N-Deoxycholic acid-N,O-hydroxyethyl Chitosan with a Sulfhydryl Modification To Enhance the Oral Absorptive Efficiency of Paclitaxel.

Abstract:

:Currently, the most prominent barrier to the success of orally delivered paclitaxel (PTX) is the extremely limited bioavailability of delivered therapeutic. In light of this issue, an amphiphilic sulfhydrylated N-deoxycholic acid-N,O-hydroxyethyl chitosan (TGA-DHC) was synthesized to improve the oral bioavailability of PTX. First, TGA-DHC demonstrated substantial loading of PTX into the inner hydrophobic core. A desirable enhancement in the bioavailability of PTX by TGA-DHC was verified by pharmacokinetic studies on rats against Taxol and non-sulfhydrylated DHC micelles. Moreover, cellular uptake studies revealed significant accumulation of TGA-DHC micelles encapsulating PTX or rhodamine-123 into Caco-2 cells via clathrin/caveolae-mediated endocytosis and inhibition of P-gp efflux of substrates. The results of the Caco-2 transport study further confirmed the mechanistic basis of TGA-DHC efficacy; which was attributed to permeabilized tight junctions, clathrin-mediated transcytosis across the endothelium, and inhibition of P-gp. Finally, in vitro mucoadhesion investigations on freshly excised rat intestine intuitively confirmed increased intestinal retention of drug-loaded TGA-DHC through thiol-mediated mucoadhesion. TGA-DHC has demonstrated the capability to overcome what is perhaps the most prominent barrier to oral PTX efficacy, low bioavailability, and serves as a prominent platform for oral delivery of P-gp substrates.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Yu Y,Huo M,Fu Y,Xu W,Cai H,Yao L,Chen Q,Mu Y,Zhou J,Yin T

doi

10.1021/acs.molpharmaceut.7b00662

subject

Has Abstract

pub_date

2017-12-04 00:00:00

pages

4539-4550

issue

12

eissn

1543-8384

issn

1543-8392

journal_volume

14

pub_type

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