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Polymeric Nanocarriers Based on Cyclodextrins for Drug Delivery: Host-Guest Interaction as Stimuli-Responsive Linker Liao Peng, Senyang Liu, Anchao Feng, and Jinying Yuan Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 02 May 2017 Downloaded from http://pubs.acs.org on May 4, 2017

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Molecular Pharmaceutics

Polymeric Nanocarriers Based on Cyclodextrins for Drug Delivery: Host-Guest Interaction as Stimuli Responsive Linker Liao Peng1, Senyang Liu1, Anchao Feng2and Jinying Yuan1* 1 Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China 2 College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, P. R. China

KEYWORDS. Host-guest chemistry; Supramolecular structures; Polymer self-assembly; Drug delivery systems; Stimuli responsive polymers

ABSTRACT. Stimuli responsive polymers have been extensively studied as nanocarriers for drug delivery systems (DDSs), especially those based on supramolecular interactions. Cyclodextrin (CD) is one kind of widely applied host molecules and the host-guest interactions between CD and different counterparts can respond to different stimuli, thus can be applied as responsive linkers for polymeric DDSs. In this review, the polymeric nanocarriers based on the host-guest interactions between cyclodextrin and ferrocene, azobenzene and benzimidazole as

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DDSs are summarized, with redox, light and pH sensitivity respectively. The mechanisms for the stimuli responsive ability of the linkers, the application of them for construction of DDSs with different polymer structures, and the controlled release behaviors have been focused. In addition, the outlook and challenge of these systems are discussed.

Stimuli responsive polymers, for example, with light1-5 or thermal6-10 sensitivity, have been extensively studied with wide applications in various fields, including cell and tissue culture, enzyme immobilization, molecular machines, and drug delivery systems (DDSs).11-17 By utilizing stimuli responsive polymers, the conventional drug delivery can be improved for advanced functions, including controlled drug release and targeted drug delivery,14 so their application in DDSs has aroused much attention. Supramolecular interactions, such as hydrogen bonding and hydrophobic/hydrophilic attraction,18-24 have been widely investigated as the basis of DDSs for their advantages compared to covalent bonds. To start with, the construction of supramolecular DDSs is cost-effective and environmentally friendly, because supramolecular systems can be formed through self-assembly by simply mixing the building blocks in solution together at ambient conditions.18-22 In comparison, the synthesis of conventional block copolymers generally requires multiple steps and more complicated purification methods.19 Secondly, the relatively weak interaction of the noncovalent linkages endows the DDSs with reversible and switchable properties, providing convenient regulation of the disassociation and reconstruction.24 This can help avoiding the debris released during drug delivery and thus decreasing the toxicity of the DDSs. Most importantly, the dynamic noncovalent interaction can respond to external stimuli under certain


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circumstances, which makes it possible to trigger structure change of supramolecular materials and to realize effective drug delivery only in the targeted time and sites.14 In particular, host-guest interaction has played a critical role in the preparation of supramolecular DDSs.24-27 Through the host-guest inclusion, two or more chemical moieties can be combined together in a facile and reversible way for the construction of supramolecular structures.28,29 Generally, the host-guest interaction is indeed the combined effect of hydrophobic interactions, hydrogen-bonding interactions, electrostatic interaction, specific molecular shape or size matching and so on.30,31 In most common cases, the host molecules with hydrophobic cavities, such as cyclodextrin (CD)32 and cucurbituril,33 can bind the hydrophobic guest molecules into their cavities in aqueous solutions. These host-guest interactions are relatively stable and can respond to certain stimuli at the same time, therefore can be used as reliable and dynamic linker for the construction of supramolecular DDSs.34-37 CD is a macrocyclic oligo sugar with wide commercial availability and ease of modification. It can interact with many guests with suitable sizes, such as adamantine (Ada),38,39 pyrene (Py),40 benzyl derivatives41 and polyethylene glycol (PEG) chains.40,42 CDs are considered as good choices for the applications in DDSs, because of their adjustable water solubility, good biocompatibility, and nontoxicity toward biological systems.34 Moreover, they can reduce the toxicity of the drug molecules, the guest molecules and the grafted polymers,34 and bring additional benefits such as membrane absorption enhancement, molecular stabilization, and improvement of water solubility as well as availability of drugs in biological systems.43-47 In the previous reviews, supramolecular DDSs based on host-guest interaction between CD and different guest molecules have been summarized,25-27,35-37,48 including Ada, benzyl


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derivatives, drug molecules and polymer chains. These DDSs have shown good performance to decrease carrier cell cytotoxicity, enhance drug solubility and capacity, and improve their therapeutic efficacy. However, these host-guest interactions are intrinsically without stimuli responsive ability, so controlled release can only be realized by introduction of other segments, including stimuli responsive polymers such as poly(N-isopropylacrylamide) (PNIPAM), 25,26,36 and cleavable covalent bonds.25,26,35-37 There are many reviews regarding the CD-based DDSs without stimuli responsive ability, or those with controlled release behavior but based on thermal/pH/enzyme sensitive polymer skeletons. However, the design, construction and applications of DDSs based on CD and sensitive guest molecules have not been specific summarized. In this review, we will mainly focus on the CD-based DDSs with the host-guest interaction as the stimuli responsive linker. As stated above, CD has hydrophobic cavity, which can encapsulate hydrophobic guest molecules with both suitable size and shape. If we alter the guest molecules from hydrophobic to hydrophilic, or change their shape by external stimuli, the hostguest interaction will weaken, which can lead to the dissociation of the inclusion complex under certain circumstances. This is the basic principle why we can control the structures of the supramolecular systems based on the host-guest interaction and realize the controlled release of loading molecules.12,13,49 Different inclusion complexes based on CD with different guest molecules can respond to different stimuli modes, because the change of hydrophilicity and size of guest molecules can be achieved by different mechanisms. As sensitive guests interacting with CD, ferrocene (Fc), azobenzene (Azo), benzimidazole (BzI) derivatives are mostly investigated during the past decades, for redox, light, and pH and CO2 responses, respectively (Scheme 1). Different features


