{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:17:21Z","timestamp":1790417841807,"version":"4.1.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T00:00:00Z","timestamp":1580947200000},"content-version":"vor","delay-in-days":10,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccby_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100005203","name":"OeAD-GmbH","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100005203","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010221","name":"Higher Education Commision, Pakistan","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100010221","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The purpose of the study was to develop a per-6-thiolated \u03b1-cyclodextrin (\u03b1-CD) by substituting all primary hydroxyl groups of \u03b1-CD with thiol groups and to assess its solubility-improving and permeation-enhancing properties for a BCS Class IV drug in vitro as well as in vivo. The primary hydroxyl groups of \u03b1-CD were replaced by iodine, followed by substitution with \u2212SH groups. The structure of per-6-thiolated \u03b1-CD was approved by FT-IR and 1H NMR spectroscopy. The per-6-thiolated was characterized for thiol content, \u2212SH stability, cytotoxicity, and solubility-improving properties by using the model BCS Class IV drug furosemide (FUR). The mucoadhesive properties of the thiolated oligomer were investigated via viscoelastic measurements with porcine mucus, whereas permeation-enhancing features were evaluated on the Caco-2 cell monolayer and rat gut mucosa. Furthermore, oral bioavailability studies were performed in rats. The per-6-thiolated \u03b1-CD oligomer displayed 4244 \u00b1 402 \u03bcmol\/g thiol groups. These \u2212SH groups were stable at pH \u2264 4, exhibiting a pKa value of 8.1, but subject to oxidation at higher pH. Per-6-thiolated \u03b1-CD was not cytotoxic to Caco-2 cells in 0.5% (m\/v) concentration within 24 h. It improved the solubility of FUR in the same manner as unmodified \u03b1-CD. The addition of per-6-thiolated \u03b1-CD (0.5% m\/v) increased the mucus viscosity up to 5.8-fold at 37 \u00b0C within 4 h. Because of the incorporation in per-6-thiolated \u03b1-CD, the apparent permeability coefficient (Papp) of FUR was 6.87-fold improved on the Caco-2 cell monolayer and 6.55-fold on the intestinal mucosa. Moreover, in vivo studies showed a 4.9-fold improved oral bioavailability of FUR due to the incorporation in per-6-thiolated \u03b1-CD. These results indicate that per-6-thiolated \u03b1-CD would be a promising auxiliary agent for the mucosal delivery of, in particular, BCS Class IV drugs.<\/jats:p>","DOI":"10.1021\/acsami.9b21335","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T11:27:57Z","timestamp":1580124477000},"page":"7942-7950","source":"Crossref","is-referenced-by-count":43,"title":["Per-6-Thiolated Cyclodextrins: A Novel Type of Permeation\nEnhancing Excipients for BCS Class IV Drugs"],"prefix":"10.1021","volume":"12","author":[{"given":"Mulazim Hussain","family":"Asim","sequence":"first","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.184, ,","place":["Innsbruck, Austria, 6020"]},{"name":"University of Sargodha , , , ,","place":["Sargodha, Punjab, Pakistan, 40100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran","family":"Nazir","sequence":"additional","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.184, ,","place":["Innsbruck, Austria, 6020"]},{"name":"COMSATS University Islamabad , , Abbottabad Campus , , ,","place":["Abbottabad, Khyber Pakhtunkhwa, Pakistan, 22060"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aamir","family":"Jalil","sequence":"additional","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.184, ,","place":["Innsbruck, Austria, 6020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-6741","authenticated-orcid":true,"given":"Flavia","family":"Laffleur","sequence":"additional","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.184, ,","place":["Innsbruck, Austria, 6020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-8739","authenticated-orcid":true,"given":"Barbara","family":"Matuszczak","sequence":"additional","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.132, ,","place":["Innsbruck, Austria, 6020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4187-8277","authenticated-orcid":true,"given":"Andreas","family":"Bernkop-Schnu\u0308rch","sequence":"additional","affiliation":[{"name":"University of Innsbruck , , Innrain 80 , L.04.184, ,","place":["Innsbruck, Austria, 6020"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,1,27]]},"reference":[{"key":"2026090117063764000_cit1","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ijpharm.2012.08.045","article-title":"Preactivated Thiomers: Permeation\nEnhancing Properties","volume":"438","author":"Wang","year":"2012","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit2","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jsps.2018.09.002","article-title":"Vitro Dissolution and Bioavailability\nStudy of Furosemide Nanosuspension Prepared Using Design of Experiment\n(DoE)","volume":"27","author":"Shariare","year":"2019","journal-title":"Saudi Pharm. J."