N-mercapto acetyl-N′-octyl-O, N″-glycol chitosan as an efficiency oral delivery system of paclitaxel. (1st February 2018)

• Record Type: Journal Article
• Authors: Huo, Meirong; Fu, Ying; Liu, Yanhong; Chen, Qinyu; Mu, Yan; Zhou, Jianping; Li, Lingchao; Xu, Wei; Yin, Tingjie
• Is Part Of: Carbohydrate polymers. Volume 181(2018)
• Page Start: 477
• Page End: 488
• Publication Date: 2018-02-01
• Subjects: Paclitaxel -- N-mercapto acetyl-N′-octyl-O, N″-glycol chitosan -- Oral delivery -- Mucoadhesion -- Micelles -- P-glycoprotein; Polysaccharides -- Periodicals; Polysaccharides -- Periodicals; Polysaccharides -- Périodiques; Electronic journals; 547.78
• DOI: 10.1016/j.carbpol.2017.10.066
• Languages: English
• ISSNs: 0144-8617

Abstract

Highlights: N-mercapto acetyl-N′-octyl-O, N″-glycol Chitosan (SH-OGC) was synthesized. SH-OGC exhibited thiol-mediated mucoadhesion and P-glycoprotein inhibition, also played a role in tight junctions opening. Endocytosis of SH-OGC-PTX into Caco-2 cells was mediated by caveola while its endothelium transcytosis was mediated by clathrin. SH-OGC significantly enhanced oral bioavailability of hydrophobic P-gp substrates including PTX. Abstract: Herein, thioglycolic acid modified N-octyl-O, N′-glycol chitosan (N-mercapto acetyl-N′-octyl-O, N″-glycol chitosan, abbreviated as SH-OGC) was synthesized to improve the oral bioavailability of paclitaxel (PTX). PTX was readily solubilized into the hydrophobic inner core of SH-OGC. Pharmacokinetic studies demonstrated that the bioavailability of PTX was greatly enhanced when delivered by SH-OGC compared to Taxol ® or non-sulfhydrylated OGC micelles. Caco-2 cell experiments confirmed PTX or rhodamine-123-loaded SH-OGC demonstrated effective cellular accumulation via caveola-mediated endocytosis along with the inhibition of P-gp efflux. Furthermore, Caco-2 transport studies demonstrated that the mechanistic basis of SH-OGC efficacy was attributed to P-gp inhibition, enhanced permeability of tight junctions and clathrin-mediated transcytosis across the endothelium. In addition, SH-OGC exhibited increased intestinal retention through thiol-mediated mucoadhesion compared with OGC according to results of mucoadhesion evaluation on freshly excised rat intestine. In summary, SH-OGC micelles may present as a promising delivery vehicle for enhancing the oral bioavailability of P-gp substrates.