基于Re-Fe合金纳米壳的可降解诊疗制剂的设计制备及肿瘤靶向治疗应用

以金为代表的贵金属纳米粒子具有良好的生物相容性，在生物医学领域有广泛的应用，但是其不可降解特性限制了其在肿瘤诊疗中的临床应用。本项目基于Re纳米粒子在过氧化氢中的降解特性，设计并制备具有肿瘤微环境响应降解特性的Re-Fe合金纳米壳诊疗制剂，利用合金纳米壳显著的光热效应和对肿瘤微环境中过氧化氢分子的响应性降解行为，使肿瘤局部快速升温，降解的Fe2+离子可通过芬顿反应产生羟基自由基，从而实现对肿瘤的光热和化动力协同治疗；利用荷载的葡萄糖氧化酶高效催化葡萄糖转化为葡萄糖酸和过氧化氢，进一步提高化动力的疗效以及纳米合金的体内降解速率；借助细胞膜包衣伪装，利用同种癌细胞膜上黏附分子的相互亲和作用，实现肿瘤区域同源靶向富集；并利用Re自身的光吸收及对X射线的衰减特性，实现对恶性程度高、易转移的三阴性乳腺癌的光声/CT多模态影像导引下的光热/化学动力治疗，为开发具有临床应用价值的诊疗纳米制剂奠定基础。

Noble metal nanoparticles, including representative member of Au, have great potentials in biomedical fields for its high biocompatibility, however, the un-degradability of Au nanoparticles hinders its clinical applications in cancer theranostics. Herein, we proposed the design and fabrication of degradable Re-Fe nanoshell theranostic agents based on the hydrogen peroxide-sensitive degradation of Re nanoparticles, and the utilization of photothermal and chemodynamic synergistic therapy of cancer, which are achieved by photothermal effect and the presence of hydroxyl radical upon Fenton reaction of released Fe2+ at the cost of Re-Fe nanoshell degradation by hydrogen peroxide from tumor microenvironment, respectively. The glucose oxidase loaded on Re-Fe nanoshells is supposed to catalyze the conversion of glucose to glucose acid and hydrogen peroxide, which can promote the efficiency of chemodynamical therapy as well as in vivo degradation of Re-Fe nanoshells. Upon coating of cancer cell membrane, Re-Fe nanoshell agents can be homologous-targeting accumulated in tumor region through the affinity interaction of adhesion molecules on the membrane of homogenous cancer cells, paving way for PA/CT bimodal-guided photothermal and chemodynamical synergistic therapy of triple negative breast carcinoma with high malignancy and metastasis by utilization of the photo-absorption and attenuation of X-ray with Re. This project is thus an important step towards the development of theranostics nanoagents with clinical potentials.