},{"key":"2026090117063764000_cit3","first-page":"220","article-title":"Flutamide-Hydroxypropyl-\u00df-Cyclodextrin\nComplex: Formulation, Physical Characterization, and Absorption Studies\nUsing the Caco-2 In Vitro Model","volume":"3","author":"Zuo","year":"2000","journal-title":"J. Pharm. Pharm.\nSci."},{"key":"2026090117063764000_cit4","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1023\/a:1023088423667","article-title":"Cyclodextrins and the Biopharmaceutics\nClassification System of Drugs","volume":"44","author":"Loftsson","year":"2002","journal-title":"J. Inclusion\nPhenom. Macrocyclic Chem."},{"key":"2026090117063764000_cit5","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/s0168-3659(98)00182-5","article-title":"Cyclodextrins as Permeation Enhancers: Some Theoretical\nEvaluations and In Vitro Testing","volume":"59","author":"Ma\u0301sson","year":"1999","journal-title":"J. Controlled\nRelease"},{"key":"2026090117063764000_cit6","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1517\/17425247.2011.572069","article-title":"Cyclodextrin-poly\n(anhydride) Nanoparticles as New Vehicles for Oral Drug Delivery","volume":"8","author":"Agu\u0308eros","year":"2011","journal-title":"Expert Opin. Drug Delivery"},{"key":"2026090117063764000_cit7","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.jcis.2018.07.062","article-title":"S-protected\nThiolated Cyclodextrins as Mucoadhesive Oligomers for Drug Delivery","volume":"531","author":"Asim","year":"2018","journal-title":"J. Colloid Interface Sci."},{"key":"2026090117063764000_cit8","doi-asserted-by":"publisher","first-page":"4003","DOI":"10.2147\/ijn.s153226","article-title":"Non-Ionic\nThiolated Cyclodextrins-the Next Generation","volume":"13","author":"Moghadam","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"2026090117063764000_cit9","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.ijpharm.2017.10.054","article-title":"Development of Pre-Activated \u03b1-Cyclodextrin\nas a Mucoadhesive Excipient for Intra-Vesical Drug Delivery","volume":"534","author":"Ijaz","year":"2017","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit10","doi-asserted-by":"publisher","first-page":"2848","DOI":"10.1016\/j.xphs.2016.04.021","article-title":"Thiolated \u03b1-Cyclodextrin:\nThe Invisible Choice to Prolong Ocular Drug Residence Time","volume":"105","author":"Ijaz","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"2026090117063764000_cit11","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.ijpharm.2015.10.013","article-title":"An In-Vitro Exploration of Permeation\nEnhancement by Novel Polysulfonate Thiomers","volume":"496","author":"Mahmood","year":"2015","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit12","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3390\/pharmaceutics11120638","article-title":"Validation of an Ex Vivo Permeation Method For the\nIntestinal Permeability of Different BCS Drugs and Its Correlation\nwith Caco-2 In Vitro Experiments","volume":"11","author":"Sa\u0301nchez","year":"2019","journal-title":"Pharmaceutics"},{"key":"2026090117063764000_cit13","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1007\/s12272-011-1120-1","article-title":"The effects\nof PLGA Microparticles on Intestinal Absorption of p-Glycoprotein\nSubstrate Using the Everted Rat Intestinal Sac Model","volume":"34","author":"Derakhshandeh","year":"2011","journal-title":"Arch. Pharmacal Res."},{"key":"2026090117063764000_cit14","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1002\/anie.199100781","article-title":"Selective Halogenation at Primary Positions of Cyclomaltooligosaccharides\nand a Synthesis of Per-3, 6-Anhydro Cyclomaltooligosaccharides","volume":"30","author":"Gadelle","year":"1991","journal-title":"Angew. Chem."},{"key":"2026090117063764000_cit15","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1021\/ja00106a036","article-title":"Supported Monolayers Containing Preformed Binding sites.\nSynthesis and Interfacial Binding Properties of a Thiolated. Beta.-Cyclodextrin\nDerivative","volume":"117","author":"Rojas","year":"1995","journal-title":"J. Am. Chem. Soc."