Thiomer

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Thiomers are capable of forming disulfide bonds with cysteine substructures of the mucus gel layer covering mucosal membranes. Because of this property they exhibit up to 100-fold higher mucoadhesive properties in comparison to the corresponding unthiolated polymers.{{cite journal|last1=Grabovac|first1=V|last2=Guggi|first2=D|last3=Bernkop-Schnürch|first3=A|title=Comparison of the mucoadhesive properties of various polymers|journal=Adv. Drug Deliv. Rev.|date=2005|volume=57|issue=11|pages=1713–1723|doi=10.1016/j.addr.2005.07.006|pmid=16183163}}{{cite journal|last1=Bernkop-Schnürch|first1=A|last2=Kast|first2=CE|last3=Richter|first3=MF|title=Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine|journal=J. Control. Release|date=2001|volume=71|issue=3|pages=277–285|doi=10.1016/S0168-3659(01)00227-9|pmid=11295220}}{{cite journal|last1=Zahir-Jouzdani|first1=F|last2=Mahbod|first2=M|last3=Soleimani|first3=M|last4=Vakhshiteh|first4=F|last5=Arefian|first5=E|last6=Shahosseini|first6=S|last7=Dinarvand|first7=R|last8=Atyabi|first8=F|title=Chitosan and thiolated chitosan: Novel therapeutic approach for preventing corneal haze after chemical injuries|journal=Carbohydr. Polym. |date=2018|volume=179|pages=42–49|doi=10.1016/j.carbpol.2017.09.062|pmid=29111069}} Because of their mucoadhesive properties, thiolated polymers are an effective tool in the treatment of diseases such as dry eye, dry mouth, and dry vagina syndrome where dry mucosal surfaces are involved.{{cite journal|last1=Partenhauser|first1=A|last2=Bernkop-Schnürch|first2=A|title=Mucoadhesive polymers in the treatment of dry X syndrome|journal=Drug Discovery Today|date=2016|volume=21|issue=7|pages=1051–62|doi=10.1016/j.drudis.2016.02.013|pmid=26944445}}{{cite journal|last1=Schmidl|first1=D|last2=Werkmeister|first2=R|last3=Kaya|first3=S|last4=Unterhuber|first4=A|last5=Witkowska|first5=KJ|last6=Baumgartner|first6=R|last7=Höller|first7=S|last8=O’Rourke|first8=M|last9=Peterson|first9=W|last10=Wolter|first10=A|last11=Prinz|first11=M|last12=Schmetterer|first12=L|last13=Garhöfer|first13=G|title=A controlled, randomized double-blind study to evaluate the safety and efficacy of chitosan-N-acetylcysteine for the treatment of dry eye syndrome|journal=J. Ocul. Pharmacol. Ther.|date=2017|volume=33|issue=5|pages=375–382|doi=10.1089/jop.2016.0123|pmid=28441068}}{{cite journal|last1=Bielory|first1=L|last2=Wagle|first2=P|title=Ocular surface lubricants |journal=Curr. Opin. Allergy Clin. Immunol.|date=2017|volume=17|issue=5|pages=382–389|doi=10.1097/ACI.0000000000000392|pmid=28796122|s2cid=205434357}}

