双靶向多靶点纳米放疗增敏剂的构建及其增敏放射治疗脑胶质瘤的研究

Glioma is the most common intracranial tumor, threatening human health and life. Radiation therapy played an important role in treatment of glioma after surgery. Irradiation of glioma has little effect, due to the presence of blood brain barrier and its resistant to radiation. In previous studies, we have demonstrated that a hypoxic radiosensitizer-prodrug nanoparticle can overcome these problems and increase radiosensitivity of glioma. The result was published on Biomaterials (IF 8.3). In this study, we prepared a PEG2000-Ploy-Lys-PMTZ prodrug nanocarrier with blood brain barrier and glioma targets, which contained hypoxic radiosensitizer nitroimidazoles, to deliver DNA repair inhibitor Dbait and arrest cell cycle in G2/M to sensitive radiation paclitaxel to increase radiosensitivity of glioma. Before formal experiment, a portion of material was synthesized. Our expected results will provide a multitargeted nano-radiosensitization for clinical radiotherapy application and improve the effect of radiotherapy on glioma.

脑胶质瘤是颅内最常见的难治性恶性肿瘤，术后放疗是重要的治疗手段，但因血脑屏障的存在和胶质瘤细胞对射线的不敏感，放疗效果不好。前期研究发现，将放疗增敏剂制备成纳米前药可以克服上述问题，有效地增敏脑胶质瘤的放射治疗，该结果发表于Biomaterials（IF 8.3）。在此基础上，本项目预合成和制备“靶向血脑屏障和靶向脑胶质瘤”双靶向修饰的PEG2000-Poly-Lys-PMTZ（含有阳离子聚合物的Poly-Lys和具有聚甲硝唑的PMTZ乏氧细胞增敏剂）前药纳米载体，递送抑制DNA修复能力来增敏肿瘤细胞的Dbait分子和将细胞周期阻滞在放射敏感的G2/M期来增加放疗敏感性的紫杉醇，实现双靶向、多靶点纳米放疗增敏剂增敏脑胶质瘤放射治疗，有效的杀死脑胶质瘤。预实验已经完成部分材料的合成。本研究的如期完成，将为临床放射治疗脑胶质瘤提供有应用价值的纳米放疗增敏剂，提高放射治疗效果。

脑胶质瘤是颅内最常见的难治性恶性肿瘤，术后放疗是重要的治疗手段，但因血脑屏障的存在和胶质瘤细胞对射线的不敏感，放疗效果不好。鉴于此，本研究制备了如下三种纳米放疗增敏剂增强了脑胶质瘤的放射治疗疗效。具体包括以下三方面研究内容：1）具放疗增敏和缺氧响应的脂质-聚合物纳米颗粒递送疏水性化疗药物实现放化疗协同治疗脑胶质瘤的实验研究；2）具缺氧放疗增敏功能纳米载体靶向递送替莫唑胺协同放射治疗脑胶质瘤的实验研究；3）缺氧放疗增敏脂质体递送金纳米颗粒协同脑胶瘤放射治疗的实验研究。上述研究发表在包括Theranostics（IF = 11.556）、Biomaterials（IF = 12.479）等在内18篇SCI论文, 授权5项中国发明专利。研究成果《脑胶质瘤分子靶点筛选及转化的关键技术创新》获得2020年江苏省科学技术奖一等奖和2020年江苏省医学科技奖一等奖。我们通过将缺氧放疗增敏剂甲硝唑制备成疏水内核，首次通过脂质-聚合物的组装方式递送化疗药物阿霉素，联合放化疗治疗脑胶质瘤，该结果被生物医学领域TOP期刊Theranostics选作封面。上述结果在脑胶质瘤放疗化疗疗效方面被Chem Soc Rev (IF：40.443) 进行了重点评述；在将缺氧放疗增敏剂制备成聚合物前药纳米载体，有效地提高了载药量方面被Angew Chem Int Ed Engl (IF: 12.257)给予了肯定。本研究为临床放射治疗脑胶质瘤提供有应用价值的纳米放疗增敏 剂，提高放射治疗效果。