Thiomer: Difference between revisions

[[File:Chemical structures|thumb|]] Thiolated [[polymer]]s {{ndash}} designated '''thiomers''' {{ndash}} are functional [[polymer]]s used in [[biotechnology]] product development with the intention to prolong mucosal drug residence time and to enhance absorption of [[drug]]s. The name thiomer was coined by [[Andreas Bernkop-Schnürch]] in 2000.<ref>{{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}}</ref> Thiomers have [[thiol]] bearing [[side chain]]s.<ref>{{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=11|pages=876–881|pmid=16176846|doi=10.1016/j.addr.2005.07.002}}</ref><ref>{{cite journal|last1=Bernkop-Schnürch|first1=Andreas|last2=Steininger|first2=Sonja|title=Synthesis and characterisation of mucoadhesive thiolated polymers|journal=Int. J. Pharm.|date=2000|volume=194|issue=2|pages=239–247|pmid=10692648|doi=10.1016/S0378-5173(99)00387-7}}</ref> Sulfhydryl ligands of low molecular mass are [[covalent]]ly bound to a polymeric backbone consisting of mainly [[biodegradable]] polymers, such as [[chitosan]],<ref>{{cite journal|last1= Bernkop-Schnürch|first1=A|last2=Hornof|first2=M|last3=Guggi|first3=D|title=Thiolated chitosans|journal=Eur. J. Pharm. Biopharm.|date=2004|volume=57|issue=1|pages=9–17|pmid=14729077|doi=10.1016/S0939-6411(03)00147-4}}</ref><ref>{{cite journal |last1=Zhang |first1=Z |last2=Lin |first2=S |last3=Yan |first3=Y |last4=You |first4=X |last5=Ye |first5=H |title=Enhanced efficacy of transforming growth factor-β1 loaded an injectable cross-linked thiolated chitosan and carboxymethyl cellulose-based hydrogels for cartilage tissue engineering |journal=J Biomater Sci Polym Ed.ed |date=2021 |volume=32 |issue=18 |pages=2402–2422 |doi=10.1080/09205063.2021.1971823 |pmid=34428384|s2cid=237290902 }}</ref> [[hyaluronic acid]],<ref>{{cite journal|last1=Zheng Shu|first1=X|last2=Liu|first2=Y|last3=Palumbo|first3=FS|last4=Luo|first4=Y| last5=Prestwich|first5=GD|title=In situ crosslinkable hyaluronan hydrogels for tissue engineering |journal=Biomaterials|date=2004|volume=7–8|issue=7–8|pages=1339–1348|pmid=14643608|doi=10.1016/j.biomaterials.2003.08.014}}</ref> [[cellulose]] derivatives,<ref>{{cite journal |last1=Laffleur |first1=F |last2=Bacher |first2=L |last3=Vanicek |first3=S |last4=Menzel |first4=C |last5=Muhammad |first5=I |title=Next generation of buccadhesive excipient: Preactivated carboxymethyl cellulose |journal=Int J Pharm |date=2016 |volume=500 |issue=1–2 |pages=120–127 |doi=10.1016/j.ijpharm.2016.01.012 |pmid=26773600}}</ref> [[pullulan]],<ref>{{cite journal |last1=Leonaviciute |first1=G |last2=Suchaoin |first2=W |last3=Matuszczak |first3=B |last4=Lam |first4=HT |last5=Mahmood |first5=A |last6=Bernkop-Schnürch |first6=A |title=Preactivated thiolated pullulan as a versatile excipient for mucosal drug targeting |journal=Carbohydr Polym |date=2016 |volume=151 |pages=743–751 |doi=10.1016/j.carbpol.2016.06.005 |pmid=27474621}}</ref><ref>{{cite journal |last1=Priya |first1=SS |last2=Rekha |first2=MR |title=Disulphide cross linked pullulan based cationic polymer for improved gene delivery and efflux pump inhibition |journal=Colloids Surf B Biointerfaces |date=2016 |volume=146 |pages=879–887 |doi=10.1016/j.colsurfb.2016.07.013 |pmid=27459414}}</ref> [[starch]],<ref>{{cite journal |last1=Jelkmann |first1=M |last2=Bonengel |first2=S |last3=Menzel |first3=C |last4=Markovic |first4=S |last5=Bernkop-Schnürch |first5=A |title=New perspectives of starch: Synthesis and in vitro assessment of novel thiolated mucoadhesive derivatives |journal=Int J Pharm |date=2018 |volume=546 |issue=1–2 |pages=70–77 |doi=10.1016/j.ijpharm.2018.05.028 |pmid=29758345|s2cid=44071363 }}</ref> [[gelatin]],<ref>{{cite journal|last1= Duggan |first1=S|last2= O'Donovan |first2=O|last3= Owens|first3=E|last4=Cummins|first4=W|last5=Hughes|first5=H|title=Synthesis of mucoadhesive thiolated gelatin using a two-step reaction process|journal=Eur. J. Pharm. Biopharm.