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人体必需微量元素铜是细胞线粒体呼吸酶复合体的重要组成成分。既往研究发现，清除线粒体的铜，可将代谢从有氧呼吸转换为无氧酵解，并减少能量产生，能有效抑制癌细胞氧化磷酸化。不过，现有铜螯合剂只能清除全身铜，仅用于治疗铜中毒或白血病等全身疾病，对于乳腺癌等局部肿瘤而言，有效性和安全性不高，临床意义不大。 2020年10月19日，英国《自然》旗下《生物技术》在线发表美国斯坦福大学、霍普金斯大学、伊利诺伊大学、索尔克生物研究所、中国华东理工大学药学院、中国科学院长春应用化学研究所、中国药科大学、瑞士洛桑联邦理工学院的研究报告，开发了一种针对癌细胞线粒体的清铜纳米颗粒，可安全抑制三阴性乳腺癌细胞生长。 该研究表明，清铜纳米颗粒可减少三阴性乳腺癌细胞的氧消耗量和氧化磷酸化，引起代谢转换为无氧酵解，并减少三磷酸腺苷的产生，继而造成能量缺乏、线粒体膜电位下降、氧化应激水平升高，最终导致癌细胞凋亡。清铜纳米颗粒主要清除癌细胞线粒体的铜，而非清除全身的铜，故其毒性小于现有铜螯合剂。实际上，该研究也证实了清铜纳米颗粒对于健康小鼠毒性较低。此外，将3种三阴性乳腺癌细胞（MDA-MB-231、MDA-MB-468、4T1）注入小鼠体内建立肿瘤模型，随后注射清铜纳米颗粒，可抑制肿瘤生长，并可显著提高生存率。 因此，该研究结果表明，清铜纳米颗粒的有效性和安全性令人鼓舞，有望成为治疗三阴性乳腺癌的新方法，故有必要进一步开展临床研究进行验证。 Nat Biotechnol. 2020 Oct 19. Online ahead of print.
Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Liyang Cui, Arvin M. Gouw, Edward L. LaGory, Shenghao Guo, Nabeel Attarwala, Yao Tang, Ji Qi, Yun-Sheng Chen, Zhou Gao, Kerriann M. Casey, Arkadiy A. Bazhin, Min Chen, Leeann Hu, Jinghang Xie, Mingxi Fang, Cissy Zhang, Qihua Zhu, Zhiyuan Wang, Amato J. Giaccia, Sanjiv Sam Gambhir, Weiping Zhu, Dean W. Felsher, Mark D. Pegram, Elena A. Goun, Anne Le, Jianghong Rao. Stanford University, Stanford, CA, USA; Johns Hopkins University, Baltimore, MD, USA; University of Illinois at Urbana-Champaign, Urbana, IL, USA; Salk Institute for Biological Studies, San Diego, CA, USA; East China University of Science and Technology, Shanghai, China; Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China; China Pharmaceutical University, Nanjing, China; Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach. DOI: 10.1038/s41587-020-0707-9 
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