Qin Huan, Chen Qiaolin, Chen Bangtang, Wang Jun, Su Huilin, Huang Xiaojie, Dong Qiangqiang, Chen Mingzhao, Jiang Zhimin, Li Yingying, Wang Pingshan, Jiang Zhilong
Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China.
Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou Key Laboratory for Clean Energy and Materials, Guangzhou University, Guangzhou 510006, Guangdong, China.
J Am Chem Soc. 2025 Jul 9;147(27):23957-23971. doi: 10.1021/jacs.5c07313. Epub 2025 Jun 28.
Owing to its less oxygen-dependent mechanism, type I photodynamic therapy (PDT) has exhibited significant superiority over the more common type II PDT in the treatment of hypoxic tumors. Supramolecular coordination complexes (SCCs) have shown great potential in photodynamic cancer therapy; however, SCC-based photosensitizers which can achieve type I PDT have rarely been reported. Herein, we present the design and synthesis of a novel heteroleptic/trimetallic Os-Ru-Zn Sierpiński triangle ST-2 via coordination-driven self-assembly. The distinctive SCC ST-2 displayed high generation ability of reactive oxygen species (ROS) and boosted the production of O involved in the type I mechanism. Detailed in vitro investigations demonstrated ST-2 exhibited excellent PDT efficacy against all tested cancer cell lines with low IC values in the subnanomolar range and high phototoxicity indexes (PI) up to 750 even under hypoxic conditions and induced cancer cell death mainly through type I PDT. The anticancer mechanism could be ascribed to the mitochondrial and lysosomal damages as well as cell apoptosis and cell cycle arrest. Further studies confirmed that ST-2 disintegrated 3D multicellular tumor spheroids and effectively inhibited the growth of solid hypoxic tumors in mice with minimal side effects. This work not only provides an alternative strategy for the development of highly efficient type I photosensitizers but also opens new possibilities for Sierpiński triangles in biomedicine.
由于其一型光动力疗法（PDT）对氧的依赖性较低，在治疗缺氧肿瘤方面，一型光动力疗法相较于更常见的二型光动力疗法已展现出显著优势。超分子配位络合物（SCCs）在光动力癌症治疗中显示出巨大潜力；然而，能够实现一型光动力疗法的基于SCC的光敏剂鲜有报道。在此，我们通过配位驱动自组装展示了一种新型异金属/三金属Os-Ru-Zn谢尔宾斯基三角形ST-2的设计与合成。独特的SCC ST-2表现出高活性氧（ROS）生成能力，并促进了一型机制中所涉及的氧的产生。详细的体外研究表明，即使在缺氧条件下，ST-2对所有测试癌细胞系均表现出优异的光动力疗法疗效，其半数抑制浓度（IC）值低至亚纳摩尔范围，光毒性指数（PI）高达750，且主要通过一型光动力疗法诱导癌细胞死亡。抗癌机制可归因于线粒体和溶酶体损伤以及细胞凋亡和细胞周期阻滞。进一步研究证实，ST-2可分解三维多细胞肿瘤球体，并有效抑制小鼠体内实体缺氧肿瘤的生长，且副作用极小。这项工作不仅为开发高效一型光敏剂提供了一种替代策略，也为谢尔宾斯基三角形在生物医学领域开辟了新的可能性。
