of the hydroxyl
bonds involved. These findings identified SBE2-β-CD as the most effec­ group on the aryl ring, conformational flexibility, and chirality (Holm
tive in terms of encapsulation (Bucur, Fulop, & Sipos, 2022). et al., 2011; Y. Liu et al., 2002; Rekharsky & Inoue, 1998). Additionally,
Computer simulations are valuable for studying pure substances with the stability of the complexes is enhanced when the guest molecule and
varying DS and substitution sites. However, they do have limitations. SBE-β-CD carry opposite charges. Conversely, when the molecules carry
Optimized structures for SBE-β-CDs with varying DS and substitution the same type of charge, the stability constants of the complexes
sites are not available in the structure database. Therefore, it is neces­ decrease (Masson, Loftsson, Jonsdottir, Fridriksdottir, & Petersen,
sary to model SBE-β-CDs with different DS and sites of substitution for 1998).
structure optimization. Optimizing the structure of SBE-β-CDs poses
challenges due to its molecular weight ranging from 1000 to 3000 and 2.2.2. Solvent
the long and flexible sulfobutyl branched chain. The optimization of the The choice of solvent also plays a significant role in encapsulation
structures of highly substituted SBE-β-CDs demands substantial (Buchwald, 2002). Lisa et al. conducted an investigation into the impact
computational resources and is challenging to converge. of 11 different buffers and ionic strength on the binding of sulfuric goose
deoxycholate bile salts to SBE-β-CD. Their findings revealed that higher
ionic strength led to an increase in the stability constant, while the
2.2. Influencing factors
competitive effect of the buffer reduced this constant. Both of these ef­
fects, ionic strength, and competitive binding coexist but exert opposite
There are many factors that affect the determination of binding
influences, which can make direct comparisons challenging. Therefore,
constants, including guest molecules, solvents, water content, and so on.
when determining binding constants, it is essential to ensure and report
the specific ionic strength and buffer conditions (Samuelsen, Holm, &
2.2.1. Guest molecule
Schonbeck, 2021).
The non-covalent binding of a guest molecule to the host is influ­
enced by various factors, including the molecular weight of the guest
molecule, the presence of hydroxyl and methylene groups in the

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J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

