Zheng Jianguo, Zhang Aijing, Du Qinglong, Li Chi, Zhao Zhongwei, Li Luchao, Zhang Zhao, Qin Xin, Li Yi, Wang Kang-Nan, Yu Nengwang
Department of Urology, Qilu Hospital of Shandong University, Jinan 250100, China; Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100, China.
J Colloid Interface Sci. 2025 Apr;683(Pt 1):420-431. doi: 10.1016/j.jcis.2024.12.073. Epub 2024 Dec 12.
Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and has a high recurrence rate and treatment resistance. Recent results indicate that mitochondrial metabolism influences the therapeutic outcomes of BC. Mitochondria-targeted photosensitizer (PS) is a promising anticancer therapeutic approach that may overcome the limitations of conventional BC treatments. Herein, two mitochondria-targeted iridium(III) PSs, Ir-Mito1 and Ir-Mito2, have been designed for BC treatment. Mechanically, Ir-Mito2 induced a decrease in mitochondrial membrane potential via white light activation, further triggering a reduction of the B-cell lymphoma 2 protein (Bcl-2)/Bcl-associated X protein (Bax) ratio and increment of cleaved caspase3. Meanwhile, the reduction of glutathione, deactivation of glutathione peroxidase 4 (GPX4), increase of acyl-CoA synthetase long chain family member 4 (ACSL4), and accumulation of lipid peroxide resulted in synergistically activating of ferroptosis and apoptosis. The results demonstrated that Ir-Mito2 exhibited excellent antitumor efficacy with superior biosafety in vivo. This work on light-activated and mitochondrial-targeted PS provides an innovative therapeutic platform for BC.
膀胱癌（BC）是泌尿系统最常见的恶性肿瘤之一，具有高复发率和治疗抗性。最近的研究结果表明，线粒体代谢会影响膀胱癌的治疗效果。线粒体靶向光敏剂（PS）是一种很有前景的抗癌治疗方法，可能会克服传统膀胱癌治疗方法的局限性。在此，已设计出两种用于膀胱癌治疗的线粒体靶向铱（III）光敏剂，即Ir-Mito1和Ir-Mito2。机制上，Ir-Mito2通过白光激活导致线粒体膜电位降低，进一步引发B细胞淋巴瘤2蛋白（Bcl-2）/Bcl相关X蛋白（Bax）比值降低和裂解的半胱天冬酶3增加。同时，谷胱甘肽减少、谷胱甘肽过氧化物酶4（GPX4）失活、酰基辅酶A合成酶长链家族成员4（ACSL4）增加以及脂质过氧化物积累协同激活铁死亡和细胞凋亡。结果表明，Ir-Mito2在体内表现出优异的抗肿瘤疗效和卓越的生物安全性。这项关于光激活和线粒体靶向光敏剂的研究为膀胱癌提供了一个创新的治疗平台。
