ABSTRACT
Tumor stem cells have emerged as the new targets for anti-cancer therapy, besides tumor cells themselves. To eradicate both breast cancer cells and breast cancer stem cells which can not be eliminated by the conventional chemotherapy, octreotide (Oct)-modified paclitaxel (PTX)-loaded PEG-b-PCL polymeric micelles (Oct-M-PTX) and salinomycin (SAL)-loaded PEG-b-PCL polymeric micelles (M-SAL) were developed and investigated in combination. In this study, Oct that targets somatostatin receptors (SSTR) overexpressed in tumors including breast cancer, was coupled to the PEG end of PEG-b-PCL, and all the micelles were prepared using thin film hydration method. Results showed that the particle size of all the micelles was approximately 25-30 nm, and the encapsulation efficiency was >90%. Quantitative and qualitative analysis demonstrated that Oct facilitates the uptake of micelles in SSTR overexpressed breast cancer MCF-7 cells while free Oct inhibited cellular uptake of Oct-modified micelles, revealing the mechanism of receptor-mediated endocytosis. Breast cancer stem cells (side population cells, SP cells) were sorted from MCF-7 cells and identified with the CD44+/CD24- phenotype. M-SAL was capable of decreasing the proportion of SP cells, and its suppression was more potent in SP cells than that in cancer cells. As compared to PTX-loaded micelles (M-PTX), the inhibition of Oct-M-PTX against MCF-7 cells was stronger while such effect significantly increased when applying Oct-M-PTX in combination with M-SAL. In the MCF-7 xenografts, the combination therapy with Oct-M-PTX plus M-SAL produced the strongest antitumor efficacy, in accord with the combination treatment in vitro. Compared with free SAL, M-SAL was found to be more effective in suppressing breast cancer stem cells in vivo. Thus, this combination therapy may provide a strategy to improve treatment of breast cancers for eradication of breast cancer cells together with breast cancer stem cells.