2.2.3. Other factors Table 1

The water content of SBE-β-CD is another influential factor. Water Commercial products with SBE-β-CD.
molecules, which were initially situated within SBE-β-CD are released Trade name Active ingredient Route of Firms
during the formation of an inclusion complex between the guest and administration
host. This release of water molecules can significantly impact inclusion Vfend® Voriconazole Intravenous infusion Pfizer
(Biedermann, Nau, & Schneider, 2014; Thorsteinn Loftsson et al., 2023; (lyophilized powder)
Rekharsky & Inoue, 1998). Research has shown that the presence of Geodon® Ziprasidone Intravenous infusion Pfizer
water can have a pronounced negative effect on the formation of com­ mesylate (lyophilized powder)
Cerenia® Maropitant citrate Pfizer
plexes involving SBE-β-CD and carbamazepine (Xiaofeng, Huijuan, Jing,
–
Nexterone® Amiodarone Intravenous infusion Baxter
Xinyue, & Rui, 2022). In contrast, Miskolczy et al. researched the hydrochloride International
encapsulation of five alkaloids with SBE-β-CD and found that the process Kyprolis® Kafizome Intravenous infusion Onyx
was driven by an increase in entropy. Water molecules are expelled from (lyophilized powder) Pharmaceuticals
Noxafil® Posaconazole Intravenous infusion Merck Sharp &
the hydrophobic core of the host, the sulfobutyl ether substituent, and
Dohme
the hydration layer of the guest molecule in this process. This expulsion Evomela® Melphalan Intravenous infusion Spectrum
plays a central role in the increase of entropy, facilitating the formation (loanword) (lyophilized powder) Pharmaceuticals
of these inclusion complexes (Thorsteinn Loftsson et al., 2023). Carnexiv® Carbamazepine Intravenous injection Lundbeck
Baxdela® Delafloxacin Intravenous infusion Melinta
meglumine (lyophilized powder) Therapeutics
3. Pharmaceutics Veklury® Ridgiver Intravenous infusion Gilead
(lyophilized powder)
Bonding to hydrophobic cavities of SBE-β-CD significantly enhances Abilify® Aripiprazole Intramuscular Bristol Myers
the solubility of insoluble materials, reducing the contact between the injection Squibb
Zulresso® Allopregnanolone Intravenous infusion Sage Therapeutics
guest and the surroundings. Consequently, SBE-β-CD is extensively
Sesquient® Fosphenytoin Intravenous infusion Sedor
employed as a co-solvent and stabilizer. Nowadays SBE-β-CD has led to sodium
other uses in pharmaceutics as research has progressed due to the Kyprolis® Carfilzomib Intravenous infusion Amgen
excellent encapsulation capabilities. SBE-β-CD exhibits organ-protective (lyophilized powder)
properties when forming complexes with specific drugs having signifi­ https://www.accessdata.fda.gov/scripts/cder/daf/.
cant side effects. In addition, the selectivity of SBE-β-CD can be fine-
tuned for acid dissociation constant (pKa). Moreover, SBE-β-CD acts as
Fig. 5) (Rowe et al., 2016). The protective mechanism may be related to
a part of the matrix and binds the drug to the matrix like a “clamp”.
protein binding, where SBE-β-CD binds to the hydrophobic amino acid
side chains of the relevant proteins. This interference disrupts the
3.1. Co-solvents, stabilizers
interaction of the relevant proteins with the mitochondrial membrane or
with each other, preventing the formation of pores in the mitochondrial
SBE-β-CD exhibits high inherent solubility and the ability to encap­
membrane and blocking apoptosis. In 2021, the research team con­
sulate insoluble drugs to form complexes, leading to improvements in
ducted an in-depth investigation and discovered that SBE-β-CD-iohexol
drug solubility and stability. They are commonly employed as co-
outperformed iohexol alone in safeguarding cardiomyocyte integrity
solvents (Li et al., 2018; Maeda, Shiobara, Tanaka, Kajinami, &
and preserving myocardial function during myocardial ischemia. This
Nakayama, 2021; V. J. Stella & Rajewski, 2020; Szente et al., 2021) and
treatment is currently in Phase II clinical trials (Rowe, Rowe, Hunter,
stabilizers (Biernacka, Ilyich, Zavodnik, Palecz, & Stepniak, 2022; X.
Gralinski, & Neves, 2021). Similarly, Eszter et al. discovered that SBE-
Wang et al., 2022). SBE-β-CD is currently marketed under trade names
β-CD mitigated the loss of cell viability induced by chlorpromazine
like Captisol® (Al-Heibshy, Basaran, Ozturk, & Demirel, 2020; Franco
(CPZ) in dose-dependent cellular experiments and reduced CPZ-induced
et al., 2023; Khurana et al., 2019; Rundfeldt et al., 2023), Dexolve®
mortality in animal studies. This effect might be attributed to the for­
(Shukla et al., 2020) and others, with an average DS ranging from 6.2 to
mation of a complex between CPZ and SBE-β-CD, which restricts cellular
6.9. The excipient has received FDA approval for incorporation into over
uptake, thereby diminishing the toxic effects of antipsychotic drugs
14 drugs (refer to Table 1).
(Fliszar-Nyul, Csepregi, Benkovics, Szente, & Poor, 2022).
While SBE-β-CD is commonly employed as a stabilizers, it is note­
The SBE-β-CD utilized in the aforementioned studies was a mixture,
worthy that it can expedite the degradation of specific drugs (Popielec &
and they did not consider the influence of substitution sites and DS on
Loftsson, 2017). Jinyang et al. conducted research in which they pre­
the protective effect. It would be advantageous to elucidate the pro­
pared inclusion complexes of ziprasidone with various CDs and evalu­
tective mechanism of SBE-β-CD, including identifying the optimal sub­
ated their stability at elevated temperatures. Surprisingly, they observed
stitution sites and DS when used as a “protective agent”. This
that SBE-β-CD had an adverse effect on the stability of ziprasidone, both
clarification holds substantial importance in expediting the utilization of
in solution and in solid forms (J. Hong, Shah, & McGonagle, 2011). The
SBE-β-CD concerning nephrotoxic drugs. Determining the optimal sub­
oxidative degradation of ziprasidone in a solution is influenced by the
stitution sites and DS for SBE-β-CD as a “protective agent” is a crucial
electron-donating side chain, while the degradation of the drug in its
step in promoting their comprehensive application, particularly in
solid state primarily arises from the high mobility of the ziprasidone
nephrotoxicity and cardiotoxicity drugs.
inclusion complex in its amorphous state. Therefore, it is crucial to
consider both the potential positive effects on solubility and any po­
tential negative impacts on the stability of the drug complex during the 3.3. Adjusting the pKa value
development of a pharmacological formulation.
The encapsulation selectivity of SBE-β-CD can be utilized to fine-tune
3.2. Protective effect the pKa. Kadam et al. discovered that the protonated form of haemato­
genin (SG+) exhibited a stronger interaction with SBE7-β-CD compared
SBE-β-CD demonstrates organ-protective properties when forming to the neutral form of haematogenin (SGOH). This interaction led to a
complexes with specific drugs that exhibit significant side effects. In notable increase in the pKa value of haematogenin by over 0.6 units
2016, Elizabeth et al. demonstrated that the addition of small amounts (refer to Fig. 6). Consequently, the guest molecule became more basic. It
of SBE-β-CD (iohexol: SBE-β-CD = 40:1) significantly protects rodent was observed that this increase in the pKa value correlated with
kidneys and reduces contrast-induced acute kidney injury (refer to enhanced bioactivity of the imide-salt form of sanguinarine (SGR),

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J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

Fig. 5. (a) Light microscopic examination of mouse kidney tissue (H&E, PAS, 200×). Comparing the renal cortex (A) and medulla (C) in the kidneys treated with
iohexol, the experimental group that was concurrently administered iohexol: SBE-β-CD (mole ratio 1:0.025) significantly attenuated the morphological changes in the
cortex (B) and medulla (D). (b) A: Effect of SBE-β-CD on six parameters measured pathologically in the outer renal cortex of mice at 24 h. B: Effect of SBE-β-CD on six
parameters measured pathologically in the outer renal cortex of rats at 48 h. Comparison of the addition of SBE-β-CD resulted in a decrease in all six parameters in
both species, especially in terms of reduction of pathological changes such as tubular dilatation, vacuolization, and loss of brush border. (c) Survival of rats in a model
of kidney injury injected intravenously with placebo, iohexol, or iohexol + SBE-β-CD (mole ratio 1:0.025) at 2.5 g Iodine/kg. N = 8 in each group.

