Department of Radiology, Drum Tower Hospital, School of Medicine, Nanjing University , Nanjing, Jiangsu 210008, China.
Collaborative Innovation Center of Chemistry for Life Sciences, College of Engineering and Applied Sciences, Nanjing University , Nanjing, Jiangsu 210093, China.
ACS Nano. 2017 Oct 24;11(10):10159-10174. doi: 10.1021/acsnano.7b04737. Epub 2017 Oct 11.
Although ultrasmall metal nanoparticles (NPs) have been used as radiosensitizers to enhance the local damage to tumor tissues while reducing injury to the surrounding organs, their rapid clearance from the circulatory system and the presence of hypoxia within the tumor continue to hamper their further application in radiotherapy (RT). In this study, we report a size tunable nanocluster bomb with a initial size of approximately 33 nm featuring a long half-life during blood circulation and destructed to release small hypoxia microenvironment-targeting NPs (∼5 nm) to achieve deep tumor penetration. Hypoxic profiles of solid tumors were precisely imaged using NP-enhanced computed tomography (CT) with higher spatial resolution. Once irradiated with a 1064 nm laser, CT-guided, local photothermal ablation of the tumor and production of radical species could be achieved simultaneously. The induced radical species alleviated the hypoxia-induced resistance and sensitized the tumor to the killing efficacy of radiation in Akt-mTOR pathway-dependent manner. The therapeutic outcome was assessed in animal models of orthotopical breast cancer and pancreatic cancer, supporting the feasibility of our combinational treatment in hypoxic tumor management.
尽管超小金属纳米颗粒（NPs）已被用作放射增敏剂，以增强肿瘤组织的局部损伤，同时减少对周围器官的损伤，但它们在循环系统中的快速清除和肿瘤内的缺氧仍然阻碍了它们在放射治疗（RT）中的进一步应用。在本研究中，我们报告了一种具有约 33nm 初始尺寸的可调节尺寸的纳米簇炸弹，其在血液循环中具有较长的半衰期，并被破坏以释放小的缺氧微环境靶向 NPs（~5nm），从而实现肿瘤的深层渗透。使用 NP 增强的计算机断层扫描（CT）以更高的空间分辨率精确成像实体瘤的缺氧情况。一旦用 1064nm 激光照射，就可以同时实现 CT 引导的肿瘤局部光热消融和自由基的产生。诱导的自由基减轻了缺氧诱导的耐药性，并以 Akt-mTOR 通路依赖性方式使肿瘤对辐射的杀伤效果敏感。在原位乳腺癌和胰腺癌动物模型中评估了治疗效果，支持了我们在缺氧肿瘤管理中联合治疗的可行性。
