肿瘤微环境响应的多功能支化大分子给药系统及其对胶质瘤的放疗--化疗协同治疗研究

Glioma is one of the biggest problems to human health. However, current chemotherapy or radiotherapy is limited as the chemotherapeutic agents are largely limited by extremely low permeability of the blood brain barrier (BBB), resulting in low therapy index and high side-effects to healthy tissues. Additionally, no efficient radiosensitizer can be used for radiotherapy in glioma therapy. Nanoscale drug delivery systems have been extensively evaluated as anticancer therapeutics and cancer diagnosis. In our previous studies, linear polymers and dendrimers-based nanoscale drug delivery vehicles have showed great potential as gene/drug/imaging probe delivery for cancer therapy and diagnosis. In this project, multifunctionlized and environmental response branched oligo(ethylene glycol) methacrylate (PEGMA) copolymers will be designed and prepared as nanoscale vehicles for synergistic anti-glioblastoma multiforme therapy by combination of chemotherapy and radiotherapy. The contents of this project included three parts: 1) the design and preparation of environmental response and nanoscale branched copolymers; 2) the studies on the MRI-imaging guided synergistic anti-glioma by combination of chemotherapy and radiotherapy, and the relationship between the results and compositions of drug delivery systems, 3) the studies on biocompatibility of the drug delivery systems. Our prepared drug delivery systems will be possible to achieve 1) increased BBB permeability; 2) targeted delivery of chemotherapeutics and radiosensitizer to cancer glioma cells/tissues for synergistic anti-glioma by combination of chemotherapy and radiotherapy; 3) the stimuli-responsive drug release and degradation of the nanoscale vehicles; and 4) real-time read on the in vivo efficacy of therapeutics by MRI imaging. The studies will overcome some bottle-neck problems to preparation of multifunctional branched copolymers based nanoscale drug delivery systems with significant increased therapeutic efficacy and good biosafety for anti-glioma. This targeted strategy will contribute to the development of polymeric nanoscale drug delivery systems entranced into clinical application for glioma therapy.

本项目针对胶质瘤面临的精准和放化疗协同治疗难题，立足我们在大分子给药系统研究的积累，融合国际前沿，以水溶性良好的聚寡乙二醇甲基丙烯酸酯（PEGMA）聚合物为载体材料，通过可逆加成-断裂链转移（RAFT）聚合等合成方法构建肿瘤微环境响应、可同时偶联具有放疗增敏的化疗药（吉西他滨、奈达铂）、2-硝基咪唑类放疗增敏剂、开启血脑屏障（BBB）的激动剂、胶质瘤高靶向基团和MRI分子探针的多功能支化大分子纳米给药系统，实现诊断、化疗和放疗协同治疗一体化；建立高效跨BBB、胶质瘤高靶向和高效抗胶质瘤、安全的可降解支化大分子给药系统的构建技术与方法；揭示纳米给药系统在MRI成像指导下的精准放疗-化疗协同治疗胶质瘤的原理以及相关分子机制；获得具有我国自主知识产权、用于胶质瘤治疗的支化大分子纳米给药系统，为研究和开发高效、安全的、影像技术指导下放化疗协同治疗胶质瘤的纳米给药系统奠定基础。

神经胶质瘤是影响人类健康的最大疾病之一。然而，目前的化疗或放疗受到限制，化疗药物很大程度上受到血脑屏障（BBB）通透性极低的限制，导致治疗指数低，对健康组织的副作用大。本项目针对胶质瘤面临的精准和放化疗协同治疗难题，立足我们在大分子给药系统研究的积累，融合国际前沿，以水溶性良好的甲基丙烯酸羟丙酯（HPMA）分子为载体材料，通过可逆加成-断裂链转移（RAFT）聚合等合成方法构建肿瘤微环境响应、可同时偶联具有化疗药物、胶质瘤高靶向基团和MRI分子探针的多功能线性及支化大分子纳米给药系统，实现诊断和化疗协同治疗一体化；建立高效跨BBB、胶质瘤高靶向和高效抗胶质瘤、安全的可降解线性及支化大分子给药系统的构建技术与方法；揭示纳米给药系统在MRI成像指导下的精准治疗胶质瘤的原理以及相关分子机制；获得具有我国自主知识产权、用于胶质瘤治疗的支化大分子纳米给药系统，为研究和开发高效、安全的、影像技术指导下放化疗协同治疗胶质瘤的纳米给药系统奠定基础。本项目进一步研究了光动力给药系统对乳腺癌肿瘤细胞有效的作用机制以及是否存在与阿霉素联用治疗肿瘤的理论依据，我们着重于探索PDT给药系统能有效控制恶性肿瘤转移的一些分子机制，并研究这些机制是否能为将PDT给药系统和阿霉素联用提供理论基础，从而借助给药系统的优势实现将PDT和阿霉素化疗这两种治疗手段联合应用来解决恶性肿瘤转移的问题。本项目以第一/通讯作者发表SCI论文28篇，获得中国发明专利5项，参与出版英文书籍1本。