DOXORUBICIN-LOADED MICELLES OF Y-SHAPED PEG-(PCL)2 AGAINST DRUG-RESISTANT BREAST CANCER CELLS

Y-shaped amphiphilic copolymers have been synthesized by various strategies. They can self-assemble to form stable micellar drug carriers. Higher ratio of hydrophobic segment in these micelles is known to stabilize encapsulated drugs. This study used methoxy poly(ethylene glycol) (mPEG, A block) and poly(ε-caprolactone) (PCL, B block) to synthesize an AB2 type amphiphilic block copolymer to encapsulate the anticancer drug, doxorubicin (DOX). The synthesized mPEG-(PCL)2 self-assembled into nanoparticles and its critical micelle concentration was 43.7 × 10-3 mg/mL. The particle size of empty micelle and DOX-loaded micelle was 95.1 and 21.4 nm, respectively. DOX-loaded micelles have a drug- loading efficiency of 22.3% and could be released from micelles up to 50% at pH 5 and 40% at pH 7.4 in 48 h in an in vitro release experiment. The nitric oxide (NO) assay indicated that the micelles could avoid the cytotoxic recognition by murine macrophage cells. The half-lethal dose (IC50) of DOX-loaded micelles for two human breast cancer cell lines (MCF-7/WT for wild-type and MCF-7/ADR for adriamycin-resistant) were 0.937 and 7.476 μg/mL, respectively. For MCF-7/ADR cells, the ratio of IC50 of free DOX vs. that of DOX-loaded micelles, which reported as resistance reversion index, was 0.125. Confocal images showed that DOX-loaded micelles accumulated mostly in the cytoplasm instead of nuclei. On the contrary, free DOX diffused throughout the cells. Flow cytometric histograms indicated that the fluorescence intensity in MCF-7/ADR cell line was about 83.2% and 50.9% for DOX-loaded micelles and free DOX, respectively. This result indicates that the DOX-loaded micelles formed by AB2 copolymer could overcome multidrug resistance of breast cancer cells as it can accumulate more in MCF-7/ADR cells compared with free DOX.