The eradication of breast cancer and cancer stem cells using octreotide modified paclitaxel active targeting micelles and salinomycin passive targeting micelles.
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.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Yang
Y
Zhang
Hua
H
Zhang
Xueqing
X
Wang
Jiancheng
J
Wang
Xuan
X
Zhang
Qiang
Q
Zhang
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007783:Lactones / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015282:Octreotide / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D000095662:Polyether Polyketides
D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D008823:Micelles; D015282:Octreotide; D017239:Paclitaxel; D011092:Polyethylene Glycols; D011108:Polymers; D011714:Pyrans; C521904:poly(ethylene glycol)-block-poly(epsilon-caprolactone); C010327:salinomycin; D000095662:Polyether Polyketides