Co-delivery of docetaxel and chloroquine via PEO–PPO–PCL/TPGS micelles for overcoming multidrug resistance

Abstract

The combination of two or more drug is a promising strategy to suppress the multidrug resistance (MDR) through different action mechanisms. Co-delivery drugs via polymeric micelle can minimize the amount of each drug and reduce toxic side effects. Here we co-encapsulate anticancer drug docetaxel (DTX) and autophagy inhibitor chloroquine (CQ) in complex micelles based on poly(ethylene oxide)-block–poly(propylene oxide)-block–poly(ϵ-caprolactone) (PEO–PPO–PCL) and d-α-tocopheryl poly(ethylene glycol) (TPGS) for enhancing anticancer effects. Two series copolymer with different length of hydrophobic chain were synthesized (PEO68–PPO34–PCL18 and PEO68–PPO34–PCL36) in our lab. The dual–drug micelles possessed nanosize and sustained release profile in vitro. Drug-loaded micelles have low hemolysis rate (<5%), indicating that they are safe for use in vivo. Studies on cellular uptake demonstrate that the micelles can effectively accumulate in cancer cells. Furthermore, in vitro cytotoxicity with different DTX/CQ mass ratio are studied and the sample with a DTX/CQ ratio of 0.8/0.2 is found to have the strongest synergism effect. The co-delivery micelles have obviously higher therapeutic effects against MCF-7 and MCF-7/ADR cells than either free drug or individually DTX-loaded micelles. The IC50 values of DTX/CQ-loaded PEO68–PPO34–PCL18/TPGS and PEO68–PPO34–PCL36/TPGS micelles are 134.16 and 194.74 fold smaller than that of free DTX after 48h treatment with MCF-7/ADR cells, respectively. Therefore, the as-prepared co-delivery of DTX and CQ based on PEO–PPO–PCL/TPGS micelles can provide a promising combined therapeutic strategy for enhanced antitumor therapy.