Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: Preparation, in vitro and in vivo evaluation

In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92 +/- 2.08% and 25.82 +/- 1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140 nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells (p < 0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C-max level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system. (C) 2012 Elsevier B.V. All rights reserved.