title: P-glycoprotein inhibitors: synthesis and in vitro evaluation of a preactivated thiomer.
abstract: The aim of this study was to synthesize the preactivated thiomer poly(acrylic acid)-cyteine-2-mercaptonicotinic acid (PAA-Cys-2MNA) and to evaluate its P-glycoprotein (P-gp) inhibitory properties. The thiomer (PAA-Cys) was synthesized by covalent immobilization of thiol groups on poly(acrylic acid) (PAA) with a molecular mass of 250 kDa followed by immobilization of 2-mercaptonicotinic acid (2MNA) to thiol groups via disulfide bond formation resulting in PAA-Cys-2MNA. P-gp inhibitory effect of this preactivated thiomer was evaluated on Caco-2 cells. Transports of rhodamine 123 at 37 °C with and without verapamil and at 4 °C were performed to evaluate P-gp function of cells. In total, 1571.81 ± 156.18 µmol thiol groups were immobilized per gram of polymer that were in the next step by 99.88% preactivated. The enhancement ratios of Pappcalculated from the ratio between Pappof rhodamine 123 in the presence of P-gp inhibitors and Pappof rhodamine 123 alone were 2.36, 2.09, and 1.84-fold in the presence of PAA-Cys-2MNA, PAA-Cys, and PAA, respectively. Because of its pronounced P-gp inhibitory effect, PAA-Cys-2MNA could be considered as promising macromolecular P-gp inhibitor for various drug delivery systems.
authors.affiliation: a Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Kesinee
authors.initials: K
authors.lastname: Netsomboon
authors.affiliation: a Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: a Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: A
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000180:Acrylic Resins / Q000138:chemical synthesis* / Q000494:pharmacology*; D018938:Caco-2 Cells; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000180:Acrylic Resins; D009539:Nicotinic Acids; D013438:Sulfhydryl Compounds; D020112:Rhodamine 123; C006903:carbopol 940; D014700:Verapamil; C083470:2-mercaptonicotinic acid
keywords: Caco-2 cell; efflux; poly(acrylic acid); rhodamine 123; transport