A novel nanopolymer based tumor targeted delivery system for paclitaxel

Abstract

11095 Background: We have developed a novel cremophor-free paclitaxel formulation-Nanoxel in which the drug is delivered as nanomicelles using a polymeric carrier. Our phase I data has previously shown that Nanoxel™ has linear pharmacokinetics and can be administered without premedication. The phase II data in metastatic breast cancers showed comparable efficacy and better safety profile than cremophor paclitaxel. We report here the putative mechanism of action of nanoxel. Methods: We have designed and synthesized a pH sensitive co-polymer of N-isopropyl acrylamide (NIPAM) and vinylpyrrolidone (VP) monomers. The nanomicelles were characterized for size and morphology by scanning electron microscopy (SEM). The journey of nanomicelles after systemic administration was tracked using chromatographic methods and transmission electron microscopy (TEM). The cellular uptake studies were carried out in target cancers and the tumor uptake was assessed in xenograft models. Release of intracellular Paclitaxel from the nanomicelles in the lysosomal compartment was correlated with the in vitro release of the drug at varying pH conditions. Tubulin polymerization and apoptosis were assessed by standard techniques. Results: Paclitaxel was found to retain the in vitro cytotoxicity in nanomicellar particles. Smooth spherical particles of 80 -100 nm were observed by SEM. Nanoxel™ showed upto three-fold higher uptake in target cancer cells as compared to cremophor paclitaxel. TEM demonstrated that the nanomicelles were endocytosed and entrapped in the acidic endolysosomal compartment. In vitro release of paclitaxel was faster at lower pH conditions. This resulted in an increase in tubulin stabilization & induction of apoptosis. Conclusion: Our data delineates the putative mechanism of action of nanoxel, which may explain its clinical efficacy & improved safety. It also suggests that this nanopolymer is a novel pH sensitive tumor targeting delivery system with potential for application to other hydrophobic drugs. No significant financial relationships to disclose.