Various polymers such as poloxamers exhibit in situ gelling properties. Because of these properties they can be administered as liquid formulations forming stable gels once having reached their site of application. An unintended rapid elimination or outflow of the formulation from mucosal membranes such as the ocular, nasal or vaginal mucosa can therefore be avoided. Thiolated polymers are capable of providing a comparatively more pronounced increase in viscosity after application, as an extensive crosslinking process by the formation of disulfide bonds between the polymer chains due to oxidation takes place. This effect was first described in 1999 by Bernkop-Schnürch et al.{{cite journal|last1=Bernkop-Schnürch|first1=Andreas|last2=Schwarz|first2=Veronika|last3=Steininger|first3=Sonja|title=Polymers with Thiol Groups: A New Generation of Mucoadhesive Polymers|journal=Pharm. Res.|date=1999|volume=16|issue=6|pages=876–881|doi=10.1023/A:1018830204170|pmid=10397608|s2cid=35984262 }} for polymeric excipients. In case of thiolated chitosan, for instance, a more than 10,000-fold increase in viscosity within a few minutes was shown.{{cite journal|last1=Sakloetsakun|first1=D|last2=Hombach|first2=JM|last3=Bernkop-Schnürch|first3=A|title=In situ gelling properties of chitosan-thioglycolic acid conjugate in the presence of oxidizing agents|journal=Biomaterials|date=2009|volume=30|issue=31|pages=6151–6157|doi=10.1016/j.biomaterials.2009.07.060|pmid=19699516}} These high in situ gelling properties can also be used for numerous further reasons such as for parenteral formulations,{{cite journal|last1=Du|first1=H|last2=Hamilton|first2=P|last3=Reilly|first3=M|last4=Ravi|first4=N|title=Injectable in situ physically and chemically crosslinkable gellan hydrogel|journal=Macromol. Biosci.|date=2012|volume=12|issue=7|pages=952–961|doi=10.1002/mabi.201100422|pmid=22707249|pmc=6052871}} as coating material{{cite journal|last1=Zhao|first1=W|last2=Kong|first2=M|last3=Feng|first3=C|last4=Cheng|first4=X|last5=Liu|first5=Y|last6=Chen|first6=X|title=Investigation of gelling behavior of thiolated chitosan in alkaline condition and its application in stent coating|journal=Carbohydr. Polym.|date=2016|volume=136|pages=307–315|doi=10.1016/j.carbpol.2015.09.049|pmid=26572360}} or for food additives{{cite journal|last1=Chen|first1=J|last2=Ye|first2=F|last3=Zhou|first3=Y|last4=Zhao|first4=G|title=Thiolated citrus low-methoxyl pectin: Synthesis, characterization and rheological and oxidation-responsive gelling properties|journal=Carbohydr. Polym.|date=2018|volume=181|pages=964–973|doi=10.1016/j.carbpol.2017.11.053|pmid=29254061}}

