Abe Jiro, Yamada Yuma, Harashima Hideyoshi
Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
J Pharm Sci. 2016 Feb;105(2):734-740. doi: 10.1002/jps.24686. Epub 2016 Jan 29.
Mitochondria in human cancer cells have been implicated in cancer cell proliferation, invasion, metastasis, and even drug-resistance mechanisms, making them a potential target organelle for the treatment of human malignancies. Gentamicin (GM), an aminoglycoside drug (AG), is a small molecule that functions as an antibiotic and has ototoxic and nephrotoxic characteristics. Thus, the delivery of GM to mitochondria in cancer cells would be an innovative anticancer therapeutic strategy. In this study, we attempted mitochondrial delivery of GM in HeLa cells derived from a human cervical cancer. For the mitochondrial delivery, we used MITO-Porter, a liposomal nanocarrier for mitochondrial delivery via membrane fusion. We first encapsulated GM in the aqueous phase of the carrier to construct GM-MITO-Porter. Flow cytometry analysis and fluorescent microscopy observations permitted us to confirm that the GM-MITO-Porter was efficiently taken up by HeLa cells and accumulated in mitochondria, whereas naked GM was not taken up by the cells. Moreover, cell viability assays using HeLa cells showed that the GM-MITO-Porter induced strong cytotoxic effects related to mitochondrial disorder. This finding is the first report of the mitochondrial delivery of an AG to cancer cells for cancer therapeutic strategy.
人类癌细胞中的线粒体与癌细胞增殖、侵袭、转移甚至耐药机制有关，使其成为治疗人类恶性肿瘤的潜在靶细胞器。庆大霉素（GM）是一种氨基糖苷类药物（AG），是一种具有抗生素功能的小分子，具有耳毒性和肾毒性。因此，将GM递送至癌细胞中的线粒体将是一种创新的抗癌治疗策略。在本研究中，我们尝试将GM递送至源自人宫颈癌的HeLa细胞的线粒体中。对于线粒体递送，我们使用了MITO-Porter，一种通过膜融合进行线粒体递送的脂质体纳米载体。我们首先将GM包裹在载体的水相中以构建GM-MITO-Porter。流式细胞术分析和荧光显微镜观察使我们能够确认GM-MITO-Porter被HeLa细胞有效摄取并在线粒体中积累，而裸露的GM未被细胞摄取。此外，使用HeLa细胞进行的细胞活力测定表明，GM-MITO-Porter诱导了与线粒体紊乱相关的强烈细胞毒性作用。这一发现是关于将AG递送至癌细胞用于癌症治疗策略的线粒体递送的首次报道。
