用于脑胶质瘤治疗的多靶点靶向脂质体联合给药系统的研究

Glioma is one of the most common types of brain tumor. Although extensive efforts have been made to improve efficacy of chemotherapy, there is no effective treatment currently available for this malignant disease. In order to treat glioma as thoroughly and safely as possible, it is necessary to kill both non-tumorigenic glioma cells and glioma stem cells at the same time. To this end, co-delivery of multi-tageted liposomal systems is proposed to target brain-blood barrier (BBB), normal glioma tumor cells as well as glioma stem cells.These glioma targeted liposomal systems include: 1)brain-targeted moiety-CDX and glioma-targeted moiety-c(RGDyK) modified liposomes that will be utilized to deliver chemotherapeutics-paclitaxel to kill nronal glioma cells; 2)brain-targeted moiety-CDX and glioma stem cell-targeted moiety-AQYLNPS modified liposomes that will be utilized to deliver bortezomib (BTZ) to kill glioma stem cells.Optimized co-delivering regimen of these two targeted liposomal systems will take fully advantage of their multi-targeted effects, thus eventually leading to a new direction in the treatment of gliomas.

脑胶质瘤是最常见的脑内恶性肿瘤，尚无令人满意的药物治疗方法。本课题针对脑胶质瘤存在血-脑屏障（BBB）、普通肿瘤细胞和肿瘤干细胞，拟采用两种脑胶质瘤靶向脂质体递药系统联合给药，提高药物入脑量，共同靶向打击瘤体中普通肿瘤细胞和肿瘤干细胞，实现高效低毒的治疗目标，为临床治疗脑胶质瘤提供有益思路。脑胶质瘤靶向脂质体递药系统（一）采用脑靶向分子CDX、脑胶质瘤细胞靶向分子c(RGDyK)共修饰脂质体递药系统，赋予其跨BBB、靶向普通脑胶质瘤细胞的功能，携带紫杉醇靶向打击普通脑胶质瘤细胞；脑胶质瘤靶向脂质体递药系统（二）采用脑靶向分子CDX、脑胶质瘤干细胞靶向分子AQYLNPS类似肽共修饰脂质体递药系统，赋予其跨BBB、靶向脑胶质瘤干细胞的功能，携带硼替佐米靶向打击脑胶质瘤干细胞；利用不同靶点靶向优势互补，开展两种靶向脂质体递药系统联合给药，优化给药方案，实施对脑胶质瘤深度打击。

本课题针对脑胶质瘤治疗中存在的血-脑屏障、血-脑肿瘤屏障和脑胶质瘤细胞、脑胶质瘤干细胞以及肿瘤微环境中新生血管和拟态血管的特点，主要开展了以下研究：构建了脑靶向多肽CDX、脑胶质瘤靶向多肽A7R的纳米递药系统，以及双靶分子CDX/cRGD、CDX/A7R介导的多重靶向递药系统，对其进行了多肽靶分子稳定化与体内外靶向性研究，并探讨了稳定性靶分子提高靶向效率的机制，对递药系统包载抗肿瘤药物或抗肿瘤干细胞药物后的脑胶质瘤药效进行了评价，并对靶向机理和药效机理进行探讨；开展了抗肿瘤和肿瘤干细胞药物卡非佐米的A7R介导靶向递药系统与脑胶质瘤临床一线药物替莫唑胺的联合用药研究。实验结果表明：课题所构建的主动靶向纳米递药系统均明显增加所载药物到达脑胶质瘤的药物量，显著提高了药物疗效。其中，CDX具有良好的脑靶向作用，可介导递药系统跨越血脑屏障；A7R具有良好的脑胶质瘤靶向作用，可介导递药系统对脑胶质瘤中的肿瘤细胞、肿瘤干细胞以及微环境中的新生血管和拟态血管靶向递药，且可介导递药系统跨血-脑肿瘤屏障；引入稳定性靶分子可克服血中和脑毛细血管内皮细胞内的酶所构成的“酶屏障”，从而在体内发挥更好的介导递药系统脑靶向效应和抗脑胶质瘤效果；多肽靶分子联用构建的多重靶向递药系统可跨血-脑屏障后靶向脑胶质瘤或跨血-脑肿瘤屏障后靶向脑胶质瘤，显著提升抗脑胶质瘤药效。卡非佐米的A7R介导靶向递药系统与临床一线药物替莫唑胺联合用药后，也显著提高了替莫唑胺的抗脑胶质瘤效果。.本课题的研究成果提示，1）新靶向策略的引入，可显著改善现有药用辅料所构建递药系统的药效；2）靶向分子稳定性改善，可进一步提高递药系统靶向治疗效果。以上成果为脑胶质瘤靶向治疗的设计与优化提供了理论和实践指导。

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