Due to a sustained drug release, a prolonged therapeutic level of drugs exhibiting a short elimination half-life can be maintained. Consequently the frequency of dosing can be reduced contributing to an improved compliance. The release of drugs out of polymeric carrier systems can be controlled by a simple diffusion process. So far the efficacy of such delivery systems, however, was limited by a too rapid disintegration and/or erosion of the polymeric network.{{cite journal|last1=Bernkop-Schnürch|first1=A|last2=Scholler|first2=S|last3=Biebel|first3=RG|title=Development of controlled drug release systems based on polymer-cysteine conjugates|journal=J. Control. Release|date=2000|volume=66|issue=1|pages=39–47|doi=10.1016/S0168-3659(99)00256-4|pmid=10708877}} By using thiolated polymers this essential shortcoming can be overcome. Because of the formation of inter- and intrachain disulfide bonds during the swelling process, the stability of the polymeric drug carrier matrix is strongly improved. Hence, a controlled drug release for numerous hours is guaranteed. There are numerous drug delivery systems making use of this technology.{{cite journal|last1=Huang|first1=J|last2=Xue|first2=Y|last3=Cai|first3=N|last4=Zhang|first4=H|last5=Wen|first5=K|last6=Luo|first6=X|last7=Long|first7=S|last8=Yu|first8=F|title=Efficient reduction and pH co-triggered DOX-loaded magnetic nanogel carrier using disulfide crosslinking|journal=Mater. Sci. Eng. C|date=2015|volume=46|pages=41–51|doi=10.1016/j.msec.2014.10.003|pmid=25491958|doi-access=free}}{{cite journal|last1=Mishra|first1=BJ|last2=Kaul|first2=A|last3=Trivedi|first3=P|title=L-Cysteine conjugated poly L-lactide nanoparticles containing 5-fluorouracil: formulation, characterization, release and uptake by tissues in vivo |journal=Drug Deliv.|date=2015|volume=22|issue=2|pages=214–222|doi=10.3109/10717544.2014.883117|pmid=24524408|s2cid=23491627 |doi-access=free}}{{cite journal|last1=Moreno|first1=M|last2=Pow|first2=PY|last3=Tabitha|first3=TST|last4=Nirmal|first4=S|last5=Larsson|first5=A|last6=Radhakrishnan|first6=K|last7=Nirmal|first7=J|last8=Quah|first8=ST|last9=Geifman Shochat|first9=S|last10=Agrawal|first10=R|last11=Venkatraman|first11=S|title=Modulating release of ranibizumab and aflibercept from thiolated chitosan-based hydrogels for potential treatment of ocular neovascularization|journal=Expert Opin. Drug Deliv.|date=2017|volume=14|issue=8|pages=913–925|doi=10.1080/17425247.2017.1343297|pmid=28643528|s2cid=5898576}}{{cite journal|last1=Chen|first1=Y|last2=liu|first2=X|last3=Liu|first3=R|last4=Gong|first4=Y|last5=Wang|first5=M|last6=Huang|first6=Q|last7=Feng|first7=Q|last8=Yu|first8=B|title=Zero-order controlled release of BMP2-derived peptide P24 from the chitosan scaffold by chemical grafting modification technique for promotion of osteogenesis in vitro and enhancement of bone repair in vivo|journal=Theranostics|date=2017|volume=7|issue=5|pages=1072–1087|doi=10.7150/thno.18193|pmid=28435449|pmc=5399577}}{{cite journal|last1=Ning|first1=P|last2=Lü|first2=S|last3=Bai|first3=X|last4=Wu|first4=X|last5=Gao|first5=C|last6=Wen|first6=N|last7=Liu|first7=M|title=High encapsulation and localized delivery of curcumin from an injectable hydrogel|journal=Mater. Sci. Eng. C|date=2018|volume=83|pages=121–129|doi=10.1016/j.msec.2017.11.022|pmid=29208269}}{{cite journal|last1=Arif|first1=M|last2=Dong|first2=QJ|last3=Raja|first3=MA|last4=Zeenat|first4=S|last5=Chi|first5=Z|last6=Liu|first6=CG|title=Development of novel pH-sensitive thiolated chitosan/PMLA nanoparticles for amoxicillin delivery to treat Helicobacter pylori|journal=Mater. Sci. Eng. C|date=2018|volume=83|pages=17–24|doi=10.1016/j.msec.2017.08.038|pmid=29208276}}

Due to the binding of metal ions being essential for various enzymes to maintain their enzymatic activity, thiomers are potent reversible enzyme inhibitors. Many non-invasively administered drugs such as therapeutic peptides or nucleic acids are degraded on the mucosa by membrane bound enzymes, strongly reducing their bioavailability. In case of oral administration, this ‘enzymatic barrier’ is even more pronounced as an additional degradation caused by luminally secreted enzymes takes place. Because of their capability to bind zinc ions via thiol groups, thiomers are potent inhibitors of most membrane bound and secreted zinc-dependent enzymes. Due to this enzyme inhibitory effect, thiolated polymers can significantly improve the bioavailability of non-invasively administered drugs{{cite journal|last1=Valenta|first1=C|last2=Marschütz|first2=M|last3=Egyed|first3=C|last4=Bernkop-Schnürch|first4=A|title=Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH|journal=J. Pharm. Pharmacol.|date=2002|volume=54|issue=5|pages=603–610|doi=10.1211/0022357021778907|pmid=12005354|s2cid=45367274|doi-access=free}}{{cite journal|last1=Bernkop-Schnürch|first1=A|last2=Walker|first2=G|last3=Zarti|first3=H|title=Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase N|journal=J. Pharm. Sci.|date=2001|volume=90|issue=11|pages=1907–1914|doi=10.1002/jps.1140|pmid=11745748}}{{cite journal|last1=Bernkop-schnürch|first1=A|last2=Krauland|first2=AH|last3=Leitner|first3=VM|last4=Palmberger|first4=T|title=Thiomers: potential excipients for non-invasive peptide delivery systems|journal=Eur. J. Pharm. Biopharm.|date=2004|volume=58|issue=2|pages=253–263|doi=10.1016/j.ejpb.2004.03.032|pmid=15296953}}

