title: Thiolated graphene oxide as promising mucoadhesive carrier for hydrophobic drugs.
abstract: The aim of this study was to improve the mucoadhesive properties of graphene by conjugating thiol ligands, in order to formulate an oral delivery system for hydrophobic drugs showing long mucus residence time. Graphene oxide was obtained by oxidation of graphite and then was thiolated following two synthetic paths. On the one hand, the hydroxyl groups were conjugated with thiourea passing through the formation of a brominated intermediate. On the other hand, the carboxylic acid groups were conjugated with cysteamine via carbodiimide chemistry. The mucoadhesive properties of thiolated graphene were evaluated by rheological measurements and by residence time assay. Then, valsartan was loaded on thiolated graphene and the release profile was evaluated in simulated intestinal fluid. Following both synthetic paths it was possible to obtain thiolated graphene bearing 215-302μmol SH/g product. Both products induced after 1h incubation an increase of mucus viscosity of about 22-33-fold compared to unmodified graphite. The residence time assay confirmed that 60% of thiolated graphene could be retained on intestinal mucosa after 4h incubation, whereas just 20% of unmodified graphite could be retained. Valsartan could be loaded with a drug loading of about 31±0.3% and a sustained release profile was observed for both formulations. According to the presented data, the thiolation of graphene could improve its mucoadhesive properties. Therefore, thiolated graphene represents a promising platform for oral delivery of hydrophobic drugs, possessing a long residence time on intestinal mucosa which allows the release of the loaded drug close to the adsorptive epithelium.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Pereira de Sousa
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Buttenhauser
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Wongsakorn
authors.initials: W
authors.lastname: Suchaoin
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Partenhauser
authors.affiliation: Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", Orabona st. 4, 70125 Bari, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Perrone
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Matuszczak
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: Andreas.Bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000269:Adhesives / Q000737:chemistry*; D000818:Animals; D002234:Carbodiimides / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003543:Cysteamine / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D006108:Graphite / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D010087:Oxides / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D012212:Rheology; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine; D014783:Viscosity
chemical_list: D000269:Adhesives; D002234:Carbodiimides; D002264:Carboxylic Acids; D004337:Drug Carriers; D010087:Oxides; D004364:Pharmaceutical Preparations; D011108:Polymers; D013438:Sulfhydryl Compounds; D003543:Cysteamine; D006108:Graphite
keywords: Biological barrier; Graphene; Graphene oxide; Mucoadhesion; Thiolation; Valsartan