Yang Zhengyang, Wang Jiafeng, Liu Song, Li Xianghui, Miao Leiying, Yang Bo, Zhang Chenlin, He Jian, Ai Shichao, Guan Wenxian
Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan RD, Nanjing, 210008, China.
Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang RD, Nanjing, 210093, China.
Biomaterials. 2020 Jan;229:119580. doi: 10.1016/j.biomaterials.2019.119580. Epub 2019 Oct 31.
Hypoxia, which frequently reduces the sensitivity to many therapeutic interventions, including chemotherapy, radiotherapy and phototherapy, has been acknowledged as an important reason for poor prognosis. Burgeoning evidences have proved that the tumor hypoxia microenvironment can reduce the therapeutic effect on tumor through inhibiting the drug efficacy, limiting immune cell infiltration of tumors and accelerating tumor recurrence and metastasis. However, the relationship between oxygen supply and the proliferation of cancer cells is still ambiguous and argued. Different from the current commonly used oxygen supply strategies, this study concentrated on the reduction of endogenous oxygen consumption. Specifically, a novel photosensitizers (IR780) and metformin are packaged in PEG-PCL liposomes. Once such nanoparticles accumulated in tumor tissues, the tumor foci were irradiated through 808 nm laser, generated ROS to further release metformin and IR780. Metformin can directly inhibit the activity of complex Ⅰ in the mitochondrial electron transport chain, thus performed a potent inhibitor of cell respiration. After overcoming tumor hypoxia, the combination of mitochondria-targeted photodynamic therapy (PDT) and photothermic therapy (PTT) via IR780 may achieve superior synergistically therapeutic efficacy. Benefit from excellent characteristics of IR780, such synergistic PDT PTT with the inhibition of mitochondrial respiration can be monitored through near-infrared/photoacoustic dual-modal imaging. Such a conception of reducing endogenous oxygen consumption may offer a novel way to solve the important puzzles of hypoxia-induced tumor resistance to therapeutic interventions, not limited to phototherapy.
缺氧常常会降低对包括化疗、放疗和光疗在内的多种治疗干预的敏感性，已被公认为是预后不良的一个重要原因。越来越多的证据表明，肿瘤缺氧微环境可通过抑制药物疗效、限制肿瘤免疫细胞浸润以及加速肿瘤复发和转移来降低对肿瘤的治疗效果。然而，氧气供应与癌细胞增殖之间的关系仍不明确且存在争议。与目前常用的氧气供应策略不同，本研究专注于减少内源性氧消耗。具体而言，一种新型光敏剂（IR780）和二甲双胍被包裹在聚乙二醇-聚己内酯脂质体中。一旦此类纳米颗粒在肿瘤组织中积累，通过808nm激光照射肿瘤病灶，产生活性氧以进一步释放二甲双胍和IR780。二甲双胍可直接抑制线粒体电子传递链中复合物Ⅰ的活性，从而成为一种有效的细胞呼吸抑制剂。克服肿瘤缺氧后，通过IR780进行的线粒体靶向光动力疗法（PDT）和光热疗法（PTT）联合应用可能会实现卓越的协同治疗效果。得益于IR780的优异特性，这种抑制线粒体呼吸的协同PDT-PTT可通过近红外/光声双模态成像进行监测。这种减少内源性氧消耗的概念可能为解决缺氧诱导的肿瘤对治疗干预（不限于光疗）耐药这一重要难题提供一种新方法。