},{"key":"2026090117063764000_cit16","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.ijbiomac.2019.02.092","article-title":"S-protected\nGellan Gum: Decisive Approach Towards Mucoadhesive Antimicrobial Vaginal\nFilms","volume":"130","author":"Jalil","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"2026090117063764000_cit17","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1021\/bm025603c","article-title":"Disulfide Cross-Linked Hyaluronan\nHydrogels","volume":"3","author":"Shu","year":"2002","journal-title":"Biomacromolecules"},{"key":"2026090117063764000_cit18","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/s0378-5173(03)00271-0","article-title":"Thiolated Polymers\u2500Thiomers:\nSynthesis and In Vitro Evaluation of Chitosan\u20132-Iminothiolane\nConjugates","volume":"260","author":"Bernkop-Schnu\u0308rch","year":"2003","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit19","first-page":"117","article-title":"A phase Solubility Technique","volume":"4","author":"Higuchi","year":"1965","journal-title":"Adv. Anal. Chem. Instrum."},{"key":"2026090117063764000_cit20","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1007\/s11051-014-2360-z","article-title":"Formulation, Optimization, and In Vitro\/In Vivo Evaluation\nof Furosemide Nanosuspension for Enhancement of its Oral Bioavailability","volume":"16","author":"Sahu","year":"2014","journal-title":"J. Nanopart. Res."},{"key":"2026090117063764000_cit21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1177\/0885328203017003557","article-title":"Preparation\nand Characterization of the Inclusion Complex of Furosemide with Hydroxypropyl-\u03b2-Cyclodextrin","volume":"17","author":"Vlachou","year":"2003","journal-title":"J. Biomater. Appl."},{"key":"2026090117063764000_cit22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.ijpharm.2015.11.037","article-title":"Preactivated\nThiolated Nanoparticles: A Novel Mucoadhesive Dosage Form","volume":"497","author":"Menzel","year":"2016","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit23","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1038\/nprot.2007.303","article-title":"Determination of Drug Permeability and Prediction of\nDrug Absorption in Caco-2 Monolayers","volume":"2","author":"Hubatsch","year":"2007","journal-title":"Nat. Protoc."},{"key":"2026090117063764000_cit24","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.jconrel.2012.12.001","article-title":"Thiomer-Coated Liposomes\nHarbor Permeation Enhancing and Efflux Pump Inhibitory Properties","volume":"165","author":"Gradauer","year":"2013","journal-title":"J. Controlled Release"},{"key":"2026090117063764000_cit25","unstructured":"Trinh, A.\n          \n          A Case Study in Method Development for the Extraction and Analysis\nof Lasix (Furosemide) from Horse Serum; Sigma-Aldrich\nCo. LLC, 2013."},{"key":"2026090117063764000_cit26","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.1002\/hlca.19780610622","article-title":"Cyclodextrin Chemistry. Selective\nModification of all Primary Hydroxyl Groups of \u03b1-and \u03b2-Cyclodextrins","volume":"61","author":"Boger","year":"1978","journal-title":"Helv. Chim. Acta"},{"key":"2026090117063764000_cit27","doi-asserted-by":"publisher","first-page":"5001","DOI":"10.1016\/s0040-4039(01)85153-4","article-title":"Sels d\u2019alkyloxyphosphonium\nIII-Activation Selective de l\u2019hydroxyle Primaire du methyl,\n\u03b1-D-glucopyrannoside","volume":"13","author":"Castro","year":"1972","journal-title":"Tetrahedron Lett."},{"key":"2026090117063764000_cit28","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1021\/cr970012b","article-title":"Methods for Selective Modifications of Cyclodextrins","volume":"98","author":"Khan","year":"1998","journal-title":"Chem. Rev."},{"key":"2026090117063764000_cit29","doi-asserted-by":"publisher","first-page":"411","DOI":"10.2217\/fmb-2018-0288","article-title":"Mucoadhesive\nS-protected Thiolated Cyclodextrin-Iodine Complexes: A promising Strategy\nto Prolong Mucosal Residence Time of Iodine","volume":"14","author":"Asim","year":"2019","journal-title":"Future Microbiol."},{"key":"2026090117063764000_cit30","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1007\/s10856-013-4901-x","article-title":"Synthesis of a Disulfide Cross-Linked Polygalacturonic\nacid Hydrogel for Biomedical Applications","volume":"24","author":"Peng","year":"2013","journal-title":"J.\nMater. Sci.: Mater. Med."},{"key":"2026090117063764000_cit31","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1016\/j.addr.2005.07.002","article-title":"Thiomers:\nA New Generation of Mucoadhesive Polymers","volume":"57","author":"Bernkopschnurch","year":"2005","journal-title":"Adv.\nDrug Delivery Rev."