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

摘要

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(epsilon-caprolactone) (PEO-PPO-PCL) and D-alpha-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 48 h 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. (C) 2015 Elsevier B.V. All rights reserved.