In vitro, thiomers were shown to have antimicrobial activity towards Gram-positive bacteria.{{cite journal|last1=Fernandes|first1=MM|last2=Francesko|first2=A|last3=Torrent-Burgues|first3=J|last4=Tzanov|first4=T|title=Effect of thiol-functionalisation on chitosan antibacterial activity: Interaction with a bacterial membrane model|journal=React. Funct. Polym.|date=2013|volume=73|issue=10|pages=1384–1390|doi=10.1016/j.reactfunctpolym.2013.01.004|bibcode=2013RFPol..73.1384F |hdl=2117/22395|hdl-access=free}}{{cite journal|last1=Geisberger|first1=G|last2=Gyenge|first2=EB|last3=Hinger|first3=D|last4=Käch|first4=A|last5=Maake|first5=C|last6=Patzke|first6=GR|title=Chitosan-thioglycolic acid as a versatile antimicrobial agent|journal=Biomacromolecules|date=2013|volume=14|issue=4|pages=1010–1017|doi=10.1021/bm3018593|pmid=23470196}} In particular, N-acyl thiolated chitosans show great potential as highly efficient, biocompatible and cost-effective antimicrobial compounds.{{cite journal|last1=Croce|first1=M|last2=Conti|first2=S|last3=Maake|first3=C|last4=Patzke|first4=GR|title=Synthesis and screening of N-acyl thiolated chitosans for antibacterial applications|journal=Carbohydr. Polym.|date=2016|volume=151|pages=1184–1192|doi=10.1016/j.carbpol.2016.06.014|pmid=27474669|doi-access=free}} Metabolism and mechanistic studies are under way to optimize these thiomers for clinical applications. Because of their antimicrobial activity, thiolated polymers are also used as coatings that avoid bacterial adhesion.{{cite journal|last1=Costa|first1=F|last2=Sousa|first2=DM|last3=Parreira|first3=P|last4=Lamghari|first4=M|last5=Gomes|first5=P|last6=Martins|first6=MCL|title=N-acetylcysteine-functionalized coating avoids bacterial adhesion and biofilm formation|journal=Sci. Rep.|date=2017|volume=7|issue=1|pages=17374|doi=10.1038/s41598-017-17310-4|pmid=29234086|pmc=5727138|bibcode=2017NatSR...717374C}}

Thiomers are able to reversibly open tight junctions. The responsible mechanism seems to be based on the inhibition of protein tyrosine phosphatase being involved in the closing process of tight junctions.{{cite journal|last1=Clausen|first1=AE|last2=Kast|first2=CE|last3=Bernkop-Schnürch|first3=A|title=The role of glutathione in the permeation enhancing effect of thiolated polymers|journal=Pharm. Res.|date=2002|volume=19|issue=5|pages=602–608|doi=10.1023/A:1015345827091|pmid=12069161|s2cid=25841768 }} Due to thiolation the permeation enhancing effect of polymers such as polyacrylic acid or chitosan can be up to 10-fold improved.{{cite journal|last1=Bernkop-Schnürch|first1=A|last2=Kast|first2=CE|last3=Guggi|first3=D|title=Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems|journal=J. Control. Release|date=2003|volume=93|issue=2|pages=103–110|doi=10.1016/j.jconrel.2003.05.001|pmid=14636716}}{{cite journal|last1=Langoth|first1=N|last2=Kalbe|first2=J|last3=Bernkop-Schnürch|first3=A|title=Development of a mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary adenylate cyclase-activating polypeptide)|journal=Int. J. Pharm.|date=2005|volume=296|issue=1–2|pages=103–111|doi=10.1016/j.ijpharm.2005.03.007|pmid=15885461}}{{cite journal|last1=Liu|first1=Y|last2=Chiu|first2=GN|title=Dual-functionalized PAMAM dendrimers with improved P-glycoprotein inhibition and tight junction modulating effect|journal=Biomacromolecules|date=2013|volume=14|issue=12|pages=4226–4235|doi=10.1021/bm401057c|pmid=24219381}} In comparison to most low molecular weight permeation enhancers, thiolated polymers offer the advantage of not being absorbed from the mucosal membrane. Hence, their permeation enhancing effect can be maintained for a comparatively longer period of time and systemic toxic side effects of the auxiliary agent can be excluded.

