In-vitro cytotoxicity and combination effects of the docetaxel-conjugated and doxorubicin-conjugated poly(lactic acid)-poly(ethylene glycol)-folate-based polymeric micelles in human ovarian cancer cells.
The pH-sensitive doxorubicin (DOX)-conjugated and docetaxel (DTX)-conjugated poly(lactic acid)-poly(ethylene glycol)-folate (PLA-PEG-FOL)-based polymeric micelles were developed and characterized in this study. The drugs were released from the micelles (particle size, ~185 nm) in a pH-dependent manner. The drug-conjugated PLA-PEG-FOL micelles showed higher cellular uptake than nontargeting ones. Single agent and combination in-vitro cytotoxicity studies were also performed using the two drugs in both free and their micellar forms in SKOV3 human ovarian cancer cells using three different cytotoxicity assays. Like the free drugs, DOX-conjugated and DTX-conjugated targeting micelles showed significant cytotoxic effects in SKOV3 cell line. Moreover, the drug-conjugated targeting micelles improved cytotoxicity compared to the FOL-free ones. Different ratios of IC50 of free drugs were used for combination therapy, and synergistic, additive or antagonistic effects were evaluated. The synergistic effect was observed in specific DOX : DTX mixing ratios, which result in the increase in therapeutic efficacy using low doses of each test compound without formulation related side effects. The prepared micelles may provide appropriate delivery systems for doxorubicin and docetaxel in both single and combination therapies.