Wang Xia, Wang Zhaobin, Hang He, Feng Fude
MOE Key Laboratory of High Performance Polymer Material and Technology of Ministry of Education, Department of Polymer Science & Engineering, School of Chemistry & Chemical Engineering, Nanjing University, Jiangsu, Nanjing, 210023, P. R. China.
Chembiochem. 2025 Feb 1;26(3):e202400767. doi: 10.1002/cbic.202400767. Epub 2024 Nov 28.
The long-lasting activity of photosensitizers during photodynamic therapy (PDT) causes excessive damage and arouses great concerns about biosafety. Herein, we synthesized a pyridinium-decorated diiodo-BODIPY compound (PyBDP) and investigated its photosensitizing activity under hypoxic condition in the presence of NADH that is abundant in the mitochondria of hypoxic tumors. The unique property of PyBDP lies in the redox environment-dependent photo-response. At green light exposure, PyBDP is converted into a colorless inactive form by interacting with NADH in a two-step one-electron transfer process. Interestingly, the NADH-dependent hydrogenation of PyBDP is affected by the presence of cytochrome c (Cyt c) that is an important component of mitochondrial electron transport chain (Mito-ETC), unless Cyt c is exhausted. Active radical species is produced during the photocatalytic reaction, which adds the understanding of PyBDP-induced photodamage. Therefore, we applied the strategy of auto-deactivation PDT using a BODIPY photosensitizer by tethering triphenylphosphonium to PyBDP. After PDT effect in a type I pathway, the photosensitizer underwent almost entire auto-deactivation in hypoxic HeLa cells. This work paves a way for the development of reductive PDT with enhanced safety and efficacy in fighting hypoxic tumors independent on reactive oxygen species (ROS).
光动力疗法（PDT）过程中光敏剂的持久活性会造成过度损伤，并引发对生物安全性的高度关注。在此，我们合成了一种吡啶修饰的二碘硼二吡咯化合物（PyBDP），并研究了其在缺氧条件下，在缺氧肿瘤线粒体中大量存在的烟酰胺腺嘌呤二核苷酸（NADH）存在时的光敏活性。PyBDP的独特性质在于其依赖氧化还原环境的光响应。在绿光照射下，PyBDP通过在两步单电子转移过程中与NADH相互作用，转化为无色的非活性形式。有趣的是，除非细胞色素c（Cyt c）耗尽，PyBDP的NADH依赖性氢化反应会受到线粒体电子传递链（Mito-ETC）的重要组成部分细胞色素c的影响。光催化反应过程中会产生活性自由基，这加深了对PyBDP诱导光损伤的理解。因此，我们通过将三苯基膦连接到PyBDP上，应用了一种使用硼二吡咯光敏剂的自动失活PDT策略。在I型途径的PDT效应后，光敏剂在缺氧的HeLa细胞中几乎完全自动失活。这项工作为开发在对抗缺氧肿瘤时具有更高安全性和疗效且不依赖活性氧（ROS）的还原型PDT铺平了道路。
