Self-assembled micelles based on N-octyl-N'-phthalyl-O-phosphoryl chitosan derivative as an effective oral carrier of paclitaxel.

Herein, we describe a novel amphipathic chitosan derivative (N-octyl-N'-phthalyl-O-phosphoryl chitosan, abbreviated as OPPC) as an effective oral delivery platform for P-gp substrates, especially paclitaxel (PTX). OPPC could readily self-assemble into micelles, solubilize and encapsulate PTX into the hydrophobic inner core of OPPC with superior loading capacity to chitosan. PTX/OPPC micelles possessed improved intestinal epithelial permeability and oral bioavailability of PTX evaluated by in situ perfusion and pharmacokinetic studies. In vivo fluorescence imaging revealed enhanced stability and integrity of OPPC micelles in mice gastrointestine. Furthermore, cellular uptake studies revealed effective transport and accumulation of OPPC micelles loading PTX or rhodamine-123 into Caco-2 cells via clathrin/cavelin-mediated endocytosis and OPPC-mediated P-gp inhibition. Mechanistically, the inhibition of P-gp efflux pumps by OPPC resulted from the reduction of membrane fluidity and decreased P-gp ATPase activity. In summary, OPPC micelles may serve as an efficient and promising delivery system for enhancing oral bioavailability of P-gp substrates.

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