resulting in increased antimicrobial activity at physiological pH (Kadam SBE-β-CD, which were coated with thiol hyaluronic acid. The nano-
et al., 2020). Similarly, Gayathry et al. observed that upon complexation formulation displayed prolonged retention in the conjunctival capsule,
with SBE7-β-CD, coumarin 7 exhibited a 0.4-unit increase in pKa showcasing its potential utility in treating inflammatory disorders in the
(Gayathry et al., 2023). anterior segment of the eye (Ricci et al., 2022). Federica et al. designed
chitosan nanoparticles (CS NPs) with SBE-β-CD as the carrier with the
3.4. Matrix potential for nose-to-brain delivery of Idebenone (IDE), aimed at
enhancing IDE penetration into cells (De Gaetano et al., 2022). Wenhui
The incorporation of SBE-β-CD within a pharmaceutical formulation et al. fabricated antifungal tebuconazole-loaded nanoparticles through
matrix harnesses its physicochemical properties. Within this matrix, electrostatic self-assembly of positively charged poly dimethyl diallyl
SBE-β-CD acts as a “clamp”, forming complexes with drugs and immo­ ammonium chloride and negatively charged SBE-β-CD inclusion com­
bilizing the drug. The approach, encompassing the synthesis of nano­ plexes. These nanoparticles exhibited slow-release properties and
particles, hydrogels and nanosponges, has demonstrated efficacy in improved antifungal activity (Shi et al., 2022).
pharmaceutical applications.
3.4.2. Hydrogels
3.4.1. Nanoparticles When inclusion complexes formed by SBE-β-CD and the drug are
SBE-β-CD, carrying a negative charge, spontaneously generates incorporated into liquid formulations, the drug undergoes dilution upon
nanoparticles through electrostatic attraction with positively charged administration, impacting its absorption in the body. This issue is
substances, such as chitosan (CS), resulting in nanoparticles (refer to effectively addressed by employing hydrogel crosslinked networks.
Fig. 7) with a slow-release effect (Pardeshi et al., 2023). Ludan et al. Furthermore, SBE-β-CD yields rigid, non-fluid elastic gels, in contrast to
employed the ionic gelation technique to fabricate nanoparticles. They gels produced from neutral CDs, which form weaker, relatively fluid gels
utilized CS as the cationic phase and SBE-β-CD as the anionic phase for (Domiński, Konieczny, & Kurcok, 2020). Researchers attempted to uti­
delivering ibrutinib. This formulation, preserving the drug’s activity, lize SBE-β-CD for encapsulating anticancer drugs in 2016 (Zivic et al.,
achieved controlled release and demonstrated mucosal adhesion prop­ 2016). Subsequently, Han et al. developed a biobased hydrogel con­
erties, enhancing drug retention on the mucosal surface (L. Zhao et al., taining SBE-β-CD through electrostatic and host-guest interactions. The
2020). Similarly, Fabrizio et al. fabricated nanoparticles comprising CS/ incorporation of SBE-β-CD endowed the hydrogel with enhanced drug

6
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

of tumors (C. Zhang et al., 2024).

3.4.3. Nanosponges
Nanosponges are solid, crosslinked polymers with nano-sized porous
structures. The combination of external hydrophilic and internal hy­
drophobic surfaces creates a unique “microenvironment”. The micro­
environment enables CDs to exhibit a special ability to form host-guest
complexes with various hydrophobic substances (Mane, Wakure, &
Wakte, 2021). Currently, cyclodextrins based nanosponges primarily
focus on β-CD. There is limited research on SBE-β-CD in the context of
nanosponges. Olteanu et al. compared the impact of nanosponges pre­
pared with β-CD and SBE-β-CD on the solubility of raloxifene and found
that nanosponges prepared with β-CD exhibited better solubilizing ef­
fects (Olteanu, Aramă, Radu, Mihăescu, & Monciu, 2014). Andreea et al.
synthesized a range of nanosponges using β-CD, SBE-β-CD, and HP-β-CD
with epichlorohydrin as a cross-linking agent. They investigated the
complexation properties of these CD nanosponges with enalapril,
captopril, and cilazapril. Fourier Transform Attenuated Total Reflection
Infrared Spectroscopy confirmed the inclusion of guest molecules, which
enhances drug stability and bioavailability, while also mitigating po­
tential drug-excipient interactions (Olteanu, Arama, Bleotu, Lupuleasa,
& Monciu, 2015).
While research on nanosponges is predominantly focused on β-CD,
the hemolytic and nephrotoxic effects of β-CD cannot be overlooked. In
contrast, nanosponges prepared with SBE-β-CD possess certain advan­
tages in terms of safety, offering promising prospects for wider
applications.
The unique physicochemical properties and excellent encapsulation
ability of SBE-β-CD position it as a suitable substrate for nanoparticles,
gels, nanosponges, etc. Current studies, however, predominantly focus
on SBE7-β-CD. The impact of the substitution distribution of SBE-β-CD on
the matrix remains unknown, representing a worthwhile direction for
further development.