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and mechanisms of these host-guest interactions, their utilization in constructing supramolecular systems based on polymers with different structures, especially their applications as DDSs and regulation of the DDSs to realize controlled drug release will be discussed in the following parts. Brief information of the stimuli, the host-guest linker, the drugs applied, the design, composition as well as morphology of the DDSs, has been summarized in Table 1. In the interest of brevity, we mainly focus in nanocarriers including vesicles, micelles, nanotubes and other nanostructures, and supramolecular hydrogels

50-54

and surfaces

55,56

also based on these interactions will be

excluded.

Scheme 1 Inclusion complexes based on host-guest interaction of CD and Fc, Azo, BzI derivatives with different responsiveness


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Table 1. Summary of the stimuli, host-guest linker, drugs applied, design, as well as composition and morphology of various polymeric nanocarriers for controlled release.

Stimuli mode

Stimuli details

Host-guest linker

Drug/model moleculesa

Redox

Potential of +1.0 V, +2.0 V and +4.0 V

RB

Redox

Potential of +1.0 V

PTX

Redox

NaClO as oxidant; TECPb as reductant

DOX

Redox and pH

NaClO as oxidant; pH 5.0

Redox

H2O2 as oxidant

RB

Redox

Potential of +0.8 V

DOX

Redox and pH

H2O2 as oxidant; pH 5.0

DOX

β-CD/Fc MTX

Design

Terminal modified linear polymers

Double head linker and terminal modified linear polymers

Branched polymers

Light

β-CD/Azo

DOX

Light

α-CD/Azo

RB

Light

α-CD/Azo

R6G

UV irradiation at 365nm

Other


Crosslinked polymer networks

α-CD/Azo β-CD/Azo

PyMA

Light

α-CD/Azo

α-CD-RB

Other

Light

β-CD/Azo

IBU

Other

Light

pH

pH 5.5

β-CD/BzI

DOX

pH

pH 5.5

β-CD/BzI

DOX


Composition and morphology

Ref

PS-β-CD/PEG-Fc vesicles

68

PEG-β-CD/PLLA-Fc micelles Fc-SS-βCD/POEGMA-Fc micelles and vesicles β-CD-Fc-Ace/PEGAda micelles β-CD/PEG-bPMAEFc vesicles 4A PCL-β-CD/PEGFc micelles β-CD-DOX/PEG-Fc micelles PNIPAM-β-CD/PEGAzo micelles PCL-α-CD/PAA-Azo nanotubes PDA/PNADA/α-CD vesicles PA-α-CD, PA-β-CD and PA-Azo, aggregates CMD-g-α-CD/PAAC12-Azo microcapsules HMS-β-CD/PPP-Azo nanocomposite Dex-β-CD/BzI-PCL miclles PLLA-β-CD/BzI-PEG micelles

69

70

81 77 81 83 90 94 98

100

114

116 124 125 126

a Abbreviation for drug molecules: RB = Rhodamine B, R6G = Rhodamine 6G, DOX = Doxorubicin, PTX = Paclitaxel, MTX = Methotrexate, IBU = Ibuprofen b TECP= tris(2-carboxyethyl) phosphine


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1. DDSs based on CD-Fc interaction with redox sensitivity Fc has been widely investigated as the guest molecule with several types of CDs in the past decades, for its wide commercial availability, wide applications and redox activity.56-60 Fc and its derivatives are neutral in nature and can undergo monoelectronic oxidation to cationic state (Fc+). This redox process can be realized by many mild oxidants such as Fe3+ or H2O2, or by electrochemical oxidative method. When interacting with Fc derivatives, β-CD has the strongest binding ability under an equivalent molar ratio, with a formation constant of 2.2 × 103 M -1.60 However, no host-guest interaction can be detected when hydrophobic Fc is oxidized to hydrophilic Fc+. Therefore, by regulating of the redox status of Fc using redox reagent or electrochemistry, the structures of the polymer self-assemblies based on CD-Fc interaction as well as the release of loading drug molecules can be controlled reversibly. Much effort has been paid to redox control of DDSs because many important biological processes involve redox reactions, such as cellar respiration and apoptosis. Reactive oxygen species (ROS) has been reported to form as a byproduct of the normal cell but increase dramatically due to environmental stress, especially in cancer development, which may result in significant damage to cell structures.61,62 The DDSs based on CD-Fc linker can not only dissociate and subsequently release drug molecules as response to ROS as biological stimuli, but also achieve compromising of the proliferation of cancer cells simultaneously by direct consumption of ROS.63-67 The conventional redox stimuli are realized by addition of redox reagent, for example, NaClO, H2O2, and Fe3+ as oxidant and glutathione (GSH) as reductant. They are effective but accumulative, and the concentration of the added substance and redox byproduct will increase


