Abstract
In this study, we prepared mixed micelles composed of a pH-sensitive poly(ethylene glycol)-doxorubicin conjugate prodrug and d-alpha-tocopheryl polyethylene glycol succinate (TPGS). The average hydrodynamic size of the mixed micelles was approximately 144nm, measured by dynamic light scattering. In an MTT assay the pH-sensitive prodrug was non-cytotoxic at low concentration but inhibited drug-resistant cancer cell (MCF-7/ADR) growth at high dose. The mixed micelles showed concentration-dependent cytotoxicity and significantly increased the cytotoxicity of the prodrug in MCF-7/ADR cells. Confocal laser scanning images revealed that higher concentrations of doxorubicin were successfully delivered into cell nuclei, enabling effective drug-induced cell death. Fluorescence microscopy indicated that there was less escape of the internalized doxorubicin from cells. Therefore, the enhanced drug efficacy in MCF-7/ADR cells is most likely attributed to a synergistic effect of drug-release from the pH-sensitive prodrug inside cells and suppression of P-glycoprotein efflux activity by TPGS.
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