Polymer micelle-based combination therapy of paclitaxel and resveratrol with enhanced and selective antitumor activity

Abstract

Owing to the low therapeutic efficacy and high toxicity associated with conventional single drug chemotherapy, combination therapy has been adopted in clinics. We employed polymer micelles for sequential delivery of resveratrol (RES) and paclitaxel (PTX) to obtain a synergistic anticancer activity. Briefly, PTX and RES co-encapsulated micelles were prepared by a thin film method using mPEG-b-PLA block copolymers as carriers with a particle diameter of 20 nm and high encapsulation efficiencies of 95% for both PTX and RES. Furthermore, time-dependent sequential release of two drugs resulted in sensitizing the cancer cells to apoptosis. In vitro cytotoxicity tests the combination strategy exerted a synergistic effect (combination index, CI = 0.7–0.8) both in the PTX-resistant human lung adenocarcinoma epithelial (A549/T) cell line and mice sarcoma 180 (S180) cells while showing very limited toxicity towards the normal human hepatic (L02) cell strain and normal human kidney (HK-2) cell line, which could be illustrated from manipulating ROS levels by redox modulation and reducing protective autophagy. In vivo, the combination therapy achieved the best antitumor effect in all treatment groups in S180 bearing mice and evoked the most significant changes in the cytoarchitecture leading to tumor regression according to the histological studies. In conclusion, PTX and RES co-encapsulated micelles would provide a potential strategy to selectively treat cancers by inducing ROS-dependent apoptosis and inhibiting autophagy.