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with the stimuli cycles, which may have harmful effect on the viability of cells or the mechanical properties of materials. To conduct the redox stimuli in a cleaner way, the electrochemical stimuli are developed, which can be realized without adding any extra redox reagent or solution. The mode and magnitude of the electrochemical stimuli can be regulated readily by using potentiostat. Moreover, electron transfer reaction is well understood and the change of potential plays a fundamental role in membrane activities of living organisms, such as membrane fusion and disassembly. 1.1 DDSs based on CD-Fc interaction and linear homopolymers with terminal modification When utilizing host-guest interaction for construction of DDSs, the terminal modification of linear homopolymer is one of the most frequently applied strategies. In general, one hydrophilic and another hydrophobic linear homopolymer are modified by host and guest molecules in the terminal respectively, and they can form supramolecular block copolymer with “polymer-hostguest-polymer” structure. Base on the amphiphilic property, the copolymers can self-assemble in aqueous solution to nanostructures such as vesicles and micelles, with sensitivity to corresponding stimuli (Figure 1a). This strategy was applied by Yuan et al. to construct supramolecular vesicles for electrochemical controlled release.68 For the synthesis of host and guest polymers, β-CD and Fc were modified to polystyrene (PS-β-CD) and PEG methyl ether (PEG-Fc), respectively. Based on the β-CD-Fc linker, supramolecular block copolymer PS-βCD/PEG-Fc formed, which could further self-assemble into vesicles in aqueous solution. Because of the redox sensitivity of the β-CD-Fc linker, the assembly and disassembly of the vesicles can be regulated by different external potential. Specifically, an oxidation potential of +1.5 V could break the structures of the vesicles and reductive potential of -1.5 V can made the vesicles return back. Rhodamine B (RB) and 6G (R6G) are common used model molecules in


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drug delivery for their good solubility in various solvents and easily detectable fluoresce. By utilizing this potential-responsive vesicle as DDS, the controlled release of RB as a model molecule was investigated. The vesicles loading RB could stably exist without release when no stimuli were conducted, while obvious release was detected with potential stimuli. Moreover, when the potential increased from +1.0 to +4.0 V, the time for complete release of RB decreased from 450 to 32 min, which means that the release rate of RB can be precisely regulated by the strength of the potential.

Figure 1 Schematic illustration of the two generally used ways for the construction of DDSs with stimuli responsive host-guest linker: the controlled disassembly and drug delivery of DDSs based on two linear homopolymers with terminal modification (a), and based on one double head linker and one linear homopolymer with terminal modification (b). The work above confirmed that the electrochemical method is a clean and readily way in regulating the structures of DDSs and the drug release, and polymer skeletons with better


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biocompatibility were employed to further explore the applications of DDSs in biological systems. Biocompatible PEG and poly(L-lactide) homopolymers were modified by β-CD and Fc terminals to PEG-β-CD and PLLA-Fc respectively, and they could self-assemble into supramolecular micelles in aqueous solution, with ability to realize controlled release of paclitaxel (PTX) by potential stimuli.69 Compared with the vesicles based on PS-β-CD/PEG-Fc, this micelle has good biocompatibility and no obvious cytotoxicity, as evaluated by incubation with C26 cell line. Combining the similar modification strategy and β-CD-Fc linker with other stimuli responsive polymers, multi-responsive DDSs can also be constructed. To this end, a thermal responsive PNIPAM chain and a PEG chain were modified by β-CD and Fc to PNIPAM-β-CD and PEG-Fc respectively.70 They could form supramolecular block copolymer and self-assemble into micelles in aqueous solution. Because of the temperature-dependent solubility of PNIPAM, the supramolecular block copolymer was molecularly soluble under the low critical solution temperature (LCST) of PNIPAM, but self-assembled into PNIPAM-core micelles at 37 oC, which is over LCST. The dissociation of the micelles could be regulated by the addition of H2O2 as oxidant, which is one type of ROS that plays an important role and constitutively accumulates in cancer development. Therefore, the redox-responsive micelles can be applied in the treatment of cancer by releasing the anti-cancer drug and decreasing the concentration of H2O2 at the same time. It is worth noting here that the thermal and redox stimuli can lead to a different degree of drug release by the micelles. The increase in temperature could result in a burst of DOX release in the first 15 h, and approximately 91 % of the DOX was released after 48 h. However, only 48 % of the DOX was released with the addition of H2O. The slow and incomplete release by redox is due to the formation of smaller PNIPAM-β-CD micelles after the dissociation of PNIPAM-β-


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CD/PEG-Fc micelles. The dual responsiveness endows the micelles well-defined release properties, which can be fine and selectively tuned by each stimulus independently or combined stimuli together. 1.2 DDSs based on CD-Fc interaction and double head linkers Apart from construction of DDSs by linear homopolymers with terminal modification, double head linkers can also be applied for the construction of DDSs (Figure 1b). For example, Fc and β-CD group can be connected by disulfide bonds to a double head linker, Fc-SS-β-CD, and it can form supramolecular block copolymer with another linear homopolymer modified with Fc, namely, poly[oligo(ethylene glycol) methyl ether methacrylate]-Fc (POEGMA-Fc).

71

The

copolymer can self-assemble into different morphologies at different molar ratios of Fc-SS-β-CD and Fc-POEGMA. Uniform core-shell micelles can be formed at molar ratio of 1:1 while vesicle formation can be visualized at molar ratio of 3:1, due to different hydrophilic weight fractions. It is reported that the stability of disulfide bonds is sensitive to the concentration of GSH. Specifically, GSH in intracellular compartments (mostly cytosol, 2-10 mM) cannot significant reduce disulfide bonds, but disulfide bonds degrade in cancer cells, which have 4-5 times higher concentration of GSH than normal ones.72-75 Therefore, the micelles and vesicles based on β-CDFc linkers and disulfide bonds can dissociate to both oxidant and reductant, thus can be applied for controlled drug release. Both the DOX-loading vesicles and micelles can exist stably in PBS buffer at 37 oC, and can realize drug release under addition of 1 mM NaClO as oxidant or 10 mM tris(2-carboxyethyl)phosphine (TCEP) as reductant. Taking the vesicle as an example, the oxidation stimuli can result in over 52 % DOX release, while reduction stimuli can realize over 43 % DOX release after 72 h.


