Zeng Li-Zhen, Li Xue-Lian, Deng Yu-Ang, Zhao Run-Yu, Song Ran, Yan Yu-Fei, Wang Meng-Fan, Wang Xiang-Han, Ren Xiaoxia, Gao Feng
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Provincial Center for Research and Development of Natural Products; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China.
Animal Research and Resource Center, School of Life Sciences, Yunnan University, Kunming 650500, P. R. China.
Inorg Chem. 2025 Jan 20;64(2):967-977. doi: 10.1021/acs.inorgchem.4c04282. Epub 2025 Jan 7.
A series of dinuclear Ir(III) complexes have been constructed for enhanced photodynamic and photothermal therapy (PDT and PTT) for cisplatin-resistant non-small-cell lung cancer. They enter cells via caveolar endocytosis, target mitochondria but not nuclear, generate both singlet oxygen and superoxide anion, and release heat when exposed to infrared (IR) irradiation, thus inducing reactive oxygen species (ROS)-associated cell disruption and thermal ablation. The IR-generated ROS can further activate caspases, triggering apoptosis. Additionally, the ROS deplete intracellular glutathione, lead to lipid peroxidation, and induce ferroptosis. The selected dinuclear Ir(III) complex can completely eradicate cisplatin-resistant non-small-cell lung tumor in 75% of the phototreated mice with an inhibition rate of tumor growth above 96%. They have an extremely low toxicity to normal liver and kidney cells. After therapy, metal was not detected in the collected organs of mice except the tumor. A synergistic therapy consisting of potent IR-driven PDT and mild PTT accomplished by single-molecule dinuclear Ir(III) complexes is highly significant for the safe and effective PDT of large, deep-seated tumors as well as for overcoming the complicated drug resistance mechanisms of cancer.
已构建了一系列双核铱（III）配合物，用于增强对顺铂耐药的非小细胞肺癌的光动力和光热疗法（PDT和PTT）。它们通过小窝内吞作用进入细胞，靶向线粒体而非细胞核，产生单线态氧和超氧阴离子，并在受到红外（IR）照射时释放热量，从而诱导活性氧（ROS）相关的细胞破坏和热消融。红外产生的ROS可进一步激活半胱天冬酶，触发细胞凋亡。此外，ROS消耗细胞内谷胱甘肽，导致脂质过氧化，并诱导铁死亡。所选的双核铱（III）配合物可在75%的光治疗小鼠中完全根除顺铂耐药的非小细胞肺癌肿瘤，肿瘤生长抑制率超过96%。它们对正常肝和肾细胞的毒性极低。治疗后，除肿瘤外，在收集的小鼠器官中未检测到金属。由单分子双核铱（III）配合物实现的强效红外驱动PDT和温和PTT组成的协同疗法，对于大型深部肿瘤的安全有效PDT以及克服癌症复杂的耐药机制具有重要意义。
