重塑胶质瘤微环境的新型高精准纳米诊疗体系构建与评价

Malignant glioma is characterized by complex etiology and pathogenesis, rapid growth, strong invasiveness, easy recurrence after surgery, and difficulty in radical treatment. Currently, effective treatments for complex immune signal network and tumor microenvironment are still scarce. In our previous study, we found that the polymer-modified metal-organic framework can target delivery of multi-drug for multiple steps of carcinogenesis, but the efficacy and mechanism of multi-drug synergistic treatment for brain tumors need to be further studied. We designed a novel integrated intelligent magnetic resonance imaging diagnosis and treatment platform by grafting T2ex principle pH-sensitive cationic copolymer contrast agent on the surface of MOFs using SI-ATRP technology and cyclic peptide using amide bonding technology, which is a "functional cocktail" gene/chemical/immune drug delivery system with immune tolerance relief, double targeting, controlled intelligent drug release and magnetic resonance tracing function. The purpose of this project is to clarify the efficacy of gene-chemo-immune (GCIT) network treatment of glioma in multilevel and multilevel. At the same time, this project intends to adopt imaging, genomics, and proteomics to explore its mechanism for treatment of glioma at the cells and genetic level. This novel targeted drug delivery system would provide data to support the development and clinical application of the treatment for gliomas.

恶性胶质瘤是一种病因及发病机制复杂、生长迅速、手术后易复发、难根治的强侵袭性肿瘤，目前尚缺少靶向胶质瘤复杂免疫信号网络及肿瘤微环境的有效多药协同治疗策略。我们前期研究发现基于聚合物修饰的金属有机骨架材料能够针对致癌的多个步骤进行靶向多药协同递送，但是多药协同治疗脑肿瘤的疗效和机制有待深入研究。我们通过MOFs表面SI-ATRP和酰胺键键合技术设计了一种新型T2ex类磁共振成像的智能载体，具有免疫耐受解除、双重靶向、药物可控智能释放与磁共振示踪功能。本项目拟通过该载体协同负载基因/化药/免疫药物获得“功能鸡尾酒”型纳米诊疗体系，并在整体、细胞和分子水平明确基因-化药-免疫（GCIT）网络协同多水平、多层次治疗胶质瘤的疗效。同时，项目结合分子生物学、影像学、基因组学与蛋白质组学阐明其在细胞和基因水平治疗胶质瘤的作用机制。本项目的实施将为胶质瘤的新型靶向载药系统开发与临床应用提供数据支撑。

金属有机骨架基纳米药物在抗肿瘤领域的应用取得了重大进展，但其靶向性低等问题严重限制了其在临床中应用。本项目通过构建多种金属有机骨架基纳米药物筛选获得具有肿瘤微环境特异性催化、高酶活性和优良光热性能的多功能集成金属有机骨架纳米药物传输系统。并实现金属有机骨架基纳米药物结合光动力、光热及声动力治疗等多种治疗方式，并在细胞、动物（小鼠人源肿瘤异种移植模型和肺癌脑转移模型）和基因水平上系统评估其靶向作用机制与介导的协同抗肿瘤效果、分子作用机制和临床安全性。本项目的实施为肿瘤精准靶向金属有机骨架基纳米药物的构建提供了一种新颖而实用的方法，对阐明肿瘤新型治疗方式的规律具有重要意义，为金属有机骨架基纳米药物的研究开发、标准化及临床应用提供新的思路。