Amphiphilic star copolymers-mediated co-delivery of doxorubicin and avasimibe for effective combination chemotherapy

The combination therapy by using two or more chemotherapeutic agents with different action mechanisms has shown to be an attractive strategy for cancer treatment with synergistic therapeutic effects, and also the side effects reduction by one agent replacing part of another one. In this work, an amphiphilic star copolymer with an H40 hyperbranched polyester as the core and poly(ε-caprolactone)-poly(2-dimethylaminoethylmethacrylate) copolymer incorporated with the fluorescent DTM groups as the arms were designed to encapsulate the model anti-cancer drug, doxorubicin (DOX), and a novel potential agent, avasimibe (Ava). Those two drugs could inhibit DNA replication and block acyl-CoA cholesterol acyltransferase-1 (ACAT-1) to induce the cell apoptosis, respectively. The model drugs could be easily loaded into the micelles with a high total drug-loading content toward 24.6% by altering the feeding drug ratios. Three molar ratios (DOX:Ava = 3:1, 1:1, and 1:3) of the drug-loaded micelles were prepared and evaluated for in vitro antitumor efficacy. Results showed that the micelles with 1:1 ratio exhibited the best synergistic cytotoxic activity against both K562 and HeLa cells. Furthermore, the dual-drug combination with efficient anticancer performance was also confirmed by live/dead staining, apoptosis, and cell cycle analysis. Moreover, the internalization of these dual-drug-loaded micelles could be monitored by fluorescent DTM groups and DOX. All these results suggested that the addition of Ava could cut down the dose of DOX to reduce its potential side effects and the co-delivery system could be a promising approach for an effective combination chemotherapy.