|date=2015|volume=91|pages=75–81|doi=10.1016/j.ejpb.2015.01.027|pmid=25661588}}</ref> [[polyacrylates]],<ref>{{cite journal|last1=Hornof|first1=M|last2=Weyenberg|first2=W|last3=Ludwig|first3=A|last4=Bernkop-Schnürch|first4=A|title=Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans|journal=J. Control. Release|date=2003|volume=89|issue=3|pages=419–428|pmid=12737844|doi=10.1016/S0168-3659(03)00135-4}}</ref> [[cyclodextrins]],<ref>{{cite journal|last1=Ijaz|first1=M|last2=Ahmad|first2=M|last3=Akhtar|first3=N|last4=Laffleur|first4=F|last5=Bernkop-Schnürch|first5=A|title=Thiolated α-cyclodextrin: the invisible choice to prolong ocular drug residence time|journal=J. Pharm. Sci.|date=2016|volume=105|issue=9|pages=2848–2854|doi=10.1016/j.xphs.2016.04.021|pmid=27233687|doi-access=free}}</ref><ref>{{cite journal|last1=Ijaz|first1=M|last2=Prantl|first2=M|last3=Lupo|first3=N|last4=Laffleur|first4=F|last5=Hussain Asim|first5=M|last6=Matuszczak|first6=B|last7=Bernkop-Schnürch|first7=A|title=Development of pre-activated α-cyclodextrin as a mucoadhesive excipient for intra-vesical drug delivery|journal=Int. J. Pharm.|date=2017|volume=534|issue=1–2|pages=339–347|doi=10.1016/j.ijpharm.2017.10.054|pmid=29111098}}</ref> or [[silicones]].<ref>{{cite journal|last1=Partenhauser|first1=A|last2=Laffleur|first2=F|last3=Rohrer|first3=J|last4=Bernkop-Schnürch|first4=A|title=Thiolated silicone oil: synthesis, gelling and mucoadhesive properties|journal=[[Acta Biomater.]]|date=2015|volume=16|pages=169–177|doi=10.1016/j.actbio.2015.01.020|pmid=25660565|pmc=4362771}}</ref>

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.<ref>{{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}}</ref> 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.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref>

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<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref>

[[In vitro]], thiomers were shown to have antimicrobial activity towards Gram-positive bacteria.<ref>{{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}}</ref><ref>{{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}}</ref> In particular, N-acyl thiolated chitosans show great potential as highly efficient, biocompatible and cost-effective antimicrobial compounds.<ref>{{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}}</ref> 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.<ref>{{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}}</ref>

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.<ref>{{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 }}</ref> Due to thiolation the permeation enhancing effect of polymers such as [[polyacrylic acid]] or chitosan can be up to 10-fold improved.<ref>{{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}}</ref><ref>{{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}}</ref><ref>{{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}}</ref> 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.

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.<ref>{{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}}</ref><ref>{{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 }}</ref><ref>{{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 Biointerfaces|date=2016|volume=140|pages=392–402|doi=10.1016/j.colsurfb.2016.01.008|pmid=26780252|doi-access=free}}</ref><ref>{{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}}</ref> Furthermore thiolated polymers such as thiolated hyaluronic acid<ref>{{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}}</ref> and thiolated chitosan<ref>{{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}}</ref> were shown to exhibit wound healing properties.