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In addition to redox responsive ability, redox and pH dual-responsive DDSs have also been prepared and investigated, considering the significance of pH changes in cells, tissues and organisms.76 One hydroxyl group in β-CD was conjugated with Fc to a double head linker β-CDFc and the residue hydroxyls were modified with hydrophobic acetal (β-CD-Fc-Ace), while PEG was modified by Ada groups to PEG-Ada.77 They can form supramolecular block copolymer βCD-Fc-Ace/PEG-Ada, and further self-assembly to micelles with hydrophilic PEG segment and hydrophobic β-CD parts. The micelles were stable at pH 7.4, which is similar to normal physiological conditions and in the blood (pH ≈ 7.4). Due to the redox sensitivity of β-CD-Fc linker and acid degradability of Ace moiety, this supramolecular micelle can dually respond to oxidation and change of pH. Upon the addition of NaClO as an oxidant or change of pH to 5.0, the micelles disassociated owing to the dissociation of β-CD-Fc linker, or to the change of β-CD from hydrophobic to hydrophilic by hydrolysis of Ace, respectively. To apply the dualresponsive micelles as nanocarriers for controlled release, MTX (methotrexate), a water insoluble anticancer drug was chosen as a model molecule. What is interesting, the micelles show different drug release behavior upon pH and redox stimuli. Relatively slower and continuous release can be observed at pH 5.0, in which over 80 % of drug released in 7 h. However, burst release was detected after the addition of NaClO, in which over 90 % of the drug was released in only 1 h, due to the complete disassociation of the DDSs (Figure 2c). The application of pH 5.0 and addition of NaClO are both to mimic the environment in cancer cells, with the more acidic environment and higher concentration of ROS. 1.3 DDSs based on CD-Fc interaction and branched polymers In addition to linear polymers, polymers with branched structure have also been applied in the construction of redox sensitive DDSs, due to their advantages such as adjustability of


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functionality, different rheological properties and diversity of self-assembly structures. It is reported that the polymer composition and concentration, especially the ratios of hydrophilic and hydrophobic parts, have effect on the morphology of the supramolecular self-assemblies. To illustrate the influence of these factors in DDSs based on β-CD-Fc linkers, a Fc-containing amphiphilic block copolymer PEG-b-poly [2-(methacryloyloxy) ethyl Fc-carboxylate] (PEG-bPMAEFc) was synthesized and its self-assembly in the presence of different concentrations of βCD was investigated systematically.78 PEG-b-PMAEFc could form vesicles in aqueous solution, andtransform to interconnected aggregates, compacted microstrucutres, and large compound vesicles with molar ratio of β-CD/Fc at 0.5, 1 and 3 respectively. The vesicles based on PEG-bPMAEFc could dissociate upon oxidation with H2O2, because of the oxidation of Fc to Fc+ and the accompanying change of the amphiphilicitiy of the block copolymers (Figure 2a). However, when oxidized by KMnO4, the original vesicles turned to mesoporous-like ones. The distinct results for two oxidants is due to their different diffuse rates in the bilayer of the vesicles and the different charge states.79 This vesicle was further applied for the controlled release of RB as a model molecule with H2O2 as oxidant. The vesicles were stable with nearly no release of RB in PBS buffer, while significant increase in the fluorescence intensity could be detected, showing the release of RB upon oxidation of H2O2.


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Figure 2 Schematic illustration of the controlled assembly and disassembly, as well as drug release of vesicles and micelles based on β-CD and PEG-b-PMAEFc (a), micelles based on 4APCL-β-CD/PEG-Fc (b), and micelles based on β-CD-hydrazone-DOX and PEG-Fc (c). Adapted from ref 78, 82 and 83 with permission. Copyright 2015 Royal Society of Chemistry, and 2014 and 2016 Elsevier. Star polymers have lower intrinsic viscosity and lower degree of crystallinity compared with their linear analogs, thus can degrade more easily and have better compatibility.17,80,81 In addition, they are reported to show more stable loading and release behavior in the applications as DDSs.81 Therefore, we tried to apply the star amphiphilic copolymers with the same β-CD-Fc linker. Specifically, star polymer 4-arm polycaprolactone with β-CD terminal (4A PCL-β-CD) and PEG modified with Fc group (PEG-Fc) were synthesized, respectively. They can form star amphiphilic supramolecular copolymers 4A-PCL-β-CD/PEG-Fc (Figure 2b), and further selfassemble into micelles.82 Because of the more amorphous structures that can anchor more drug molecules, the micelles were detected to have higher drug loading content and efficiency of DOX, compared with micelles based on linear PCL analogs. Over 75 % of the DOX can be


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released in about 15 h, and such more sustained drug release behavior is attributed to the unique properties of star polymers. In addition, + 0.8 V potential was employed as the electrochemical stimulus, which is milder than what we used for the PS-β-CD/PEG-Fc vesicles and PEG-βCD/PLLA-Fc micelles in the previous work. 1.4 DDSs based on CD-Fc interaction with other structures For DDSs with drug loading based on non-covalent interactions such as hydrophobic interaction, there is a common problem that the drugs will release automatically due to diffusion, even without stimuli. In order to avoid the release caused by diffusion, prodrugs in which drug molecules are attached on DDSs with cleavable covalent bonds are desired and are also applied in the redox controlled DDSs. In this system, DOX were modified on β-CD by acid sensitive hydrazone linkers to β-CD-hydrazone-DOX, and it can form supramolecular block copolymer with PEG modified with Fc at terminal (PEG-Fc). The formed PEG-Fc/β-CD-DOX copolymer can further self-assemble into micelles in aqueous solution (Figure 2c).83 Due to the different sensitivity of the two linkers, the micelles can show responsive and release behavior to pH and redox stimuli. When H2O2 was added to oxidize Fc, the micelles will be broken down, but the DOX will not be released because it is still linked on β-CD. On the contrary, at pH 5.0, DOX will release fast because the disassociation of the hydrazone linker but the micelles can maintain its form. If these two stimuli are combined together, the release rate of DOX will increase dramatically. The acid condition with excess ROS was also utilized to mimic the environment of endosome and lysosome of cancer cells,75,76 where micelles will most likely be after being internalized by cells first. Further study also indicates that the assembled supramolecular prodrug micelles could be internalized by cancer cells, suggesting their promising applications in cancer therapy.


