One-Step Self-Assembling Nanomicelles for Pirarubicin Delivery To Overcome Multidrug Resistance in Breast Cancer

Tumor cells can acquire multidrug resistance (MDR) as a result of drug efflux mediated by P-glycoprotein (P-gp). Here we report a targeted delivery system to carry pirarubicin (THP) to MDR breast cancer both in vitro and in vivo. PEG-derivatized vitamin E (PAMV₆) amphiphiles loaded with THP were self-assembled in a single step. The PAMV₆ micelles showed unimodal size distribution and high drug loading efficiency. Cytotoxicity of PAMV₆/THP was higher than that of free THP on MCF-7/ADR cells but comparable to that of THP on MCF-7 cells. PAMV₆/THP was able to reverse MDR more than free THP in MCF-7/ADR cells, likely reflecting the remarkably higher intracellular THP concentration in micelle-treated cells and PAMV₆-mediated inhibition of P-gp activity. PAMV₆/THP micelles were internalized into MCF-7/ADR cells via macropinocytosis and caveolin-mediated endocytosis, further avoiding P-gp-mediated efflux. Mechanistic studies revealed that blank PAMV₆ micelles inhibited P-gp activity but did not affect P-gp expression, by significantly reducing mitochondrial membrane potential and slightly decreasing intracellular ATP levels. In a nude mouse xenograft model, PAMV₆/THP led to much greater THP accumulation in tumors and much slower tumor growth than free THP. At the same time, PAMV₆/THP was associated with significantly less severe bone marrow suppression and organ toxicity than free THP. Our results indicate that this PAMV₆-based micelle system holds promise for combating MDR in cancer therapy.