State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Biomaterials. 2012 Jan;33(2):565-82. doi: 10.1016/j.biomaterials.2011.09.055. Epub 2011 Oct 7.
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.
乳腺癌干细胞在乳腺癌的复发中起着至关重要的作用，因为它们对标准化疗具有抗性，并且残留的癌症干细胞能够无限增殖。本研究的目的是构建一种靶向线粒体的柔红霉素加吖啶橙脂质体，用于治疗和预防源自癌症干细胞的乳腺癌复发。MCF-7 癌症干细胞被鉴定为 CD44(+)/CD24(-)细胞，并在无血清培养基中培养。通过将 MCF-7 癌症干细胞异种移植到雌性 NOD/SCID 小鼠中，对 MCF-7 癌症干细胞、MCF-7 癌症干细胞类器官和复发肿瘤进行评估。靶向线粒体的柔红霉素加吖啶橙脂质体的粒径约为 98nm。靶向线粒体的脂质体明显增加了药物的线粒体摄取，选择性地积聚在线粒体中，激活促凋亡 Bax 蛋白，耗散线粒体膜电位，打开线粒体通透性转换孔，通过易位释放细胞色素 C，并启动 caspase9 和 3 反应级联，从而诱导 MCF-7 癌症干细胞凋亡。靶向线粒体的脂质体在体外对 MCF-7 癌细胞、体外对 MCF-7 癌症干细胞以及对小鼠复发肿瘤的治疗效果最强。靶向线粒体的柔红霉素加吖啶橙脂质体为治疗和预防源自癌症干细胞的乳腺癌复发提供了一种新策略。