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2. DDSs based on CD-Azo interaction with light sensitivity In the past decades, photo therapy have drawn much attention because of their nonaccumulative properties, and the precise and remote spatiotemporal control, and many photo sensitive DDSs have been designed to achieve drug release regulated by different wavelengths of light. Azo and its derivatives have been widely studied as photo active molecules, for their unique properties to undergo reversible isomerization of trans and cis isomers upon external photoirradiation of ultraviolet (UV) or visible (vis) light.84-87 Additionally, the two isomers have distinct binding ability as guest molecules with α-CD or β-CD. For example, trans-Azo can be strongly bound by α-CD and form 1 : 1 inclusion complex with a binding constant of 2.0 × 103 M -1, while cis- Azo can rapidly slide out of the cavity because of the mismatch of the shape and the binding constant will decrease to 3.5× 10 M

-1 88

.

Therefore, the host-guest interaction

between Azo and CD can be regulated by external photo stimuli, which makes CD-Azo a suitable linker in the supramolecular systems for light controlled drug delivery and release. 2.1 DDSs based on CD-Azo interaction and homopolymers with terminal modification Precise regulation of the structures of the stimuli responsive polymer self-assemblies is a significant topic, and it is reported that the binding sites and the cooperativity also have effect on the polymeric DDSs.89 To illustrate their influences in detail, two types of thermal and photo dual stimuli responsive supramolecular polymers (SSP) were prepared by one PNIPAM chain and two PEG arms with different structures, one of which is consisted of only one β-CD/Azo binding site (SSP), and another with two (SSP2). 90 Owing to the photo sensitivity of β-CD/Azo interaction and thermal sensitivity of PNIPAM, the self-assembly of SSPs could be controlled by altering the light irradiation and the temperature of the solution. With the temperature increasing,


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the self-assembly of SSP2 showed a flower-like form, with a smaller size and higher stability compared with SSP1. This difference come from the positive cooperativity produced by the two binding sites on the surfaces of SSP2 self-assemblies.91, 92 Therefore, the DDSs based on SSP2 are supposed to have more controllable drug release behavior. To confirm that, SSP1 and SSP2 self-assemblies were utilized as DDSs for controlled release of DOX. SSP2 DDSs released 14.3 % of the DOX at 37 oC after 48 h, and 19.5 % after UV irradiation, which were both less than SSP1 and thus indicated better controllability of DOX release behaviours. This study demonstrated that the enhancement of cooperativity with a high binding site distribution can bring in the high controllability of drug release behavior, thus providing guidance for the design of the supramolecular DDSs in the future. Different from zero-dimensional self-assemblies such as vesicles and micelles, onedimensional polymeric nanomaterials such as nanotubes and nanowires are reported to have better pharmacokinetics and efficiency in drug delivery and gene transport systems.93 To construct light-responsive one-dimensional nanomaterials, the strategy of terminal modification of linear homopolymers (Figure 1a) was utilized and two homopolymer was modified with αCD and trans-Azo at terminal to get PCL-α-CD and PAA-Azo, respectively.94 Based on α-CDAzo linker, they could form supramolecular copolymer PCL-α-CD/ PAA-Azo, which could further self-assemble into one-dimensional nanotubes in aqueous solution. The nanotubes dissociated through UV irradiation, owing to the isomerization of azo which breaks host-guest interaction. The visible light could make the nanotubes fabricate again, which enables the reversibility of system. This light-responsive nanotube can be further applied as a feasible medium to encapsulate and release small molecules. RB was chosen as model molecule to be loaded into the nanotubes. Without light stimuli, only 17 % of the RB was released within 10 h.


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However, if the solution is irradiated by UV light, the release rate will increase dramatically and 100 % of the RB can be released in shorter time. Moreover, the release rate can be precisely controlled by the time of the UV irradiation. When the UV irradiation time increased from 60 s to 420 s, the time for the complete release decreased from 5.6 h to 0.8 h. It is notable that the release quantities of RB can all reach approximately 100 %, which show advantages over other polymeric nanocapsulated systems. 2.2 DDSs based on CD-Azo interaction and cross-linked polymer networks Polydiacetylenes (PDAs) are polymers synthesized by the 1,4-topochemical polymerization of diacetylenes. PDA-based vesicles have been employed in developing ingestible formulations, gene carriers and drug carriers, because of their nontoxicity, high stability, as well as stimuli responsive conjugated structure distortion. 95-97 In order to introduce the light sensitivity into the PDA vesicles, a diacetylene monomer (10,12-pentacosadiynoic acid, DA) containing the pnitrophenyl Azo moiety (NADA) was synthesized, and PDA/PNADA complex vesicles with R6G loaded were prepared by crosslinking NADA and DA at molar ratio of NADA/DA=1:1 (Figure 3a).98 The R6G release behaviors of PDA/PNADA vesicles under different conditions were systematically studied next. Under no stimuli, R6G encapsulated in pure PDA/PNADA complex vesicles were released slowly and only 16% R6G were released after 50 min. However, when mixing with α-CD, the release rate increased dramatically (5.6 faster) and over 90 % of R6G released in the same period, which is due to the greater separation between chains in the vesicles by α-CD. Therefore, by applying the PDA/PNADA/α-CD vesicles as nanocarriers, drug release rate can be regulated by UV irradiation. Upon the UV irradiation, a significant reduction of the release rate of R6G could be detected, ascribing to the exclusion reaction of α-CD with the Azo moiety within the PDA matrix. In summary, a novel DDS with photo controlled release


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behavior was constructed, by introduction of UV sensitive α-CD-Azo linker into the conjugated polymers, which are electricity conductive and thus have potential applications as metal alternatives.

