靶向增氧纳米金笼的构建及肿瘤诊疗一体化研究

Photodynamic therapy has become a hot spot in the field of tumor treatment due to its non-invasive property and excellent ability of spatial and temporal control. However, photosensitizers used in photodynamic therapy are still facing the bottlenecks of poor targeting, oxygen dependence, photobleaching and unable for the deep tumor treatment, which greatly limit the clinical applications of photodynamic therapy. In this project, we will fabricate a targeted oxygen-elevated and anti-photobleaching gold nanocage with core-shell structure and near infrared absorption. Gold nanocage as the core will play the role in photodynamic and photothermal therapy under near infrared radiation. Manganese dioxide as the shell will trigger the tumor-specific oxygen generation in acid and hydrogen peroxide-rich tumor microenvironment, which may overcome tumor hypoxia and enhance photodynamic effect. The size, composition and properties of gold nanocage can be tuned by controlling the reaction time and the ratio among the reactors. The fluorescence, photoacoustic and magnetic resonance imaging ability of gold nanocage will be employed to monitor the tumor targeting efficiency and oxygen supply in tumor. For triple-modal imaging-guided cancer treatment, we will carry out the evaluation of photodynamic/photothermal synergistic therapeutic effect, and clarify the mechanism of oxygen-intervening photodynamic/photothermal therapy. The successful implementation of this project will provide theoretical and experimental information for the design of novel and efficient nano-photosensitizers and their applications in tumor theranostics.

光动力治疗因具有非侵入和时空可控的优势而成为肿瘤治疗领域的研究热点。然而目前光动力治疗中使用的光敏剂仍存在靶向性差、光漂白、氧依赖和治疗深度不足等瓶颈，限制了光动力治疗的临床应用。本项目拟采用模板法构筑具有核壳结构的肿瘤靶向增氧、抗光漂白和近红外光吸收的纳米金笼。其中，金笼作为内核，在近红外光激发下发挥光动力和光热疗效；二氧化锰作为壳层，在酸性/富含过氧化氢的肿瘤微环境中降解并释放氧气，从而改善肿瘤缺氧微环境，增强光动力疗效；最外层修饰的透明质酸发挥肿瘤主动靶向能力。通过改变反应时间和投料量，对靶向增氧纳米金笼的尺寸、组成和性能进行调控。采用荧光/光声/磁共振成像技术监控纳米金笼的肿瘤富集效率和靶向增氧情况。利用三模成像引导肿瘤治疗，评估纳米金笼的光动力/光热协同治疗效果，阐明氧干预肿瘤光动力/光热治疗的机制。本项目的顺利实施将为新型高效纳米光敏剂的构建及肿瘤诊疗一体化提供理论和实验依据。

理想的肿瘤治疗策略不仅能够高效、安全地根除原位肿瘤，而且还能通过激活机体免疫系统来识别和清除残留的肿瘤细胞，防止肿瘤的转移和复发。本研究构筑了具有核壳结构的肿瘤靶向增氧和近红外光吸收的纳米金笼@二氧化锰颗粒。纳米金笼作为内核，在近红外光激发下发挥光动力疗效；二氧化锰作为壳层，在酸性/富含过氧化氢的肿瘤微环境中降解并释放氧气，从而改善肿瘤缺氧微环境，增强光动力疗效。荧光/光声/磁共振三模成像实验结果显示，纳米金笼@二氧化锰能高效富集到肿瘤部位并显著改善肿瘤缺氧微环境，并在激光照射下，显著提升瘤内单线态氧的产生。此外，纳米金笼@二氧化锰光动力治疗不仅能有效消除原位肿瘤，还能让肿瘤细胞产生损伤相关分子模式，触发免疫原性细胞死亡，继而促进树突状细胞成熟和效应细胞活化，对肺转移瘤都具有显著的抑制效果。因此，本研究有望为晚期或转移性癌症治疗提供有效的免疫光动力治疗策略。