4. Pharmaceutical analysis
Fig. 6. pKa curves (variation of absorbance at 470 nm with pH) of SGR in the
absence of SBE7-β-CD (a), in the presence of SBE7-β-CD (b) and β-CD (c). SBE-β-CD finds common applications in pharmaceutical analysis for
the separation of chiral substances. Enantiomeric separation predomi­
encapsulation capability and controlled release performance (Han, nantly hinges on the creation of transient diastereomeric complexes
Wang, Yang, & Li, 2017). Liyuan and colleagues developed hydrogels between the analyte and the selector, reaching thermodynamic equi­
combining SBE7-β-CD and hyaluronic acid (HA), as illustrated in Fig. 8. librium. As both enantiomers of a chiral compound selectively bind to
These hydrogels exhibited notably enhanced swelling properties and in the selecting agent and form diastereomeric complexes throughout the
vitro degradation when compared to HA hydrogels (L. Zhou et al., analytical process, distinctions in their physical and chemical properties
2022). become evident, resulting in separation during analysis (Scriba, 2019).
In addition to preparing conventional hydrogels, SBE-β-CD can be During the 1990s, efforts were undertaken to incorporate SBE-β-CD into
employed for the synthesis of in-situ hydrogels. Chen et al., through the capillary electrophoresis to facilitate substance separation (Brown,
synergistic action of CS, SBE-β-CD, ferrous ions, and glucose oxidase, Szolar, & Luong, 1996). Subsequently, their unique properties were
constructed a nano-scale supramolecular cascade reactor. This reactor discovered, leading Surapaneni et al. to explore the potential use of SBE-
has the capability to form a cross-linked polymer network hydrogel β-CD as a chiral selector for enantioseparation (Surapaneni, Ruterbories,
structure in situ at the wound site, exhibiting antimicrobial effects (L. & Lindstrom, 1997). It was observed that negatively charged SBE-β-CD
Chen et al., 2022). Zhang et al. mixed CS, SBE-β-CD, and trace amounts exhibited better performance in separating peptide enantiomers
of silver ions to develop a novel polysaccharide supramolecular inject­ compared to β-CD or the neutral derivative HP-β-CD (Morin, Bellessort,
able hydrogel, achieving the continuous release of drugs in the vicinity Dreux, Troin, & Gelas, 1998; Owens, Fell, Coleman, & Berridge, 1998;

Fig. 7. SBE-β-CD form nanoparticles with positively charged substances (Take chitosan as an example).

7
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

Fig. 8. Preparation of SBE7-β-CDs/hyaluronic acid (HA) hydrogels.

Fig. 9. SBE-β-CD as a chiral selective agent in capillary electrophoresis (a), modification of the stationary phase (b), and liquid-liquid extraction (c).

