The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles

The overall objective of the present investigation was to demonstrate the effect of N-octyl-O-sulfate chitosan (NOSC) micelles on enhancing the oral absorption of paclitaxel (PTX) in vivo and in vitro, and identify the mechanism of this action of NOSC. In vivo, the oral bioavailability of PTX loaded in NOSC micelles (PTX-M) was 6-fold improved in comparison with that of an orally dosed Taxol®. In the Caco-2 uptake studies, NOSC micelles brought about a significantly higher amount of PTX accumulated in Caco-2 cells via both clathrin- and caveolae-mediated endocytosis, and NOSC had the effect on inhibiting PTX secreted by P-glycoprotein (P-gp), which was also proved by the studies on rhodamine 123 incorporated in NOSC micelles, fluorescence labeled micelles. The mechanism of NOSC on P-gp inhibition was demonstrated in connection with interfering the P-gp ATPase by NOSC rather than reducing the P-gp expression. Moreover, NOSC with the concentration approaching the critical micellar concentration (CMC) had the strongest effect on P-gp inhibition. In the Caco-2 transport studies, the presence of verapamil and NOSC both improved the transport of Taxol®, which further certified the effect of NOSC on P-gp inhibition, and PTX-M enhanced the permeability of PTX compared with Taxol®. The apparent permeability coefficient (Papp) of PTX-M decreased significantly at 4 °C in comparison with at 37 °C, which indicated a predominant active endocytic mechanism for the transport of PTX-M, a P-gp-independent way. Furthermore, the transcytosis of PTX-M was via clathrin-mediated rather than caveolae-mediated. In addition, the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers had no significant change during the transport study, which pointed out that NOSC had no effect on opening the intercellular tight junctions. Based on the obtained results, it is suggested that NOSC micelles might be a potentially applicable tool for enhancing the oral absorption of P-gp substrates.