title: Mitochondrial targeting liposomes incorporating daunorubicin and quinacrine for treatment of relapsed breast cancer arising from cancer stem cells.
abstract: Breast cancer stem cells play a crucial role in the relapse of breast cancers because they are resistant to a standard chemotherapy and the residual cancer stem cells are able to proliferate indefinitely. The objectives of present study were to construct a kind of mitochondrial targeting daunorubicin plus quinacrine liposomes for treating and for preventing the recurrence of breast cancer arising from the cancer stem cells. MCF-7 cancer stem cells were identified as CD44(+)/CD24(-) cells and cultured in free-serum medium. Evaluations were performed on MCF-7 cancer stem cells, MCF-7 cancer stem cell mammospheres, and the relapsed tumor by xenografting MCF-7 cancer stem cells into female NOD/SCID mice. The particle size of mitochondrial targeting daunorubicin plus quinacrine liposomes was approximately 98 nm. The mitochondrial targeting liposomes evidently increased the mitochondrial uptake of drugs, were selectively accumulated into mitochondria, activated the pro-apoptotic Bax protein, dissipated the mitochondrial membrane potential, opened the mitochondrial permeability transition pores, released cytochrome C by translocation, and initiated a cascade of caspase 9 and 3 reactions, thereby inducing apoptosis of MCF-7 cancer stem cells. The mitochondrial targeting liposomes showed the strongest efficacy in treating MCF-7 cancer cells in vitro, in treating MCF-7 cancer stem cells in vitro, and in treating the relapsed tumor in mice. Mitochondrial targeting daunorubicin plus quinacrine liposomes would provide a new strategy for treating and preventing the relapse of breast cancers arising from cancer stem cells.
authors: State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Liang
authors: L
authors: Zhang
authors: Hong-Juan
authors: HJ
authors: Yao
authors: Yang
authors: Y
authors: Yu
authors: Yan
authors: Y
authors: Zhang
authors: Ruo-Jing
authors: RJ
authors: Li
authors: Rui-Jun
authors: RJ
authors: Ju
authors: Xiao-Xing
authors: XX
authors: Wang
authors: Meng-Ge
authors: MG
authors: Sun
authors: Ji-Feng
authors: JF
authors: Shi
authors: Wan-Liang
authors: WL
authors: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011796:Quinacrine / Q000493:pharmacokinetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D008081:Liposomes; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D011796:Quinacrine; D003630:Daunorubicin