Thiomers are able to reversibly inhibit efflux pumps. Because of this property the mucosal uptake of various efflux pump substrates such as anticancer drugs, antimycotic drugs and antiinflammatory drugs can be tremendously improved.{{cite journal|last1=Werle|first1=M|last2=Hoffer|first2=M|title=Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine|journal=J. Control. Release|date=2006|volume=111|issue=1–2|pages=41–46|doi=10.1016/j.jconrel.2005.11.011|pmid=16377016}}{{cite journal|last1=Föger|first1=F|last2=Hoyer|first2=H|last3=Kafedjiiski|first3=K|last4=Thaurer|first4=M|last5=Bernkop-Schnürch|first5=A|title=In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein|journal=Biomaterials|date=2006|volume=27|issue=34|pages=5855–5860|doi=10.1016/j.biomaterials.2006.08.004|pmid=16919723}}{{cite journal|last1=Madgulkar|first1=AR|last2=Bhalekar|first2=MR|last3=Kadam|first3=AA|title=Improvement of oral bioavailability of lopinavir without co-administration of ritonavir using microspheres of thiolated xyloglucan|journal=AAPS PharmSciTech|date=2017|volume=17|issue=1|pages=293–302|doi=10.1208/s12249-017-0834-x |pmid=28717974|s2cid=31282625 }} The postulated mechanism of efflux pump inhibition is based on an interaction of thiolated polymers with the channel forming transmembrane domain of various efflux pumps such as P-gp and multidrug resistance proteins (MRPs). P-gp, for instance, exhibits 12 transmembrane regions forming a channel through which substrates are transported outside of the cell. Two of these transmembrane domains – namely 2 and 11 – exhibit on position 137 and 956, respectively, a cysteine subunit. Thiomers seem to enter in the channel of P-gp and likely form subsequently one or two disulfide bonds with one or both cysteine subunits located within the channel. Due to this covalent interaction the allosteric change of the transporter being essential to move drugs outside of the cell might be blocked.{{cite journal|last1=Gottesman|first1=MM|last2=Pastan|first2=I|title=The multidrug transporter, a double-edged sword|journal=J. Biol. Chem.|date=1988|volume=263|issue=25|pages=12163–6|doi=10.1016/S0021-9258(18)37730-5 |pmid=2900833|doi-access=free }}{{cite journal|last1=Grabovac|first1=V|last2=Laffleur|first2=F|last3=Bernkop-Schnürch|first3=A|title=Thiomers: Influence of molecular mass and thiol group content of poly(acrylic acid) on efflux pump inhibition|journal=Int. J. Pharm.|date=2015|volume=493|issue=1–2|pages=374–379|doi=10.1016/j.ijpharm.2015.05.079|pmid=26238816}}