Figure 3 Schematic illustration for (a) the construction of PDA/PNADA/α-CD polymeric vesicles and light-controlled release of R6G; (b) light-controlled release of PyMA for the PA-αCD/PA-β-CD/PA-Azo ternary mixture; (c) fabrication and degradation processes of (PAA-C12Azo)/(CMD-g-α-CD&α-CD-model drug) hollow microcapsules and (d) light-triggered drug release from HMS@β-CD@PPP hybrid composite. Adapted from ref 98,100, 114 and 116 with permission. Copyright 2011 and 2015 Wiley, 2011 ACS and 2012 Royal Society of Chemistry. The isomerization of Azo from trans to cis ones can lead to the decrease of binding constant with α-CD from 2.0 × 103 to 3.5 × 10, while with β-CD from 7.7 × 102 to 2.8 × 102.99 These values mean that trans Azo has stronger interaction with α-CD while cis one prefers β-CD. Therefore, the controlled release of a guest molecule which has stronger interaction with β-CD


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than trans Azo but weaker than cis one at the same time can be realized in a mixing system of αCD, β-CD and Azo (Figure 3b).100 In order to confirm that, poly (sodium acrylate) was modified by α-CD, β-CD and Azo to PA-α-CD, PA-β-CD and PA-Azo respectively, and the UV sensitivity of PA-α-CD/PA-β-CD/PA-Azo ternary mixture was studied. According to light scattering results, the ternary mixture formed aggregates with dominant peak DH=167 nm, and it shifted to DH=83 nm and a larger peak at DH=701 nm was also observed after UV irradiation. The change of the DH indicated the dissociation of the PA-α-CD/PA-trans-Azo and the formation

of

PA-β-CD/PA-cis

Azo

aggregates

at

the

same

time.

Next,

1-

pyrenemethylammonium chloride (PyMA) was chosen as a model molecule with suitable binding constant, and its release behavior was investigated. When adding PA-α-CD/PA-βCD/PA-Azo ternary aggregates loading with PyMA in water, the concentration of PyMA increased gradually and reached to the balance value at about 3.5 × 10−8 M after 9.5 h. After UV irradiation, its concentration increased suddenly and reached at about 1.8 × 10-7 M after 10 h, which is approximately 7.5 % of the total PyMA loaded. However, in two binary mixtures of PA-α-CD/PA-Azo and PA-β-CD/PA-Azo, only slight increase of release rate of PyMA was observed after UV irradiation, and the final concentration of PyMA can only reached 2.5 %. Therefore, the PA-α-CD/PA-β-CD/PA-Azo ternary mixture can be applied for controlled release of PyMA with faster rate and greater final amount, which is feasible to act as a novel lightcontrolled DDS. In addition to light sensitivity, it is also reported that by reduction of N=N bond in Azo groups to aniline derivatives, the host-guest interaction between CD and Azo can be also broken down, thus endowing the CD-Azo linker with redox sensitivity to certain reductant.101-103 The intriguing part of this reduction regulation is that the microbiota can produce one type of bacterial


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azoreductase in the colon process, as one kind of reductant of Azo, thus making the CD-Azo a promising linkage in drug delivery in the colon. 103, 104 2.3 DDSs based on CD-Azo interaction with other structures Recently, layer-by-layer (LbL) microcapsules have drawn much attention as novel type of DDSs because they can be prepared with well-defined structures and the drugs loading on the layers of LbL capsules can bypass the multidrug resistance of cancer cells.110-112 In order to obtain LbL microcapsules based on α-CD-Azo linker, carboxymethyl dextran-graft-α-CD (CMD-g-α-CD) and PAA N-aminododecane p-azobenzeneaminosuccinic acid (PAA-C12-Azo) were synthesized respectively.114 They could assemble LbL with CaCO3 particles as core, and αCD-RB w utilized as a model drug on PAA-C12-Azo layers. After self-assembly, CaCO3 particles were removed and hollow microcapsules loaded with α-CD-RB were obtained (Figure 3c). Owing to the photo sensitivity of the α-CD-Azo interaction, the hollow microcapsules could dissociate under UV light irradiation, followed by the release of α-CD-RB. In dark environment, the drug was released slowly and only less than 5 % of drug was released in 300 min. With UV irradiation, the release rate increased abruptly because of the dissociation of microcapsules, and over 60 % of drug was released from the microcapsules within 300 min. Different from either chemical bond or physical adsorption, the drug is loaded by host-guest interaction in this LbL microcapsules, which provides reliable linker and has stimuli responsive ability at the same time. Hollow mesoporous silica nanoparticles (HMSs) have also been considered as ideal drug delivery candidates, for their high drug loading capacity based on large cavity inside and the ease to be functionalized for further targeted delivery.114,115 They can also be applied to construct photo sensitive DDSs based on the CD-Azo linker. To this end, HMSs were modified with β-CD


