Reduction-sensitive Paclitaxel Prodrug Self-assembled Nanoparticles with Tetrandrine Effectively Promote Synergistic Therapy Against Drug-sensitive and Multidrug-resistant Breast Cancer.

Abstract

Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.