Thiomers have the ability to form complexes with different metal ions, especially divalent metal ions, due to their thiol groups. Thiolated chitosans, for instance, were shown to effectively absorb nickel ions.{{cite journal |last1=Federer |first1=C |last2=Kurpiers |first2=M |last3=Bernkop-Schnürch |first3=A |title=Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications |journal=Biomacromolecules |date=2021 |volume=22 |issue=1 |pages=24–56 |doi=10.1021/acs.biomac.0c00663 |pmid=32567846|pmc=7805012 }}{{cite journal |last1=Leichner |first1=C |last2=Jelkmann |first2=M |last3=Bernkop-Schnürch |first3=A |title=Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature |journal=Adv Drug Deliv Rev |date=2019 |volume=151-152 |pages=191–221 |doi=10.1016/j.addr.2019.04.007 |pmid=31028759|s2cid=135464452 }}

As thiolated polymers exhibit biocompatibility, cellular mimicking properties and efficiently support proliferation and differentiation of various cell types, they are used as scaffolds for tissue engineering.{{cite journal|last1=Kast|first1=CE|last2=Fric|first2=W|last3=Losert|first3=U|last4=Bernkop-Schnürch|first4=A|title=Chitosan-thioglycolic acid conjugate: a new scaffold material for tissue engineering?|journal=Int. J. Pharm.|date=2003|volume=256|issue=1–2|pages=183–189|doi=10.1016/S0378-5173(03)00076-0|pmid=12695025}}{{cite journal|last1=Bae|first1=IH|last2=Jeong|first2=BC|last3=Kook|first3=MS|last4=Kim|first4=SH|last5=Koh|first5=JT|title=Evaluation of a thiolated chitosan scaffold for local delivery of BMP-2 for osteogenic differentiation and ectopic bone formation|journal=Biomed Res. Int.|date=2013|volume=2013|pages=878930|doi=10.1155/2013/878930|pmid=24024213|pmc=3760211|doi-access=free }}{{cite journal|last1=Bian|first1=S|last2=He|first2=M|last3=Sui|first3=J|last4=Cai|first4=H|last5=Sun|first5=Y|last6=Liang|first6=J|last7=Fan|first7=Y|last8=Zhang|first8=X|title=The self-crosslinking smart hyaluronic acid hydrogels as injectable three-dimensional scaffolds for cells culture|journal=Colloids Surf. B |date=2016|volume=140|pages=392–402|doi=10.1016/j.colsurfb.2016.01.008|pmid=26780252|doi-access=free}}{{cite journal|last1=Gajendiran|first1=M|last2=Rhee|first2=JS|last3=Kim|first3=K|title=Recent developments in thiolated polymeric hydrogels for tissue engineering applications|journal=Tissue Eng. Part B Rev.|volume=24|issue=1|pages=66–74|date=2017|doi=10.1089/ten.TEB.2016.0442|pmid=28726576}} Furthermore thiolated polymers such as thiolated hyaluronic acid{{cite journal|last1=Bauer|first1=C|last2=Jeyakumar|first2=V|last3=Niculescu-Morzsa|first3=E|last4=Kern|first4=D|last5=Nehrer|first5=S|title=Hyaluronan thiomer gel/matrix mediated healing of articular cartilage defects in New Zealand White rabbits-a pilot study|journal=J. Exp. Orthop.|date=2017|volume=4|issue=1|pages=14|doi=10.1186/s40634-017-0089-1|pmid=28470629|pmc=5415448|doi-access=free}} and thiolated chitosan{{cite journal|last1=Zahir-Jouzdani|first1=F|last2=Mahbod|first2=M|last3=Soleimani|first3=M|last4=Vakhshiteh|first4=F|last5=Arefian|first5=E|last6=Shahosseini|first6=S|last7=Dinarvand|first7=R|last8=Atyabi|first8=F|title=Chitosan and thiolated chitosan: Novel therapeutic approach for preventing corneal haze after chemical injuries|journal=Carbohydr. Polym.|date=2018|volume=179|pages=42–49|doi=10.1016/j.carbpol.2017.09.062|pmid=29111069}} were shown to exhibit wound healing properties.

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Category: Carbohydrate chemistry

Category: Drug delivery devices

Category: Gels

Category: Materials science

Category:Organosulfur compounds

Category: Polymers

Category: Polymer chemistry

Category: Polysaccharides