Thiolated Polymers: Bioinspired Polymers Utilizing One of the Most Important Bridging Structures in Nature
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Advanced Drug Delivery Reviews 151–152 (2019) 191–221 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature Christina Leichner 1, Max Jelkmann 1, Andreas Bernkop-Schnürch ⁎ University of Innsbruck, Institute of Pharmacy, Dep. of Pharmaceutical Technology, Center for Chemistry and Biomedicine, Innrain 80/82, Room L.04.231, 6020 Innsbruck, Austria article info abstract Article history: Thiolated polymers designated “thiomers” are obtained by covalent attachment of thiol functionalities on the Received 2 March 2019 polymeric backbone of polymers. In 1998 these polymers were first described as mucoadhesive and in situ gelling Received in revised form 16 April 2019 compounds forming disulfide bonds with cysteine-rich substructures of mucus glycoproteins and crosslinking Accepted 16 April 2019 through inter- and intrachain disulfide bond formation. In the following, it was shown that thiomers are able Available online 25 April 2019 to form disulfides with keratins and membrane-associated proteins exhibiting also cysteine-rich substructures. fl Keywords: Furthermore, permeation enhancing, enzyme inhibiting and ef ux pump inhibiting properties were demon- Thiolated strated. Because of these capabilities thiomers are promising tools for drug delivery guaranteeing a strongly Thiolated polymers prolonged residence time as well as sustained release on mucosal membranes. Apart from that, thiomers are Thiomers used as drugs per se. In particular, for treatment of dry eye syndrome various thiolated polymers are in develop- Thiol/disulfide exchange reactions ment and a first product has already reached the market. Within this review an overview about the thiomer- Thiol-ene reactions technology and its potential for different applications is provided discussing especially the outcome of studies Drug delivery in non-rodent animal models and that of numerous clinical trials. Moreover, an overview on product develop- Regenerative medicine ments is given. Tissue engineering © 2019 Elsevier B.V. All rights reserved. Contents 1. Introduction.............................................................. 192 2. Synthesisofthiolatedpolymersandchemistrybehind........................................... 192 2.1. Rationaldesignofthiolatedpolymers............................................... 192 2.2. Synthesisofthiolatedpolymers.................................................. 195 2.2.1. Covalentattachmentofsulfhydrylligands......................................... 195 2.2.2. Substitutionofhydroxylgroupsbythiolgroups....................................... 197 2.2.3. Co-polymerizationreactions............................................... 197 3. Reactionsofthiolatedpolymers..................................................... 197 4. Keyfeaturesofthiolatedpolymers.................................................... 199 4.1. Bioadhesion........................................................... 199 4.1.1. Mucoadhesion...................................................... 199 4.1.2. Adhesiontokeratinoussurfaces.............................................. 205 4.1.3. Adhesiontomembrane-associatedproteins........................................ 205 4.2. In situ gelation.......................................................... 206 4.2.1. In situ gelation via oxidation and thiol/disulfideexchangereactions.............................. 206 4.2.2. In situ gelationviathiol-enereactions........................................... 206 4.3. Controlleddrugrelease...................................................... 206 4.3.1. Diffusion-controlleddrugrelease............................................. 206 4.3.2. Reduction-controlleddrugrelease............................................. 207 4.3.3. Controlledreleaseofcovalentlyattacheddrugs....................................... 207 4.4. Permeationenhancement..................................................... 208 ⁎ Corresponding author. E-mail address: [email protected] (A. Bernkop-Schnürch). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.addr.2019.04.007 0169-409X/© 2019 Elsevier B.V. All rights reserved. 192 C. Leichner et al. / Advanced Drug Delivery Reviews 151–152 (2019) 191–221 4.5. Effluxpumpinhibition...................................................... 208 4.6. Metalbindingproperties..................................................... 209 5. Applicationsofthiolatedpolymers.................................................... 209 5.1. Drugs.............................................................. 209 5.2. Drugdeliverysystems...................................................... 