8
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

Skanchy et al., 1997). Following these findings, David et al. employed medicines and their preparations. This was achieved through the utili­
SBE-β-CDs with substituents ranging from 1 to 7 as chiral selectors to zation of a dual CD system comprising SBE-β-CD and HP-β-CD (Y. Zhang
investigate the enantiomeric separation of bisdiamine (SC-40230) from et al., 2022).
five closely related known process impurities. It was observed that as the Besides enhancing separation through the use of a dual CD system,
charge of selector increased, peak distortion became more pronounced. another strategic approach involves the transformation of SBE-β-CD into
This phenomenon was attributed to electrodispersity and the significant ionic liquids. Xiaofei et al. pioneered the development of an ionic liquid
countercurrent mobility of negatively charged complexes. Notably, the chiral selective agent based on SBE-β-CD for enantioselective separation
pure charge type with a lower DS offered adequate chiral and achiral by capillary electrophoresis (CE). This ionic liquid (SBECDIL) demon­
selectivity while mitigating the pronounced peak distortion resulting strated significantly improved enantioselectivity when compared to
from electrodispersion. This made it more suitable for the separation of natural SBE-β-CD (Xiaofei Ma, Cao, Yu, & Cai, 2022).
SC-40230 (Skanchy et al., 1999). In addition to capillary electrophoresis, SBE-β-CD, serving as chiral
After more than two decades of development, research involving selective agents, find utility in high-performance liquid chromatography
SBE-β-CD in pharmaceutical analysis has significantly advanced. (HPLC). As far back as 2008, research was conducted on the incorpo­
Numerous methods have been developed, enabling the separation of a ration of SBE-β-CD into the HPLC mobile phase for enantiomeric im­
broader range of enantiomers with the assistance of SBE-β-CD. Beyond purity determination in pantoprazole (Guan et al., 2008). This method
their role as chiral selective agents, SBE-β-CD can also facilitate enan­ demonstrated excellent separation, accuracy, and linearity. Over time,
tioseparation through modifications to stationary phases and liquid- this analytical approach has continued to evolve and has been applied to
liquid extraction (refer to Fig. 9). the separation and quantification of various drugs, including amlodipine
(Xie et al., 2014), citalopram (Peng, He, & Cai, 2016), fluoxetine hy­
4.1. Chiral selector drochloride, labetalol, venlafaxine hydrochloride, trans-parosol, and
atropine sulfate (B. Chen et al., 2022), among others.
Extensive research conducted by numerous scholars has revealed an
expanding scope for separating chiral substances by incorporating SBE- 4.2. Mobile phases
β-CD as a chiral selective agent in capillary electrophoresis (refer to
Table 2). If SBE-β-CD, employed as a chiral selector, cannot differentiate be­
Furthermore, distinctive patterns have emerged from this research, tween chiral substances, an alternative approach is to explore SBE-β-CD-
highlighting that SBE-β-CD exhibits robust separation capabilities for coated stationary phases. In the case of dipeptide isomers, the SBE-β-CD-
neutral and basic drugs, but demonstrates limited selectivity when coated stationary phase demonstrated improved separation of the chiral
dealing with negatively charged analytes (Budau et al., 2017). analyte compared to HPLC using SBE-β-CD as the chiral selector
When employing SBE-β-CD as a chiral selector yield limited effec­ (Kucerova, Prochazkova, Kalikova, & Tesarova, 2016). Denisa et al.
tiveness in enantiomer separation, enhancement can be achieved developed three chiral stationary phases by dynamically coating strong
through the utilization of dual CD systems. Dual CD systems typically anion-exchange stationary phases with SBE-β-CDs featuring varying DS.
involve pairing a neutral CD with a charged CD (Hancu, Papp, Tóth, & Their study revealed that stationary phases based on SBE4-β-CD were
Kelemen, 2021; Servais & Fillet, 2019). Jing et al. employed a dual CD effective in achieving enantioseparation for nearly all basic and neutral
system comprising SBE-β-CD and α-CD for the concurrent quantification compounds. Moreover, stationary phases with higher DS of SBE-β-CD
of three isoflavones. The results exhibited excellent linearity and high proved more suitable for the enantioseparation of acidic compounds
sensitivity (Guo et al., 2019). Yiqiong et al. devised a straightforward (Folprechtova, Kalikova, Kozlik, & Tesarova, 2019). Zhou et al. devel­
and effective capillary electrophoresis technique for the complete sep­ oped an innovative monolithic column by incorporating SBE-β-CD into a
aration and quantitative analysis of furanocoumarins in Chinese herbal polymer matrix. They observed that this modified column significantly
improved the chiral separation of 26 racemic compounds, resulting in
Table 2 enhanced separation selectivity (Li Zhou, Liu, Guan, Jiang, & Guo,
SBE-β-CD as chiral selector separable in capillary electrophoresis. 2020). Lifen and colleagues developed an innovative open capillary
column for chiral separations. They incorporated SBE-β-CD within the
Substance Buffers References
copolymerized layer. The researchers evaluated the separation perfor­
pH Ingredient SBE-
mance and reproducibility of this column by successfully separating the
β-CD
dosage
enantiomers of amlodipine besilate, 2,3-diphenylpropionic acid, tropic
acid, and pantoprazole (Lifen Zhou, Lu, & Sun, 2021).
Baclofen – Water/methanol 1.75 mM (Desiderio et al.,
(30:70, v/v) 2008)
3 % Formic acid 4.3. Liquid-liquid extraction
Chloroquine 2.5 100 mM sodium 30 mg/ (Wongwan &
phosphate buffer mL Scriba, 2011) When dealing with the separation of a large amount of enantiomers,
Pantoprazole 6.5 50 mM borax 20 mg/ (Guan, Yan, Shi, &
the use of SBE-β-CD for extraction becomes a viable option. Zhou et al.
150 mM mL Wang, 2012)
phosphate buffer employed SBE-β-CD for the enantioselective extraction of chlorphenir­
Benzofurys 4.5 50 mM 14 or 16 (Taschwer, Hofer, & amine (CPE) enantiomers, achieving complete separation of the racemic
MPA ammonium mM Schmid, 2014) CPE (C. Zhou et al., 2014). Similarly, Wanru et al. identified SBE-β-CD
Thiothinone acetate solution and 1,2-dichloroethane as optimal extractants and organic solvents for
Ethylphenidate 10 %
Diphenidine Acetonitrile
the efficient extraction of 2,3-diphenylpropionic acid (W. Wang, Xu,
Methoxphenidine Dai, Zhang, & Tang, 2019). Furthermore, the team explored a ternary
4F-PV8 solvent extraction system incorporating SBE-β-CD for the selective
Methedrone extraction of glabridin, which was proved effective, high-yield, high-
4-MeO-α-PVP
purity, environmentally friendly, and cost-effective (W. Wang, Yang, &
3-MeOMC
Lenalidomide 6.5 30 mM 30 mM (Szabo et al., 2018) Tang, 2023). There are alternative strategies beyond direct extractant
phosphate use. Ben et al. designed magnetic silica nanoparticles functionalized
Reshagiran 2.0 50 mM glycine- 35 mM (Szabó, Ludmerczki, with SBE-β-CD for liquid-liquid extraction, yielding excellent separation
HCl buffer Fiser, Noszál, & results. This approach exhibited remarkable enantiomer recognition
Tóth, 2019)
capabilities and could be employed multiple times, representing a green,