},{"key":"2026090117063764000_cit32","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.ejpb.2017.06.011","article-title":"Preactivated Thiolated Glycogen as\nMucoadhesive Polymer for Drug Delivery","volume":"119","author":"Perrone","year":"2017","journal-title":"Eur.\nJ. Pharm. Biopharm."},{"key":"2026090117063764000_cit33","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1111\/j.2042-7158.1994.tb03746.x","article-title":"Factors Influencing\nGel-Strengthening at the Mucoadhesive-mucus Interface","volume":"46","author":"Mortazavi","year":"1994","journal-title":"J. Pharm. Pharmacol."},{"key":"2026090117063764000_cit34","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1023\/a:1015345827091","article-title":"The Role of\nGlutathione in the Permeation Enhancing Effect of Thiolated Polymers","volume":"19","author":"Clausen","year":"2002","journal-title":"Pharm. Res."},{"key":"2026090117063764000_cit35","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/s0171-9335(98)80020-4","article-title":"Increased Tyrosine Phosphorylation Causes Redistribution\nof Adherens Junction and Tight Junction Proteins and Perturbs Paracellular\nBarrier Function in MDCK Epithelia","volume":"76","author":"Collares-Buzato","year":"1998","journal-title":"Eur. J.\nCell Biol."},{"key":"2026090117063764000_cit36","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1242\/jcs.108.2.609","article-title":"Evidence that Tyrosine Phosphorylation\nMay Increase Tight Junction Permeability","volume":"108","author":"Staddon","year":"1995","journal-title":"J.\nCell Sci."},{"key":"2026090117063764000_cit37","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.ejpb.2018.10.014","article-title":"The Function and Mechanism\nof Preactivated Thiomers in Triggering Epithelial Tight Junctions\nOpening","volume":"133","author":"Zhang","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"2026090117063764000_cit38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101414","article-title":"Enhancing\nEffect of Borneol and Muscone on Geniposide Transport Across the Human\nNasal Epithelial Cell Monolayer","volume":"9","author":"Chen","year":"2014","journal-title":"PLoS One"},{"key":"2026090117063764000_cit39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079954","article-title":"The Reversible Increase in Tight\nJunction Permeability Induced by Capsaicin is Mediated Via Cofilin-Actin\nCytoskeletal Dynamics and Decreased Level of Occludin","volume":"8","author":"Shiobara","year":"2013","journal-title":"PLoS One"},{"key":"2026090117063764000_cit40","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ejpb.2015.11.019","article-title":"Novel In Vitro Transport Method for\nScreening the Reversibility of P-glycoprotein Inhibitors","volume":"100","author":"Netsomboon","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"2026090117063764000_cit41","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1023\/a:1016065715308","article-title":"Comparison\nBetween Permeability Coefficients in Rat and Human Jejunum","volume":"13","author":"Fagerholm","year":"1996","journal-title":"Pharm. Res."},{"key":"2026090117063764000_cit42","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.ijpharm.2017.04.072","article-title":"Mucopenetrating Nanoparticles for Enhancement of Oral\nBioavailability of Furosemide: In Vitro and In Vivo Evaluation\/Sub-acute\nToxicity Study","volume":"526","author":"Radwan","year":"2017","journal-title":"Int. J. Pharm."},{"key":"2026090117063764000_cit43","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/j.2042-7158.1998.tb06171.x","article-title":"Evaluation of Oral Mucoadhesive Microspheres in Man on the Basis\nof the Pharmacokinetics of Furosemide and Riboflavin, Compounds with\nLimited Gastrointestinal Absorption Sites","volume":"50","author":"Akiyama","year":"1998","journal-title":"J.\nPharm. Pharmacol."}],"container-title":["ACS Applied Materials &amp; Interfaces"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsami.9b21335","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aamick\/article-pdf\/12\/7\/7942\/67524263\/acsami.9b21335.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aamick\/article-pdf\/12\/7\/7942\/67524263\/acsami.9b21335.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:06:44Z","timestamp":1788296804000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aamick\/article\/12\/7\/7942\/583223\/Per-6-Thiolated-Cyclodextrins-A-Novel-Type-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,27]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,1,27]]},"published-print":{"date-parts":[[2020,2,19]]}},"URL":"https:\/\/doi.org\/10.1021\/acsami.9b21335","relation":{},"ISSN":["1944-8244","1944-8252"],"issn-type":[{"value":"1944-8244","type":"print"},{"value":"1944-8252","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,27]]}}}