靶向脑胶质瘤干细胞的双修饰纳米递药系统的构建及其介导siSurvivin抑制脑胶质瘤耐药和复发的研究

Our previous studies on “dual targeting effect” delivery system has been published in the “Biomaterials ”(IF=7.6), but the inherent resistance and recurrence of glioma have not be alleviated. In this study, we mainly aims at the glioma stem-like cells(GSCs), which usually are thought to be the culprit of glioma recurrence and resistance. The main problem need to overcome is how to effective target to GSCs and how to mediate siSurvivin to glioma stem cells for inhibition of drug resistance and recurrence of glioma. We firstly designed the nanosystem with double targets to penetrate the blood- brain barrier, accumulate into gliomas, active target to CD133+ glioma stem cell. The targeting efficiency and apoptosis induction effect of the double targets modified nanosystem were investigated in vitro and in vivo, and then the effect of the double targets modified nanosystem on drug resistance and recurrence of brain gliomas was furtherly investigated . Selective killing of cancer stem-like cells may make a breakthrough for the targeted therapy of malignant glioma. Our expected results will provide siSurvivin delivery carrier for clinical application and new therapeutic strategies and methods for the treatment of gliomas.

申请人前期制备了具有脑血管内皮及脑瘤“双重”靶向作用的纳米载药系统，发表在文章Biomaterials（IF=7.6）上，但上述研究并没有缓解胶质瘤固有的耐药性和较高复发率的问题，因此本项目拟针对胶质瘤极易耐药和复发的主要根源“胶质瘤干细胞”采取进一步的技术攻关，主要解决“如何靶向胶质瘤干细胞并通过siSurvivin对脑胶质瘤干细胞的有效干扰作用来抑制脑胶质瘤的耐药和复发”的难题，设计和制备出能够通过血脑屏障进入脑瘤并主动靶向CD133+胶质瘤干细胞的靶向双修饰纳米递药系统，分别从细胞水平和动物水平上探索此递药系统对CD133+胶质瘤干细胞的靶向效率其介导siSurvivin对CD133+胶质瘤干细胞的凋亡诱导效应，从而考察其对脑胶质瘤耐药和复发的影响。预期研究成果将推动siSurvivin在基因治疗脑胶质瘤中的临床应用，同时为胶质瘤干细胞的靶向治疗提供具有应用价值的递送载体。

开发安全、高效的纳米复合物用于脑胶质瘤肿瘤干细胞的靶向成像和治疗已成为一个巨大的挑战。该项目以低密度脂蛋白受体相关蛋白和结合CD133的RNA适配体为双靶向配体，制备携载survivin-siRNA和紫杉醇药物的双修饰阳离子脂质体（DP-CLPs-PTX-siRNA），用于CD133+胶质瘤干细胞后的主动靶向成像和治疗。DP-CLPs-PTX-siRNA纳米复合物给药后，能透过血脑屏障（BBB），表现出与胶质瘤细胞和脑微血管内皮细胞（BCECs）的亲和能力、并具备传递药物（PTX/siRNA）至CD133+胶质瘤干细胞的靶向能力。所制备的纳米复合物对BCECs的细胞毒性非常低，能选择性地诱导CD133+胶质瘤干细胞凋亡，促进CD133+胶质瘤干细胞向非干细胞系细胞分化，并能显著抑制肿瘤发生，在荷瘤裸鼠脑胶质瘤中诱导CD133+ 细胞凋亡，极大到延长了移植瘤裸鼠的生存期。综上所述，所制备的DP-CLPs-PTX-siRNA纳米复合物在体内外能够选择性诱导CD133+胶质瘤干细胞凋亡，在脑胶质瘤干细胞的靶向成像和治疗方面具有巨大的潜力。