title: Synthesis and characterization of pH tolerant and mucoadhesive (thiol-polyethylene glycol) chitosan graft polymer for drug delivery.
abstract: The objective of this study was to generate a water-soluble thiolated chitosan to enable the permeation-enhancing effect of chitosan at pH of at least 5.5 without losing the advantages of improved mucoadhesive properties. Therefore, the thiol-bearing polyoxyethylene ligand {O-(3-carboxylpropyl)-O'-[2-[3-mercaptopropionylamino)ethyl]-polyethyleneglycol} was conjugated via amide bond formation to the amino group of chitosan. Resulting novel chitosan derivative (Chito-PEG-SH) exhibited 250 μmol free thiol groups per gram polymer. By the attachment of the thiol-bearing PEG ligand, an improvement of permeation-enhancing effect on rat intestine (2.7-fold improvement) as well as on a Caco-2 monolayer model (1.9-fold improvement) could be found. Cytotoxicity studies on Caco-2 cells revealed no change in biocompatibility. Mucoadhesion was improved 3.1-fold by the formation of disulfide bonds with mucus glycoproteins. The mucoadhesive effect of Chito-PEG-SH turned out to be similar to thiolated chitosan and more pronounced than mucoadhesive properties of unmodified chitosan. The graft polymer is soluble in water and aqueous solutions over a broad pH range. In aqueous media, the novel polymer does not precipitate at pH of 8.6 or less. According to these results, Chito-PEG-SH might show potential as auxiliary agent in oral drug delivery where its solubility even up to pH 8 is likely beneficial.
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Biosciences, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, 6020, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauptstein
authors.forename: Sonja
authors.initials: S
authors.lastname: Bonengel
authors.forename: Julia
authors.initials: J
authors.lastname: Griessinger
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000465:Algorithms; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D010078:Oxazines; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine; D013718:Tensile Strength; D013864:Thioglycolates / Q000737:chemistry; D014014:Tissue Adhesives; D014783:Viscosity; D014966:Xanthenes
chemical_list: D007202:Indicators and Reagents; D010078:Oxazines; D013438:Sulfhydryl Compounds; D013864:Thioglycolates; D014014:Tissue Adhesives; D014966:Xanthenes; C005843:resazurin; D011092:Polyethylene Glycols; C017487:2-mercaptoacetate; D048271:Chitosan
keywords: formulation vehicle; mucoadhesion; mucosal drug delivery; pegylation; polymeric drug carrier; thiomers; toxicity; water soluble chitosan