葡萄糖氧化酶-普鲁士蓝纳米酶分子探针用于三阴性乳腺癌多重增效治疗及双模态成像研究

Triple negative breast cancer (TNBC) is highly invasive and has a poor prognosis. There is currently no effective treatment for it. Photodynamic therapy has high efficiency and small side effects, so it has the potential to improve the therapeutic effect of TNBC. However, factors such as tumor hypoxia limit the efficacy of photodynamic therapy. Therefore, the preparation of a multifunctional nanoprobe that can provide oxygen and has different therapeutic principles will improve the therapeutic effect of TNBC. Based on the catalytic characteristics of glucose oxidase (GOx) and Prussian blue nanoenzyme, this project proposes the combination of GOx and mesoporous Prussian blue to achieve targeted imaging and multiple synergistic treatment of TNBC. The HA on the probe targets to the CD44 receptor, which is highly expressed on the surface of TNBC. GOx catalyzes the production of hydrogen peroxide by glucose, and the hydrogen peroxide produced generates oxygen under the catalysis of Prussian blue. It not only accelerates the consumption of glucose to achieve starvation therapy, but also promotes the conversion of oxygen to singlet oxygen by the photosensitizer Ce6. The gluconic acid produced by GOx lowers the pH of cells and stimulates the release of doxorubicin in the probe. In addition, accurate imaging of TNBC can be realised by MR/photoacoustic imaging. It is expected that the GOx-Prussian blue nanoenzyme targeting probe can overcome tumor hypoxia, achieve multiple synergistic therapy of starvation-photodynamic-chemo therapy and tumor real-time imaging. It may provide new ideas for diagnosis and treatment of TNBC.

三阴性乳腺癌（TNBC）侵袭性强且预后不良，目前尚无有效治疗方案。而光动力治疗效率高且副作用小，具有提高TNBC疗效的潜力。但肿瘤乏氧等因素将限制光动力治疗疗效，因此制备一种能提供氧气且具有不同治疗原理的多功能纳米探针将提高TNBC治疗疗效。本项目参考葡萄糖氧化酶（GOx）和普鲁士蓝纳米酶的催化特点，提出将GOx和介孔普鲁士蓝联合以实现TNBC靶向成像和多重增效治疗的设想。探针上的HA靶向肿瘤表面高表达的CD44受体，GOx消耗葡萄糖生成过氧化氢，在普鲁士蓝催化下生成氧气，不仅加速了葡萄糖的消耗实现饥饿疗法，还促进光敏剂Ce6将氧气转化成单线态氧。GOx生成的葡萄糖酸使 pH下降，刺激探针中的阿霉素释放。此外通过MR/光声成像可对TNBC进行精准成像。预期该GOx-普鲁士蓝纳米酶靶向探针在克服肿瘤乏氧的同时可以实现饥饿-光动力-化疗多重增效治疗并实时观察肿瘤变化，为TNBC诊疗提供新思路。

光动力治疗（PDT）对三阴性乳腺癌（TNBC）治疗效率高且副作用小，但肿瘤乏氧及缺乏靶向等因素限制了其疗效，因此如何提高光动力治疗疗效是延长乳腺癌病人生存期的关键问题。本项目制备并表征了一系列增效PDT的纳米载体，包括中空普鲁士蓝，中空柔性纳米蛋白胶囊及沸石咪唑酯骨架-8。为实现药物的精准递送，本项目设计的沸石咪唑酯骨架-8具有肿瘤微环境响应功能，柔性中空人血清白蛋白具有肿瘤高摄取及肿瘤靶向能力，另外在载体表面交联具有主动靶向作用的透明质酸，并定量了载体与药物的质量关系，进一步提高了药物在肿瘤的富集率，减少了药物的非特异释放，同时，利用磁共振、光学成像等影像学方法示踪药物的体内分布及靶向能力；为了提高PDT疗效，本项目用普鲁士蓝提供氧气克服肿瘤乏氧导致的光动力疗效降低的问题，并联合饥饿疗法、化学疗法等治疗方式对肿瘤进行局部及全身治疗，显著提高了乳腺癌治疗疗效。本项目按照研究计划和研究内容顺利完成，为TNBC的治疗提供了新思路。依托此项目发表文章7篇，IF>5的3篇，IF>9的2篇。项目负责人以第一作者或通讯作者发表SCI论文3篇，其中IF>5 的1篇。