中山大学巢晖团队首次提出线粒体-定位铱(III)内过氧化物复合物的光降解用于在低氧条件下双光子光活化治疗。相关研究成果于2022年2月16日发表于国际一流学术期刊《美国化学会杂志》。

尽管光动力疗法（PDT）在临床上取得了成功，但这种医疗技术的应用在本质上受到癌症肿瘤中发现的低氧浓度的限制，阻碍了治疗必需的单线态氧（1O₂）的产生。

为了克服这一局限性，研究人员报道了一种新的线粒体定位的铱（III）内过氧化物前药（2-O-IrAn）。在近红外双光子照射下，该前药协同释放高度细胞毒性的铱（III）复合物（2-IrAn）、单线态氧和烷氧基。研究发现，在纳摩尔范围内，2-O-IrAn对缺氧肿瘤细胞和多细胞肿瘤球体（MCT）具有高度（光）毒性。为了揭示癌症选择性并改善2-O-IrAn的药理学性质，将其封装到生物素功能化聚合物中。一次治疗中，在小鼠模型中发现生成的纳米颗粒几乎完全消除了肿瘤。该项研究提供了第一个基于铱（III）的内过氧化物前体药物的例子，用于协同光动力疗法/光激活化疗，为治疗低氧性肿瘤开辟了新途径。

附：英文原文

Title: Photodecaging of a Mitochondria-Localized Iridium(III) Endoperoxide Complex for Two-Photon Photoactivated Therapy under Hypoxia

Author: Shi Kuang, Fangmian Wei, Johannes Karges, Libing Ke, Kai Xiong, Xinxing Liao, Gilles Gasser, Liangnian Ji, Hui Chao

Issue&Volume: February 16, 2022

Abstract: Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (1O2). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.

DOI: 10.1021/jacs.1c13137

Source: https://pubs.acs.org/doi/10.1021/jacs.1c13137