双适配体功能化外泌体促进铁死亡来靶向治疗和增强胶质瘤放射敏感性的作用和机制研究

胶质瘤的放化疗抗性主要表现在治疗分子不易通过血脑屏障和血液肿瘤屏障、肿瘤细胞放射敏感性差等问题。适配体（aptamer，即适配子）因其高特异性和高亲和力成为肿瘤靶向治疗的研究热点。适配体可运载不同分子，比抗体作为靶向分子具有更大优势。外泌体是细胞主动分泌的纳米级天然囊泡运输分子，具有穿透生物膜的功能。我们已经筛选出针对胶质瘤特异靶标EGFRvIII的适配体有体外靶向抑瘤、放射增敏、诱导铁死亡等作用。本课题拟构建双适配体(EGFRvIII适配体和AMPA受体适配体)功能化的外泌体进行脑内肿瘤动物模型的靶向抑瘤、放射敏感性及其分子机制研究，并探讨铁死亡在此过程中的作用机制。基于不同作用机制的双适配体功能化外泌体具有靶向和协同作用，可提高疗效和放射敏感性；构建的适配体功能化外泌体可携带RNA、药物、放射性核素、荧光等分子，为胶质瘤诊断治疗和药物转运提供新的技术平台。

The Radiochemotherapy resistance of gliomas is mainly manifested in the difficulty of the therapeutic molecules to cross the blood-brain barrier and tumor targeting or poor radiosensitivity of tumor cells. Aptamers have become the focus of research on tumor targeted therapy because of their high specificity and affinity. Aptamers can carry different molecules and have advantages over peptides or antibodies as targeting vectors. Exosomes are nanoscale naturally transporting vesicles secreted by cells, exhibited intrinsic capability for crossing physiologic barriers. We have obtained glioma-specific EGFRvIII aptamers with its effects of in vitro tumor suppression, radiosensitivity and inducing ferroptosis. We will construct functionalized exosomes of EGFRvIII aptamer and AMPA receptor aptamer, and to study targeted tumor suppression, radiosensitivity and molecular mechanisms of in vivo animal models, and explore the role of ferropotosis in this process. The targeting and synergy of aptamers with different mechanisms and the combination of exosomes can improve the therapeutic effect and enhance the radiosensitivity; the constructed aptamer-functional exosomes can carry RNA, drugs, radioactive nuclide and fluorescence moleculesand provide a new technology platform for glioma treatment and drug delivery.