9
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

innovative, and cost-effective technique for enantiomer separation (B. fluorescence quenching (C. Wang et al., 2021; Xu et al., 2023; Yan,
Chen et al., 2022). Wang, Chen, Qu, & Wen, 2022). For ACQ dyes, at higher concentrations
In comparison to capillary electrophoresis, extraction can separate a of SBE-β-CD, complex formation with the dye (often in a 1:1 ratio) alters
larger number of substances in a single operation, making it well-suited the aggregating properties of the guest. This modification facilitates
for industrial-scale production and offering promising prospects for radiative transition, resulting in enhanced fluorescence (refer to
future applications. However, the impact of DS on SBE-β-CD in extrac­ Fig. 10).
tion remains unknown. Exploring methods to enhance the extraction Apart from controlling SBE-β-CD concentration, the monomer-
efficiency of SBE-β-CD to realize higher economic value is a topic of aggregate equilibrium of dyes can also be regulated by introducing
considerable significance. competitive guests. When there is only one dye guest in the SBE-β-CD
solution, the addition of a guest with stronger affinity causes the dye
5. Biomedical engineering molecules to release from the hydrophobic cavity, returning to the
solution.
In the field of biomedical engineering, SBE-β-CD is commonly Furthermore, in the case of complexes formed by specific dyes, this
employed for encapsulating dye molecules and modifying sensors. The host-guest recognition process is significantly influenced by environ­
combination of SBE-β-CD with dyes results in complexes with physical mental factors. It can be employed in temperature sensors, ion intensity
properties differing significantly from those of guests, leading to various sensors, and related fields.
applications. The addition of SBE-β-CD to sensors primarily stems from
the selectivity of its encapsulation, enhancing the sensitivity of the 5.1.1. Chemiluminescent dyes
sensor. The luminescence intensity of some dyes increases upon binding to
SBE-β-CD. Introducing a guest with stronger affinity causes the dye to
exit the SBE-β-CD cavity, resulting in a decrease in luminescence in­
5.1. Dyestuffs tensity. This phenomenon can be utilized for determining the guest
content.
The luminescence intensity of some dyes increases upon binding to Luminol exhibits luminescence upon oxidation. The luminescent
SBE-β-CD (see Table 3). The mechanism underlying the enhanced intermediate generated by the luminol reaction forms a 1:1 complex
luminescence upon the binding of different dyes with SBE-β-CD varies. with SBE, accelerating their radiative processes, thereby enhancing the
Some dyes experience enhanced luminescence because SBE-β-CD hin­ chemiluminescent intensity and inducing the complexation enhance­
ders their non-radiative processes or accelerates their radiative pro­ ment effect of chemiluminescence (CL). The examined substance com­
cesses, and there are two mechanisms involved. At high concentrations, petes with luminol for binding to SBE-β-CD, forming a complex that
SBE-β-CD binding with dyes (often in a 1:1 ratio) influences the dye’s diminishes the luminescence intensity of luminol. Consequently, moni­
torsional dynamics (Dsouza, Pischel, & Nau, 2011; D. Zhao, Song, & toring alterations in luminal CL intensity allows for the determination of
Hou, 2021), prevents large-amplitude torsional motion of dyes in the the concentration of the tested substance. This method, characterized by
excited state, and accelerates radiative processes, thereby promoting high sensitivity and analytical efficiency, is suitable for detecting
radiative luminescence. The other mechanism occurs when SBE-β-CD, at various substances, including rutin (Wu, Song, & Zhang, 2011), risper­
low concentrations, simultaneously binds with several dyes, leading to idone (Wu, Chen, & Song, 2012), phenazopyridine (M. Shen, Lv, & Song,
aggregation among the dyes. The aggregation impedes non-radiative 2013), phenazopyridine (M. Shen et al., 2013), clozapine (M. Shen, Wu,
processes (Chen, Lam, Kwok, Liu, & Tang, 2019; Qin et al., 2009), Tan, & Song, 2014), phenolic acids (Xiong, Zhao, & Song, 2014),
resulting in radiative luminescence. This situation is mainly observed paclitaxel (Xiong, Zhao, Li, & Song, 2014), phenolic acids (Xiong, Zhao,
with dyes exhibiting the aggregation-induced emission (AIE) effect Li, & Song, 2014), paclitaxel (Xiong, Yu, & Nan, 2017), cephalosporin
(henceforth referred to as AIE dyes) (X. Cai & Liu, 2020; Y. Hong, 2016; (M. X. Shen, Tan, & Song, 2018) and other substances.
J. Ma, Gu, Ma, Lu, & Qiu, 2022; B. Wang et al., 2021).
Bringing up AIE inevitably brings to mind aggregation-caused 5.1.2. Fluorescent dyes
quenching (ACQ). Dyes with ACQ effect (henceforth referred to as Binding with SBE-β-CD can enhance the luminescence intensity of
ACQ dyes) often own large planar structures with dense ring formations. many fluorescent dyes. AuO (P. K. Singh, Mora, Murudkar, & Nath,
In a dispersed state, ACQ dyes tend to consume excited-state energy 2014), Thioflavin-T (P. K. Singh, Murudkar, Mora, & Nath, 2015), DAPI
through luminescence. However, in an aggregated state, the stacking of
molecules impedes the process of radiative transition, leading to

Table 3
Dye molecules with increased luminescence intensity by SBE-β-CD.
Dyestuffs

Chemiluminescent dye Luminol

Fluorescent dye Acridine Orange (AOH+)
Rhodamine 6G, Rhodamine B
Thiazole Orange (TO)
Thioflavin-T
4′, 6-Diamidino-2-Phenylindole (DAPI)
LDS-798 Probe
Auramine-O (AuO)
1-Pyrenemethyl Amine (PMA)
Cationic Dye Berberine (BBR)
Tetraphenylene Pyridine (TPE-Py)
BODIPY-Benzimidazole Conjugate Dye (BDZ)
Aminomethyl Coumarinic Acid (AMCA)
C.I. Basic Yellow 40 (BY40) Fig. 10. Common methods utilizing SBE-β-CD, to modulate the monomer-
Ethyl Phthalate (PhB) aggregate equilibrium of different types of dyes (blue guests represent ACQ
Coumarin 7
dyes, green guests represent AIE dyes, and yellow guests have a stronger affinity
Phosphorescent dye Naphthylpyridinium-Acrylamide Copolymers (P-BrNp)
for SBE-β-CD compared with blue and green ones).

