三级同心轴电纺丝技术构建贝伐单抗-阿苯达唑-替莫唑胺复合缓释系统局部控释治疗恶性胶质瘤及其机制研究

More than 90% of gliomas recur within 2cm of the residual cavity. The local chemotherapy system characterized by a higher drug concentration and longer treatment duration in the focal location is a promising therapeutic strategy for glioma patients. However, existing local chemotherapy systems are companied by some disadvantages such as chemoresistance and brain edema. Intratumoral hypoxia not only is an important factor of glioma resistance to bevacizumab (BEV) treatment, but also contributes to several molecular mechanisms mediating temozolomide (TMZ) resistance. As such, we preliminarily screened and verified that albendazole (ABZ) effectively inhibits intratumoral hypoxia. ABZ has a low toxicity and high activity when used as an antihelmintic drug over the decades. We will construct a BEV-ABZ-TMZ composite sustained release chemotherapy system by the tri-co-axial electrospinning technique using gelatin, polycaprolactone, and polyethylene oxide as materials, which results in accurately controlling the time and phase of drugs sequential release. BEV in the outer sheath alleviates brain edema and impairs tumor angiogenesis of the residuals, improving the safety of sustained release chemotherapy system. ABZ in the intermediate layer inhibits the expression of HIF-1α, which overcomes the chemoresistance of gliomas. TMZ in the core is cytotoxic to tumor cells so that glioma recurrence is prevented. In this study, the appropriate drug release curve, the ratio of drugs and other technique details will be determined and the safety and efficacy of this local sustained release chemotherapy system will be validated by an orthotopically implanted glioma model.

超过90％的胶质瘤复发出现于瘤腔周边2cm范围内。局部化疗可提高病灶处的药物浓度及作用时间，是防治胶质瘤复发的有效方法。然而，现有局部化疗系统存在引起脑水肿及化疗耐药等问题。肿瘤低氧不仅是胶质瘤抵抗贝伐单抗治疗的重要因素，而且参与介导多种替莫唑胺耐药的分子机制。我们前期筛选并验证了阿苯达唑可有效抑制肿瘤低氧,阿苯达唑低毒高效，是临床上应用多年的抗寄生虫药物。我们拟采用明胶、聚己内酯及聚氧化乙烯，借助三轴电纺丝技术，构建贝伐单抗-阿苯达唑-替莫唑胺新型复合缓释系统，实现对多种药物序贯释放的精确调控：外层贝伐单抗减轻术后脑水肿、阻断残存肿瘤血管生成，提高缓释系统安全性；中层阿苯达唑抑制胶质瘤产生低氧环境，逆转化疗抵抗性；核心层替莫唑胺杀伤肿瘤细胞，三药协同抑制胶质瘤复发。本研究将明确该缓释体系的药物释放曲线、药物配比等技术细节，并验证其在原位胶质瘤动物模型中的安全性及疗效。

超过90％的胶质瘤复发出现于瘤腔周边2cm范围内，而血脑屏障的存在使多数药物难以在术腔局部维持有效浓度，因此术后局部放置缓释载体独具优势。然而，传统局部缓释载体存在化疗耐药、易引发脑水肿等问题。本项目应用同心轴静电纺丝技术，将多种化疗药物一期包封于缓释体系的内外层，并在原计划基础上通过引入靶向性纳米颗粒对缓释体系进行优化升级，实现了对多药序贯性释放行为的精准调控。相比单纯负载化疗药物的传统载体，该复合体系具备更优异的靶向性、控释性、摄取率及药代动力学表现，其通过联合多种细胞死亡形式，多药协同长期抑制胶质瘤复发。本项目所构建的中枢神经系统智能化纳米载药平台，为后续临床转化提供了必要的基础研究资料，也为神经退行性疾病、创伤性疾病等其他中枢神经系统相关疾病的治疗提供了设计指引。. 本项目按计划顺利进行，取得了多项重要研究成果：.①采用同心轴电纺丝技术成功构建搭载多种化疗药物的复合缓释体系，完成了对载体理化性质的表征与测定，并通过优化技术工艺，显著提升了静电纺丝的载药量、包封率和生物相容性，前期突释效应明显降低，动物无明显不良反应，缓释特征符合胶质瘤的临床治疗场景；.②构建了纳米颗粒—静电纺丝复合缓释体系，可有效保护所载核酸药物、蛋白的生物活性（在体有效性可维持1个月以上、荷瘤小鼠总生存期延长近5倍），并联合光热等物理治疗手段，进一步提升了体系的长效性、有效性和安全性；.③研制了多种智能化载药纳米颗粒，并通过优化其理化特征、修饰靶向分子，使其高效穿透血脑屏障的同时，实现对肿瘤细胞的精准打靶，扩展了缓释体系的用药选择。. 项目研究成果已发表高水平SCI论文12篇（影响因子10分以上4篇），申请国家发明专利4项（授权3项），获省级奖励一等奖1项，培养省级人才2名；并正与相关公司洽谈，进一步推动临床转化进程。