Although as a mainstay modal for cancer treatment, the clinical effect of radiotherapy (RT) does not yet meet the need of cancer patients. Developing tumour-preferential radiosensitizers or combining RT with other treatments has been acknowledged highly necessary to enhance the efficacy of RT. The present study reported a multifunctional bioactive small-molecule (designated as IR-83) simultaneously exhibiting tumour-preferential accumulation, near-infrared imaging and radio/photodynamic/photothermal therapeutic effects. IR-83 was designed and synthesized by introducing 2-nitroimidazole as a radiosensitizer into the framework of heptamethine cyanine dyes inherently with tumour-targeting and photosensitizing effects. As results, IR-83 preferentially accumulated in tumours, suppressed tumour growth and metastasis by integrating radio/photodynamic/photothermal multimodal therapies. Mechanism studies showed that IR-83 accumulated in cancer cell mitochondria, induced excessive reactive oxygen species (ROS), and generated high heat after laser irradiation. On one hand, these phenomena led to mitochondrial dysfunction and a sharp decline in oxidative phosphorylation to lessen tissue oxygen consumption. On the other hand, excessive ROS in mitochondria destroyed the balance of antioxidants and oxidative stress balance by down-regulating the intracellular antioxidant system, and subsequently sensitized ionizing radiation-generated irreversible DNA double-strand breaks. Therefore, this study presented a promising radiosensitizer and a new alternative strategy to enhance RT efficacy via mitochondria-targeting multimodal synergistic treatment.

尽管作为癌症治疗的中流砥柱，放疗（RT）的临床效果还不能满足癌症患者的需要。开发肿瘤优先放射增敏剂或将放疗与其他治疗相结合已被认为是提高放疗疗效的必要条件。本研究报道了一种多功能生物活性小分子（命名为 IR-83），同时表现出肿瘤优先积累、近红外成像和放射/光动力/光热治疗效果。IR-83 是通过将 2-硝基咪唑作为放射增敏剂引入具有肿瘤靶向和光敏作用的七次甲基花青染料的框架中而设计和合成的。结果，IR-83 优先在肿瘤中积累，通过整合放射/光动力/光热多模式疗法来抑制肿瘤的生长和转移。机理研究表明，IR-83 在癌细胞线粒体中积累，诱导过量的活性氧（ROS），并在激光照射后产生高热量。一方面，这些现象导致线粒体功能障碍和氧化磷酸化急剧下降以减少组织耗氧量。另一方面，线粒体中过量的ROS通过下调细胞内抗氧化系统破坏了抗氧化剂平衡和氧化应激平衡，随后致敏电离辐射产生的不可逆DNA双链断裂。所以，