Docetaxel-loaded PEO-PPO-PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy

There are two major hurdles for the current anti-cancer drug delivery systems. One is the emergence of multidrug resistance (MDR) and the other is the conflict between long-circulation and cellular uptake. In the present study, the anticancer drug docetaxel (DTX) was successfully loaded into three series of micelles via self-assembly using a mixture of PEO-PPO-PCL and d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS), for the purpose of prolonging the blood circulation time as well as overcoming MDR of DTX. Three series of copolymers with different PCL molecular weights, PEO₆₈-PPO₃₄-PCL₉, PEO₆₈-PPO₃₄-PCL₁₈ and PEO₆₈-PPO₃₄-PCL₃₆, were synthesized. The prepared spherical mixed micelles (MM) were found to possess nanoscale size (25-135 nm). The PEO-PPO-PCL/TPGS mixed micelles had a low critical micelle concentration (∼10^-6 g mL^-1) and a low hemolysis rate (<5%), which has proved that they are safe for use in vivo. Moreover, they had obvious sustained release behavior in vitro and a longer circulation time than free DTX in vivo. The P-gp inhibition assay, cellular uptake and MTT assay in cancer cells exhibited that DTX-loaded MM could overcome MDR, show higher cellular uptake and higher antitumor efficacy than free DTX. The IC₅₀ values demonstrated that the three series of DTX-loaded MM were 69, 82 and 100 fold effective than free DTX after 72 h treatment with MCF-7 cells, respectively. Therefore, these results demonstrated that the prepared DTX-loaded MM provide desirable application in cancer chemotherapy.