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while amphiphilic copolymers poly(PPHM-PEGMEM) [PPP, random copolymers of 6-(4(phenyldiazenyl)phenoxy)hexyl methacrylate and PEG methyl ether methacrylate] were modified with trans-Azo groups.116 Based on β-CD-Azo host-guest interaction, PPP-Azo could cover the surface of the HMSs, leading to the formation of hybrid nanocomposite HMS@βCD@PPP. Similarly, the dissociation of the nanocomposite could be regulated by UV irradiation (Figure 3d), and ibuprofen (IBU) was utilized as the model drug for controlled release. Owing to the hollow core of HMSs with large cavity, the drug loading capacity wa as high as 782 mg/g (IBU/carrier). In the release experiment, 80 wt % of IBU was released within 100 h under UV irradiation while less than 10 wt % of IBU was released under visible light. In addition, the prepared nanocomposites can also perform a “release-stop-release” manner by converting light irradiation, which means that drug release can be started by UV light irradiation and ended by visible light. 3. DDSs based on CD-BzI interaction with pH and CO2 sensitivity In the previous literatures, BzI is reported to be a suitable guest molecule for β-CD with the binding constant as 1.6 × 103 M-1 at neutral pH. Similar to imidazole, the BzI can be pronated to cation BzI + with one charge at acidic condition or upon the addition of CO2.117,118 Because of the preference of hydrophobic molecules to CD cavities, the host-guest interaction between CD and BzI can be regulated by pronation or depronation of BzI upon addition of acid or base, as well as the CO2 gas. At the physiological pH 7.4, BzI has a hydrophobic nature and can form stable inclusion complex with β-CD. However, when the BzI is protonated under acidic conditions (pH < 6) mimicking the endosomal/lysosomal compartments, BzI+ will disassociate from the cavity of CD. Therefore, the pH and CO2 stimuli responsive drug release systems can be constructed based on the CD-BzI linker.


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The pH sensitivity of DDSs is significant, especially for the applications in biomedical fields.69,70,119,120 On one hand, the pH of different cellular compartments, body fluids, and organs are usually tightly regulated in a process called acid-base homeostasis.119 Therefore, the targeted release of drug can be realized by adjusting the responsive pH of the DDSs to the characteristic pH of certain part of an organism.120 On the other hand, the abnormal pH can be seen as portent for the disorder, or even disease. In especial, cancer cells thrive in an acidic environment, and the lactic acid produced by the cancers can make the environment more acidic with time. The difference in the pH of normal and cancer cells can guarantee the release of anticancer drug only in cancer cells by suitable design, which can achieve the therapy and preserve the normal cells at the same time. Moreover, apart from the addition of acid or base, the protonation and deprotonation of BzI can be regulated by CO2 or N2 gas. The use of CO2 gas is cost-effective since it is abundant in our environment, and it can show repeated and reversible responses via alternately purging CO2 and inert gases such as N2 without contamination. In addition, the stimulus from CO2 provides a good penetration depth due to water as a medium, allowing the CO2-responsive behaviour even deep inside the material. Moreover, CO2 is an important metabolite in human cells with good biocompatibility and membrane permeability, which endows the CO2-responsive polymers with great potential for bio-medical applications. 121-123 3.1 DDSs based on CD-BzI interaction and linear homopolymers with terminal modification In order to prepare a pH-sensitive amphiphilic supramolecular block copolymer, the strategy of terminal modification of linear homopolymer was applied again (Figure 1a). BzI modified


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poly(3-caprolactone) (PCL-BzI) and β-CD terminated dextran (Dex-β-CD) were synthesized respectively.124,125 The formed supramolecular block copolymer Dex-β-CD/PCL-BzI could selfassemble into micelles at physiological pH~7.4 and exhibited pH-sensitivity in acidic conditions (pH < 6). Therefore, the supramolecular micelles were served for intracellular drug delivery in cancer chemotherapy, using DOX as model drug molecules. pH 5.5 and 7.4 were chosen to mimic the pH in late endosome, and blood or normal tissue, respectively. Only 30 % of the DOX was released from DOX-loaded Dex-β-CD/PCL-BzI micelles in PBS at pH 7.4 in 24 h, while up to 90% of DOX was released at pH 5.5. To demonstrate the application of the pH-sensitivity, the cellular uptake, intracellular release behaviors and efficiency of DOX-loaded Dex-β-CD/PCLBzI micelle and Dex-PCL micelle were investigated and compared in HepG2 cells. As expected, the cells after incubation with Dex-β-CD/PCL-BzI micelles for 3 h showed stronger intracellular DOX fluorescence, which is attributed to the enhanced intracellular DOX release induced by acid-trigged disassociation of the supramolecular micelle. In addition, the Dex-β-CD/PCL-BzI micelle exhibited significantly higher growth inhibition efficiency compared to DOX-loaded Dex-PCL micelle, because of its sensitivity to endosomal pH. Another micelle with similar pH sensitivity was also reported by the same group, which was composed of BzI-terminated PEG (PEG-BzI) and β-CD-modified PLLA (PLLA-β-CD).126 A faster release rate of DOX in HepG2 cells was detected for the PLLA-β-CD/PEG-BzI supramolecular micelles compared with the pH-insensitive PEG-PLLA counterpart. Furthermore, the micelles showed apparently higher tumor inhibition efficacy, lower systemic toxicity and enhanced blood circulation time against free DOX in animal experiment, which were injected through intravenous into nude mice with HepG2 xenografts in the tail vein. The features of these


