GOD@Fe3O4@PPy复合纳米诊疗剂的设计与肿瘤化学动力学/光热协同治疗

To overcome the limitations of chemotherapeutic drug, such as the severe side effects and low tumor selectivity, we intend to design and fabricate a theranostic nanoplatform that can realize imaging-guided photothermal therapy and catalytic combinatorial therapy, basing on the strategy of cancer theranostics and catalytic nanomedicine. By regulating this organic/inorganic system and investigating the relationship of nanostructure-composition-enhancing performance-imaging, the composition and microstructure will be optimized. The Fe3O4 modified polypyrrole nanoparticles conjugating glucose oxidase will exhibit high photothermal conversion efficiency in second near-infrared light biowindows. Glucose oxidase effectively exhaust glucose in tumor tissue, and meanwhile overproduces peroxide for subsequent Fenton reaction catalyzed by Fe3O4 in mild acidic tumor microenvironment, followed by generating hydroxyl radicals to kill cancer cells. Furthermore, the localized heat by photothermal treatment will enhance the chemodynamic therapy performance. More importantly, the multifunctional nanotheranostics may endow the platform with photoacoustic imaging and magnetic resonance imaging capability, thereby realize dual-modal imaging guided synergistic cancer therapy. The results of this project may provide a new strategy to realize the efficiency and biosafety issues of tumor therapy based on nano-biotechnology, and serve as the scientific support for the construction of versatile nanoplatforms in cancer theranostics by integrating with the idea of catalytic nanomedicine.

针对癌症化疗药毒副作用大且肿瘤选择性低的难题，本项目基于“诊疗一体化”和“纳米催化医学”的策略，开展具有可视化光热治疗和催化治疗功能纳米诊疗平台的研究。本项目一方面通过系统性调控有机/无机杂化材料体系，考察结构-组成-增效-影像之间关系，筛选出最佳结构和组成方案，将聚吡咯（PPy）和四氧化三铁（Fe3O4）和葡萄糖氧化酶（GOD）结合，构建适用于近红外第二生物窗口的高效光热剂。另一方面通过引入生物活性酶和无机纳米酶，设计针对肿瘤微环境葡萄糖富足和微酸性特点的连锁催化反应，开启化学动力学治疗（CDT）模式，又基于纳米光热效应进一步增强CDT肿瘤治疗效率。该多功能纳米体系兼具光声成像和核磁共振成像的造影功能，最终可实现双模态成像导航下的肿瘤协同治疗。本项目采用纳米生物技术提高肿瘤治疗的高效性和安全性，并结合纳米催化医学新策略，为构建高效可视化肿瘤治疗的纳米平台提供理论支撑和实验依据。

基于癌症“诊疗一体化”的发展思路，引入“纳米催化医学”的新策略，发展一种精确导航定位的光热治疗兼具催化治疗活性的纳米诊疗剂。通过Fe（III）离子介导的氧化聚合制备带羧基官能团的聚吡咯（PPy），无需外加Fe源，利用原体系中过量的Fe（III）离子与新生成的Fe（II）离子在PPy表面原位生长四氧化三铁（Fe3O4）纳米颗粒，再经过葡萄糖氧化酶（GOD）的表面修饰，制备 GOD@Fe3O4@PPy复合纳米诊疗剂。一方面通过系统性地调控该有机/无机杂化材料体系，开拓PPy同时跨越近红外一区（NIR-I）和近红外二区（NIR-II）作为高效光热剂和高清光声成像（PAI） 造影剂的潜能；另一方面通过科学合理地组合生物活性酶和无机纳米酶，连锁且高效地进行生物酶催化反应和芬顿（Fenton）反应，实现化学动力学肿瘤治疗（CDT）。在第一步生物酶催化反应中，GOD 选择性地催化肿瘤内的葡萄糖生成过氧化氢（H2O2）与葡萄糖酸，H2O2作为Fenton反应的底物，葡萄糖酸进一步降低肿瘤微环境的pH值。在酸性条件下H2O2被体系中的Fe3O4催化生成高毒性的活性氧物种羟基自由基（OH·），诱导肿瘤细胞凋亡。PPy的光热效应也可以加快Fenton反应，提高 OH·的产生水平。此外，PPy的基底和Fe3O4的原位掺杂分别赋予其高清 PAI 和磁共振成像（MRI）精确导航的功能，最终实现 MRI/PAI双模态导航下对肿瘤的高效PTT/CDT协同治疗。