10
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

(Shinde, Bhasikuttan, & Mohanty, 2015; Shinde, Mohanty, & Bhasi­ The luminescence intensity of dyes is influenced by their aggregation
kuttan, 2020), BBR (Chakraborty et al., 2022), BDZ (Chakraborty, state. At lower SBE-β-CD concentrations, multiple guests form com­
Chattaraj, & Pal, 2023), TPE-Py (Tian et al., 2023) and coumarin 7 plexes with a single SBE-β-CD molecule, promoting aggregation.
(Gayathry et al., 2023) form inclusion complexes with SBE-β-CD, Conversely, at higher SBE concentrations, a preference for 1:1 complex
exhibiting enhanced fluorescence. The mechanism is similar to that of formation leads to dye dispersion.
luminol. After binding with SBE-β-CD, the structure of dyes undergoes DS of SBE-β-CD influences the first mechanism. Chakraborty et al.
constraint, inhibiting non-radiative decay, accelerating radiative tran­ investigated the non-covalent interactions between LDS-798 and SBE-
sition, and enhancing luminescence intensity. β-CDs with different DS. The study results suggest that SBE10-β-CD can
AuO and Thioflavin-T not only enhance fluorescence when bound to effectively modulate the photophysical properties of LDS-798. This is
SBE-β-CD but also exhibit AIE. When combined with the aggregation- attributed to the enhanced molecular recognition capability of LDS-798
promoting polymer polystyrene sulfonate (PSS), AuO and Thioflavin-T with SBE10-β-CD. The latter not only offers robust electrostatic in­
show a strong new emission band distinct from that of SBE-β-CD. In teractions but also induces a maximum hydrophobic effect through the
the ternary system of dyes/PSS/SBE-β-CD, dyes form complexes with pendant sulfobutylether groups (Chakraborty, Ray, Singh, & Pal, 2020).
SBE-β-CD, emitting fluorescence. After the addition of a competitive The impact of DS on the second mechanism remains to be explored.
guest, dyes are expelled, enabling polymerization through PSS and The aggregation state has a significant influence on dyes. A clear un­
resulting in fluorescence distinct from that of the complexes with SBE- derstanding of the effect of DS on the regulatory capacity of SBE-β-CD for
β-CD (Awasthi, Pandey, & Singh, 2021; Pandey, Awasthi, & Singh, the balance and aggregation of dye molecules is conducive to achieving
2021). This system achieves reversible control over the monomer- precise control over dyes, thereby expanding their application scope.
aggregate equilibrium.
Not all AIE dyes can enhance fluorescence by forming 1:1 complexes 5.2. Transducers
with SBE-β-CD. Khurana et al. investigated the interaction between
SBE7-β-CD and TO dyes. At lower concentrations of SBE7-β-CD, TO forms As excellent macrocyclic receptors, various CDs have found exten­
supramolecular aggregates with SBE7-β-CD in a 1:4 ratio, which pro­ sive use in the development of adaptive sensors, leveraging their su­
motes aggregation. As the concentration of SBE7-β-CD increases, TO pramolecular recognition properties (Bae et al., 2019; Ogoshi & Harada,
undergoes de-aggregation, leading to fluorescence quenching (Khurana, 2008; Sivakumar & Chaitanya, 2023). SBE-β-CD is no exception to this
Barooah, Bhasikuttan, & Mohanty, 2019). trend. When applied to sensors, their positioning is tailored to their af­
At lower concentrations of SBE-β-CD, multiple dye molecules bind to finity. If SBE-β-CD has a higher tendency to bind with impurities, they
a single SBE-β-CD molecule, thereby forming a complex that facilitates are positioned in front of the electrode without direct attachment. This
the aggregation of guest molecules. In contrast, at higher concentrations placement enhances sensor sensitivity by removing impurities.
of SBE-β-CD, fewer dye molecules bind to an individual SBE-β-CD Conversely, when they readily bind to the target substance, they are
molecule, preventing the formation of complexes and, consequently, connected to the electrode, thereby improving sensor sensitivity by
inhibiting the aggregation of guest molecules. This characteristic ex­ increasing their binding capacity to the analyte.
tends to ACQ dyes, which exhibit complex formation at elevated con­ Fengjun et al. employed platinum nanoparticles to modify a boron-
centrations of SBE-β-CD. These complexes share the same charge, doped diamond (BDD) electrode. Subsequently, they electrodeposited
resulting in the reduction of dye aggregation and a consequent decrease glucose oxidase (GO)/polytyrosamine (Pty)/SBE-β-CD on the electrode
in fluorescence quenching. Consequently, this phenomenon enhances surface, creating a glucose biosensor characterized by a low limit of
luminescence intensity. Mhejabeen et al. observed that at lower con­ detection, rapid response times, and stable performance. The SBE-β-CD
centrations of SBE-β-CD, the dye AOH+ predominantly forms dimers, readily forms inclusion complexes with impurities, effectively blocking
resulting in fluorescence quenching. Conversely, at higher concentra­ the passage of electroactive substances such as uric acid and ascorbic
tions, the transformation of the dimeric dye into the monomeric form acid through the electrode. This enhancement significantly bolsters the
happened, which enhanced fluorescence (Sayed, Jha, & Pal, 2017). sensor’s sensitivity and selectivity (Shang, Glennon, & Luong, 2008).
Rhodamine 6G, rhodamine B (Khurana et al., 2018), AMCA, BY40, and Additionally, the research team employed a similar approach to fabri­
PhB (T. Cai et al., 2023) have similar properties to AOH+. cate a dopamine sensor (Shang et al., 2009). Lirui et al. developed an
Beyond alterations in luminescence intensity, certain fluorescent electrochemical sensor based on SBE-β-CD-graphene oxide hybrids,
dyes, when complexed with SBE-β-CD, exhibit heightened sensitivity. demonstrating exceptional performance in the detection of nitrophenol
For instance, fluorescent probes like LDS-798 and PMA are noteworthy isomers. This superior performance can be attributed to the binding
in this regard. Combining fluorescent probe LDS-798 with SBE-β-CD capability of SBE-β-CD and the sulfonic acid moiety (Cong et al., 2021).
results in a significant increase in fluorescence yield, and the resulting
complex proves to be remarkably responsive to external factors such as 5.3. Others
temperature and ionic strength. This heightened sensitivity paves the
way for its potential applications in sensing (Chakraborty et al., 2019). A SBE-β-CD can serve as a “clamp” for fixing substances. To recover
parallel scenario is observed with PMA cationic fluorescent probes (G. and reuse a catalyst composed of three organic dyes (AMCA, BY40, and
Singh & Singh, 2020). PhB), Tingwei et al. cationized cotton fibers and employed SBE-β-CD to
encapsulate the catalyst. This approach aimed to address the non-
5.1.3. Phosphorescent dye uniform distribution of the catalyst on yarn and fibers, which was
The luminescence enhancement effect of SBE-β-CD extended to caused by different forces between the catalyst and cationized yarn. The
certain phosphorescent dyes as well. Upon assembly with SBE-β-CD, the complex adheres to the cationized cotton fibers through mutual
phosphorescent quantum yield of P-BrNp-0.1 increased from 64.1 % to adsorption, reducing the loss of the catalyst during usage and increasing
71.3 %. This also resulted in a change in the photoluminescent colour the catalyst’s potential for repeated use (T. Cai et al., 2023).
from white to yellow, making it suitable for multifunctional writing inks
(Hu, Dai, Dong, Huo, & Liu, 2022). 6. Discussion
SBE-β-CD regulates the luminescent effects of dye molecules through
two main mechanisms. The first mechanism involves the formation of SBE-β-CD, known for its remarkable inclusion capabilities, initially
inclusion complexes between SBE-β-CD and dyes, restricting the functioned as a solubilizing and stabilizing agent. As research advanced,
torsional motion of dyes and hindering non-radiative processes. The the inclusion behavior of SBE-β-CD revealed selectivity and competi­
second mechanism alters the monomer-aggregate equilibrium of dyes. tiveness. The physicochemical properties of complexes formed between

