非氧依赖性的自由基纳米发生器用于乏氧肿瘤的级联响应性光热-热动力-化学动力学协同治疗

The tumor hypoxia seriously impedes the therapeutic effect of chemotherapy and other aerobic therapies. Oxygen-independent free radical therapy is a novel approach for tumor therapy to overcome this limitation. However, the presence of glutathione (GSH) in tumor cells can exhibit a strong scavenging effect on the generated free radicals to decrease the therapeutic efficiency. Thus, the development of new oxygen-independent free radical therapy at the meantime reducing intracellular GSH level is a highly desirable strategy. In this project, the natural polyphenolic tannic acid, Fe3+ and azo initiator 2, 2’-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) are chosen to synthesize nanoassemblies via metal-coordination interaction followed by surface functionalization. The goal is to obtain an oxygen-independent alkyl/hydroxyl radical nanogenerator for photothermal-thermodynamic-chemodynamic cascade-responsive therapy of hypoxic tumor. Under NIR irradiation, the nanogenerator can produce photothermal effect after tumor accumulation. The hyperthermia, as a result of the photothermal effect, can directly eradicate the tumor cells, and then stimulate the thermal decomposition of AIPH to generate high-toxic alkyl radicals for thermodynamic therapy. Subsequently, the nanogenerator can collapse, releasing Fe3+ which can consume intracellular GSH and then be reduced to Fe2+. Fe2+, in turn, can react with endogenous H2O2 to initiate the Fenton reaction to generate hydroxyl radical. Meanwhile, the Fe2+ also can be oxidized back to Fe3+ for circular chemodynamic therapy, therefore to realize the multimodal synergistic therapy for improving the therapeutic efficiency of hypoxic tumors. This project will provide a new idea for the treatment of hypoxic tumor in future.

肿瘤乏氧特性严重限制化疗等需氧疗法的治疗效果。乏氧不相关的自由基疗法是目前肿瘤治疗的新切入点。然而肿瘤细胞内高表达的GSH可有效抑制自由基，限制其疗效。开发非氧依赖性且能够同时消耗GSH的自由基新疗法，并协同光热疗法是解决上述难题的有效策略。本项目拟选择天然多酚单宁酸、Fe3+和偶氮引发剂（AIPH），利用金属配位形成纳米组装体，并经表面修饰构建非氧依赖性的烷基/羟基自由基纳米发生器，实现乏氧肿瘤的光热-热动力-化学动力学级联响应性治疗。该体系富集于肿瘤后，在近红外光刺激下，产生的光热效应不仅可直接杀伤肿瘤细胞，还可触发AIPH热分解产生高毒性烷基自由基以发挥热动力治疗作用；继而该体系发生崩解，释放的Fe3+可消耗GSH并被还原为Fe2+，Fe2+又可与肿瘤细胞内源性H2O2发生芬顿反应产生羟基自由基并被氧化回归为Fe3+，实现可循环的化学动力学治疗。本项目将为乏氧肿瘤治疗提供新思路。

受本基金项目资助，项目负责人蔺金燕先后在Adv. Sci.、ACS Nano等期刊发表SCI论文5篇（基金标注）。受本基金项目资助，协助培养在读硕士1名，毕业硕士1名，毕业博士1名。. 针对目前肿瘤大部分疗法仍需要氧气的参与，难以长效解决由于乏氧导致的实体瘤疗效不佳的核心问题，本项目构建了一种“非氧依赖性的烷基/羟基自由基纳米发生器”用于乏氧肿瘤的近红外光和谷胱甘肽双重响应的光热-热动力-化学动力学协同治疗。本项目在执行期间根据计划顺利推进相关研究，完成了项目的预期目标。取得的原创性成果主要有：1)首次合成制备了尺寸均一、分散良好的肿瘤微环境响应型病毒样空心介孔硅纳米材料sHMS；2）利用sHMS负载烷基自由基前驱体AIPH并进一步修饰FeIII/TA复合物和NK细胞膜，构建了近红外光/谷胱甘肽双重响应的•C/•OH自由基纳米产生器。该纳米产生器可以首先逃逸免疫清除，并响应近红外光以暴露病毒样表面促进细胞摄取，实现纳米系统在肿瘤组织的高度蓄积。其次该纳米产生器可以响应肿瘤细胞内谷胱甘肽和过氧化氢，且在光热响应下产生•C和•OH自由基，实现光热-热动力-化动力治疗的级联反应，协同实现对乏氧肿瘤的有效抑制。项目执行期间的阶段性进展和研究成果被中科院英文网站科研进展栏目报道。