Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, 250012, China.
School of Pharmacy, Weifang Medical University, Weifang, 261053, China.
Adv Sci (Weinh). 2024 Aug;11(30):e2307765. doi: 10.1002/advs.202307765. Epub 2024 Jun 19.
Multi-drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH-sensitive photosensitizer-drug conjugates (CyR-SS-L) are designed and synthesized. CyR-SS-L localized in the mitochondria then is cleaved into CyR-SG and SG-L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR-SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG-L part is used for chemotherapy. CyR-SS-L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR-SS-L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy.
多药耐药（MDR）是癌症治疗失败的主要原因。基于光敏剂产生的活性氧（ROS），光动力疗法（PDT）是一种有前途的治疗方法，可以规避 MDR 并与化学疗法协同作用。然而，癌细胞中超量产生的谷胱甘肽（GSH）会清除 ROS，限制 PDT 的疗效。此外，PDT 治疗后不可避免地会对正常组织产生副作用。在这里，为了开发能够有效同时进行抗癌 PDT 和化疗且副作用极小的有机系统，设计并合成了三种 GSH 敏感的光敏剂-药物偶联物（CyR-SS-L）。CyR-SS-L 定位于线粒体，然后通过与细胞内高水平的 GSH 反应并消耗 GSH 被裂解成 CyR-SG 和 SG-L 部分。值得注意的是，CyR-SG 在肿瘤细胞中而非正常细胞中产生高水平的 ROS，可用于 PDT，而 SG-L 部分则用于化疗。CyR-SS-L 比临床应用中用于 PDT 的光敏剂（PS）吲哚菁绿具有更好的抑制 MDR 癌症肿瘤的活性。结果似乎首次表明，CyR-SS-L 可用作 PDT 剂的替代品，通过 PDT、GSH 耗竭和化疗的联合作用，更有效地对抗 MDR 癌症，而不会明显损伤正常细胞。
