新型载药纳米疫苗RADA-KLA/EphA/多柔比星复合体的构建和治疗恶性胶质瘤的研究

Malignant gliomas are the most common primary brain tumors with poor prognosis. Immunotherapy provide an appealing promise for patients with gliomas. In this project, based on previous research on peptide self-assembling scaffolds and using the advantage of self-assembling peptide acting as an immune adjuvant, we synthesis self-assembling peptides RADA-KLA and RADA-EphA containing an anti-cancer motif KLA and glioma-associated antigen EphA2, then we build a novel anticancer vaccine loaded with doxorubicin based on self-assembling peptide scaffold RADA-KLA/EphA. This complex could kill the tumor cells directly and have the immunogenicity of EphA2. Meanwhile, it could serve as powerful chemically defined immune adjuvant, raising and activating antigen presenting cells (APCs), present EphA2 to CD8+ T cells which have immunity effect to glioma cells after activated. Moreover, it could delivery and controlled-release doxorubicin. The cytotoxicity and immune activation of doxorubicin continue to play a role in enhancing the efficacy of nano vaccine and improving the prognosis of glioblastoma. This project treats malignant gliomas comprehensively from different aspects, presents a new way of the treatment of malignant gliomas, provides some new ideas for the adjunct therapy after surgery of solid tumors, and has important scientific significance and broad application foreground.

恶性胶质瘤是最常见的原发脑肿瘤，预后极差。免疫治疗为胶质瘤患者带来了新的曙光。本项目以前期多肽自组装材料的研究为基础，利用多肽自组装材料具有免疫激活剂功能的优势，设计合成含有抗癌多肽KLA和胶质瘤相关抗原EphA2的自组装多肽RADA-KLA和RADA-EphA，构建新型载药纳米疫苗RADA-KLA/EphA/多柔比星复合体；该体系同时具有抗癌多肽KLA直接杀伤肿瘤的功能和胶质瘤抗原EphA2的肿瘤疫苗作用；复合体独特的自组装纳米结构还具有免疫激活剂的功能，可募集并激活抗原提呈细胞，将EphA2提呈至CD8+T细胞，激活T细胞产生对胶质瘤细胞的免疫杀伤效应；复合体还负载并缓慢释放多柔比星，持续发挥多柔比星的细胞毒作用以及免疫激活作用，进一步增强纳米疫苗疗效，最大程度改善胶质母细胞瘤预后，为胶质瘤的治疗开辟新的途径，为各种实体瘤术后辅助治疗提供新的思路，具有重要的科学意义和广泛的应用前景。

胶质母细胞瘤（Glioblastoma，GBM）是最常见、最具侵袭力的原发性脑肿瘤。缺氧和抑制性的肿瘤免疫微环境（Tumor Immune Microenvironment，TIME）使GBM对常规治疗方式都不敏感。作为突破肿瘤治疗方法这一瓶颈的途径，TIME可以通过某些纳米材料进行重新编程。在这里，我们用蜂毒肽-RADA32纳米纤维杂化肽包被 C- novyi -孢子，并负载免疫调节剂二甲双胍，成功合成 MRM –Coated Spores。该纳米凝胶材料可作为靶向胶质母细胞瘤的强大抗肿瘤纳米药物，并激活TIME 的免疫反应。 MRM –Coated Spores在体外和体内均表现出持续的释放曲线和强有力的对GBM的杀伤作用。 此外， MRM –Coated Spores 可以通过诱导可持续的 CD8 + T 细胞反应、促进 M1 巨噬细胞极化以及在 TIME 中调节 HIF1-α、PDL1 和CXCL9的表达来激活先天性和适应性免疫应答。在颅内应用中， MRM –Coated Spores显示出出色的生物安全性和强大的治疗效果。总之，肽水凝胶提供了一种有前途的策略，可以结合不同治疗方法的优势，从细菌介导的纳米材料中合成具有轻微副作用的强效抗肿瘤药物。