State Key Laboratory of Chemo/Biosensing and Chemometrics, School of Biomedical Sciences, Hunan University, Changsha, 410082, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, Hunan Province, China.
Affiliated Hospital of Hunan University/ Xiangtan Central Hospital, Xiangtan, 411100, China.
Eur J Med Chem. 2024 Dec 15;280:116990. doi: 10.1016/j.ejmech.2024.116990. Epub 2024 Oct 19.
Organelle-targeted photosensitizers (PSs) offer valuable tools for improving photodynamic therapy (PDT), yet systematic studies on how different organelles influence phototherapeutic outcomes are limited. In particular, the connection between organelle targeting and various modes of programmed cell death remains unclear. In this study, we developed a series of PSs using the Coumarin-Quinazolinone (CQ) scaffold, each designed to target different organelles, including the mitochondria, endoplasmic reticulum (ER), lysosome, and nucleolus. Our results show that their PDT performance is highly dependent on their localization, with phototoxic index (PI) ranging from 2 to 245. Notably, the mitochondria-targeted CQ-Mito and ER-targeted CQ-ER exhibited profound phototherapeutic performances, with PI of 167 and 245 respectively. Our further study reveals that CQ-Mito causes cell death by both apoptosis and ferroptosis, while CQ-ER primarily triggers ferroptosis. This study not only provides new agents for PDT but also offers insights into how organelle targeting influences cell death mechanisms, which can shed light on the design of PSs for controlled cell death.
细胞器靶向光敏剂（PSs）为提高光动力疗法（PDT）提供了有价值的工具，但关于不同细胞器如何影响光疗效果的系统研究有限。特别是，细胞器靶向与各种程序性细胞死亡模式之间的联系尚不清楚。在这项研究中，我们使用香豆素-喹唑啉酮（CQ）支架开发了一系列 PSs，每个 PS 都设计用于靶向不同的细胞器，包括线粒体、内质网（ER）、溶酶体和核仁。我们的结果表明，它们的 PDT 性能高度依赖于它们的定位，光毒性指数（PI）范围从 2 到 245。值得注意的是，靶向线粒体的 CQ-Mito 和靶向 ER 的 CQ-ER 表现出显著的光疗性能，PI 分别为 167 和 245。我们的进一步研究表明，CQ-Mito 通过细胞凋亡和铁死亡导致细胞死亡，而 CQ-ER 主要触发铁死亡。这项研究不仅为 PDT 提供了新的试剂，还深入了解了细胞器靶向如何影响细胞死亡机制，这为设计用于控制细胞死亡的 PSs 提供了思路。