211 5.3. Diagnostics........................................................... 211 5.4. Regenerativemedicine...................................................... 212 5.4.1. Tissueengineering.................................................... 212 5.4.2. Tissueregeneration.................................................... 212 5.5. Cosmetics............................................................ 213 5.5.1. Antiperspirants..................................................... 213 5.5.2. Hairtreatments..................................................... 213 6. Conclusion............................................................... 213 References.................................................................. 213 1. Introduction 2. Synthesis of thiolated polymers and chemistry behind Since their introduction in the life science arena in the late 1990s 2.1. Rational design of thiolated polymers [1,2], thiolated polymers have attracted and inspired researchers from different disciplines by their versatile features resulting in Generally, the polymer backbone and the quantity as well as type of some thousands of publications, numerous clinical trials and various sulfhydryl groups have a substantial impact on the performance of marketed products. On the occasion of their 20th anniversary achieve- thiomers. ments so far are summarized and an outlook on future developments In particular chain length, chain flexibility and charged substruc- is taken. tures of the polymer backbone influence the ability to form disulfide Due to the covalent attachment of thiol moieties on polymers (Fig. 1) bonds. The longer the chain length and the less flexible the polymer various properties are strongly improved [3]. Polymers without thiols backbone is, the less reactive are thiomers [7]. As molecular move- are simply like proteins without cysteine. Soon after the first publica- ments of high molecular mass thiomers of low chain flexibility are tions about thiolated polymers the term thiomers came additionally comparatively slower, thiols need simply more time to get close to into use [4]. Their capability to form disulfide bonds – the likely most the target thiol or target disulfide to react. In addition, for such versatile bridging structure in nature – with endogenous proteins such thiomers steric hindrances become more effective. If polymer chains as mucus glycoproteins, keratins or membrane-associated proteins as repulse each other because of the same charge, the likelihood for well as within their own polymer chains through a crosslinking process thiols to get close to each other and to crosslink is also lowered render them unique among advanced materials. [8,9]. Furthermore, polymer backbones can be either biodegradable First thiomers were generated with the intention to improve such as polysaccharides and proteins or non-biodegradable such as the mucoadhesiveness of polymeric excipients for drug delivery. poly(meth)acrylates or silicones. Biodegradable thiomers are from Well-established mucolytic drugs bearing a thiol group such as N- the toxicological point of view preferred over non-biodegradable acetyl-cysteine break disulfide bonds within cysteine-rich substruc- thiomers. For the registration as drug, pharmaceutical excipient or tures of mucus glycoproteins through thiol/disulfide exchange reac- medical device in case of biodegradable thiomers, however, toxicolog- tions. The mucolytic agent is thereby covalently attached to the ical studies of not just the thiomer itself but also of different degrada- mucus glycoprotein via a newly formed disulfide bond. Based on tion products have to be shown. this observation it was assumed that not just small molecules but The reactivity of thiomers depends also on the degree of thiolation even polymers will be covalently attached to mucus glycoproteins fol- [10] and the type of sulfhydryl ligand [11]. As actually not the thiol lowing the same mechanism. Accordingly, cysteine was bound to but the thiolate anion is the reactive form, the pKa value of sulfhydryl li- polyacrylic acid via the same amide linkage as exhibited by N- gands has a substantial impact on reactivity of thiomers. The lower the acetylcysteine. Although this first synthesized thiomer showed just pKa value of thiol groups is, the higher is the concentration of thiolate two to three fold improved mucoadhesive properties, a proof-of-con- anions at physiological pH. The rate of thiol/disulfide exchange reac- cept was provided. In the same study the ability of thiomers to tions is inversely dependent on the pKa of the attacking sulfhydryl li- crosslink via the formation of inter- and intrachain disulfide bonds gand, as the thiolate anion is a better nucleophile than the thiol [12]. and to build up cohesive and robust three-dimensional networks