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two supramolecular micelles based on β-CD-BzI linker endow them promising applications in intelligent drug delivery. Considering the pH sensitivity of the host-guest interaction between β-CD and BzI, this linker also has potential to respond to CO2 stimuli. To develop a CO2-cleavable supramolecular block glycopolypeptide, two distal-functionalized biopolymers, Dex bearing a β-CD terminal (Dex-βCD) and poly(L-valine) with a BzI tail (PVal-BzI), were synthesized respectively.127 With the building blocks designed to imitate a viral composition and structure, the macromolecular adducts (Dex-β-CD/PVal-BzI) could self-assemble into either vesicular or fibrous aggregates according to their block length difference. Since the β-CD/BzI noncovalent connection can be cleaved by CO2 stimulation, both vesicles and nanofibers in water could undergo a reversible process of disassembly upon “breathing in” CO2 and re-assembly upon “breathing out” CO2. These vesicles and nanofibers have great potential in applications as DDSs for CO2 controlled drug release. 3.2 DDSs based on CD-BzI interaction with other structures Apart from supramolecular vesicles and micelles, other structures constructed on the host-guest interaction between CD and BzI are also reported, and most of them are based on mesoporous silica nanoparticles (MSNP) for controlled drug release. MSNP have been widely investigated as solid support for drug delivery and release for its high loading capacity and ease of functionalization.128-130 For example, BzI groups were modified on the surface of MSNP with cargo loaded, and β-CD could form inclusion complex with BzI, thus could be used as caps for the pores.128 Because of the pH sensitivity of this host-guest interaction, the β-CD gate could open as response to acid condition, thus leading the MSNP to release the cargos in the


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endosomal acidification conditions in human differentiated myeloid and squamous carcinoma cell lines. Similar release could also be realized by β-CD covalently modified MSNP and BzI,129 or by gold NPs modified with β-CD and BzI covalently modified MSNP.130

4. Conclusion and perspective In conclusion, the introduction of non-covalent interaction, especially the host-guest interaction between CDs and their counterparts, have provided much advantages and novel platforms to the research of DDSs. Not only the CDs themselves are biocompatible, they can also enhance the biocompatibility and water solubility of the guest molecules and drugs. Most of the inclusion complexes are constructed in aqueous solution, which are favorable in the biomedical field. Moreover, the reversible interactions between CDs and guest molecules endow the DDSs with stimuli responsive ability and thus can be realized for precise controlled release in targeted time and area. Various supramolecular DDSs, including vesicles, micelles, nanotubes, hydrogels and other materials, can be constructed based on the host-guest interaction between CDs and Fc, Azo and BzI derivatives, with different responsiveness to redox, light and pH stimuli. The release of drug or protein molecules can be regulated by these stimuli, thus to realize “on demand” or targeted release. In addition, the introduction of CD can enrich the diversity of drugs released by DDSs, for they can not only deliver the drugs that can be loaded in the conventional polymersomes without CD by physical interactions or by cleavable covalent bonds, but also form drug-CD complex, which are simpler in structures and compositions and have already been applied as commercialized pharmaceutical products.25 The most widely investigated drugs in the previous literatures include


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DOX, PTX, MTX, IBU and so on. It is also worth noting here that based on the host-guest interaction, not only the conventional stimuli such as light, pH and redox reagent can be conducted, novel stimuli mode including electrochemical and CO2 stimuli are also realized. These two stimuli have received much attention over the last decade due to their “green” inherent characteristics and ease of applying stimulation. Though many supramolecular DDSs have been constructed based on CD-guest interaction for controlled molecules release, most of the work are still realized in vitro and just proof of concept. A few have been conducted in vivo as preclinical study and rare ones have reached the clinical stage. The environment in biological system is complicated and there are much more requirements for these DDSs to be applied in real life than in vitro conditions, including the endosomal and intracellular delivery through cell barriers, localization and therapy of tumor and cancer at specific sites, the cytotoxicity and degradability of polymers and DDSs and the precise control of the release rate of drug molecules. To start with, the target of the drug release in biological system is difficult, considering the heterogeneity of the biological target and limited access of DDSs to the target cells.131-135 Though the CDs are biocompatible, the toxicity of the CD-based DDS is still a problem, partly because of the absence of degradability and the consequent accumulation, and partly for the residues of cytotoxic substances introduced during the synthesis. For example, when modifying the polymers with CD, CuAAc based click chemistry is frequently applied,68,71,82 which may leave some copper atoms in the DDSs. Moreover, the binding constant between CDs and their guest counterpart is around 1000 M-1, which is not high enough to avoid the existence of non inclusion host or guest molecules. Dialysis or modification of CD to improve binding ability can solve this problem to some extent, but more stable inclusion complex is still to be found. In addition, the cost is also an issue that


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cannot be ignored, especially in the development as a new therapies based on novel supramolecular DDSs. The complexity for design of the supramolecular DDSs, and the difficulties for the scaling-up synthesis, are all barriers for the clinical goal. Therefore, for the CD-based DDSs, to finally translate from the lab study to pharmacy, much improvement and investigation need to be conducted in the future. Simpler systems with easier stimuli mode and convenient dose administration are preferred, with a higher possibility to reach the clinic purpose. Comprehensive study of the systematic cytotoxicity of the supramolecular systems should be conducted, including the circulation dynamics, long-term observation and immunological reactions. The cost of the DDSs should be decreased by improving the reaction efficiency, finding more effective ways to construct supramolecular systems, and realizing the scale up synthesis. Apart from these problems, the supramolecular systems based on CD-guest interaction with stimuli responsive ability are promising candidates for the future therapies.

AUTHOR INFORMATION Corresponding Author * [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT


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We gratefully acknowledge the financial support of the National Natural Science Foundation of China (51574086, 21374053). REFERENCES 1

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