Coencapsulation of epirubicin and metformin in PEGylated liposomes inhibits the recurrence of murine sarcoma S180 existing CD133+ cancer stem-like cells

Cancer stem cell (CSCs), also known as tumor-initiating cells, which constitute a subpopulation of tumor cells, are key drivers of tumorigenesis and potential recurrence of cancer. The CSC theory has brought new opportunities as well as challenges to the development of sophisticated drug delivery systems for treating cancer. In the present study, CD133(+) cells were sorted from S180 cell lines by magnetic activated cell sorting and a fraction (approximately 1.01%) of CD133(+) cells with higher proliferative potential and stronger tumorigenicity in vivo compared with CD133(-) cells was identified. Furthermore, a procedure for the coencapsulation of epirubicin (EPI) and metformin (MET) was developed with the primary goal of eradicating the bulk population of CD133(-) cells and the rare population of CD133(+) cancer stem-like cells, thus ultimately preventing tumor relapse. The inhibitory effect of free MET was more potent in CD133(+) cells than in CD133(-) cells; in addition, EPI- and MET-coencapsulated liposomes exhibited increased cytotoxicity against CD133(+) cells compared with liposomal EPI alone. Meanwhile, tumors in KM mice were completely eliminated upon multiple intravenous injections of liposomal EPI and MET, and tumors virtually eliminated in the experimental period, which could be attributed to the arrest of CD133(+) cells in the G(0)/G(1) phase. The coencapsulation of an anti-CSC agent with conventional chemotherapy drugs in liposomes may be a promising drug delivery strategy for fighting cancer and eradicating tumor stem cells. (C) 2014 Elsevier B.V. All rights reserved.