11
J. Huang et al. Carbohydrate Polymers 333 (2024) 121985

SBE-β-CD and specific substrates change compared with guests, while theoretical foundation for the broader application of SBE-β-CD in the
the ratio of complexes formed with some substrates is dependent on pharmaceutical industry.
concentration. These features have significantly expanded the applica­
tions of SBE-β-CD. CRediT authorship contribution statement
Within the field of pharmaceutics, SBE-β-CD acts as a “protective
agent” and can be utilized for fine-tuning pKa values. Furthermore, it Jiaqi Huang: Writing – review & editing, Writing – original draft,
serves as an integral part of a matrix, resembling a “clamp,” effectively Visualization, Investigation. Xiaofeng Wang: Writing – review & edit­
securing pharmaceuticals. In pharmaceutical analysis, SBE-β-CD is ing, Funding acquisition. Ting Huang: Writing – review & editing. Yang
frequently employed for the separation of chiral substances. Upon Yang: Writing – review & editing. Jiasheng Tu: Writing – review &
complexation with enantiomers, SBE-β-CD forms non-racemic isomers, editing. Jian Zou: Writing – review & editing, Funding acquisition.
allowing for separation through techniques such as capillary electro­ Huiying Yang: Writing – review & editing, Funding acquisition. Rui
phoresis, high-performance liquid chromatography, and extraction. In Yang: Writing – review & editing, Funding acquisition.
the realm of biomedical engineering, SBE-β-CD is commonly utilized to
modulate the luminescence intensity of dyes. Furthermore, it can be
applied to sensors to enhance detection sensitivity. Declaration of competing interest
The commercial SBE-β-CD products currently on the market are
developed to enhance drug solubility, constituting a mixture with an The authors declare that they have no known competing financial
average DS ranging from 6.2 to 6.9. As for the subsequently developed interests or personal relationships that could have appeared to influence
applications, the most suitable substitution distribution remains un­ the work reported in this paper.
known, necessitating further in-depth exploration in future research.
The impact of substitution sites and DS on the protective efficacy of Data availability
SBE-β-CD in pharmaceutics remains to be comprehensively investigated.
Understanding the mechanism of SBE-β-CD’s protective effects and No data was used for the research described in the article.
identifying the optimal substitution site and DS for SBE-β-CD as a pro­
tective agent will enhance its extensive application. This endeavor is of Acknowledgment
considerable importance in accelerating the utilization of SBE-β-CD,
particularly in the context of nephrotoxic and cardiotoxic drugs. Addi­ The work was supported by grants from Foundation for the Devel­
tionally, SBE-β-CD can function as a “clamp” within the matrix, effec­ opment of Middle-aged and Young Scientists (2023C9), National In­
tively immobilizing active substances within the matrix. The utilization stitutes for Food and Drug Control, and National Key Research and
of SBE-β-CD in formulations such as nanoparticles, hydrogels, and Development Program of China (2023YFC3403200).
nanosponges introduces an unknown influence of DS on their prepara­
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