肿瘤穿透肽介导的神经胶质瘤靶向脂质体递药系统研究

发布时间：2018-07-15 22:05

【摘要】：神经胶质瘤发病率高、患者存活期短，临床现有手段难以将其治愈。现有的神经胶质瘤靶向分子由于在肿瘤组织中的低渗透性而无法介导靶向递药系统渗透到整个肿瘤组织。神经毡蛋白-1（NRP-1）是一种在神经胶质瘤细胞和肿瘤血管内皮细胞表面均有高表达的受体。RGERPPR多肽，NRP-1的特异性配体，是一种肿瘤穿透肽，具有穿透肿瘤血管壁和肿瘤组织的能力。本研究拟采用“NRP-1介导靶向”策略，开展RGERPPR多肽修饰的阿霉素脂质体递药系统对神经胶质瘤的靶向治疗研究，以期达到：通过静脉注射给药，脂质体与神经胶质瘤血管内皮细胞表面NRP-1受体特异性结合，穿透肿瘤血管壁，并渗透进入整个肿瘤组织内部；在神经胶质瘤细胞表面NRP-1受体的介导作用下，脂质体进入肿瘤细胞，，发挥阿霉素的抗肿瘤生长作用，实现对神经胶质瘤靶向治疗的目的。本论文首先合成了RGERPPR-PEG-DSPE并利用其制备了RGERPPR多肽修饰的脂质体（RGE-LS），经检测，脂质体平均粒径约为90nm，分布均匀。细胞摄取实验和近红外活体成像实验表明RGE-LS显示出增加的神经胶质瘤细胞摄取和颅内神经胶质瘤分布。细胞毒性实验和体内抗神经胶质瘤研究证明RGERPPR多肽的修饰可显著增加阿霉素脂质体对神经胶质瘤细胞的生长抑制作用，并显著延长神经胶质瘤动物模型的生存时间。最后，免疫荧光染色分析实验证明RGE-LS能够穿透肿瘤血管和肿瘤实质，并渗透进入整个肿瘤组织。实验结果表明肿瘤穿透肽修饰是提高阿霉素脂质体抗神经胶质瘤作用的一种有效策略。本研究成果将为解决当前神经胶质瘤和其它肿瘤的主动靶向治疗困境提供一种新的思路。
[Abstract]:The incidence of glioma is high and the survival time of patients is short. The existing glioma targeting molecules can not mediate the targeting delivery of drugs to the whole tumor tissue due to their low permeability in tumor tissues. Felt protein 1 (NRP-1) is a specific ligand with high expression on the surface of glioma cells and tumor vascular endothelial cells. NRP-1 is a tumor penetrating peptide and has the ability to penetrate tumor vascular wall and tumor tissue. In this study, the "NRP-1 mediated targeting" strategy was used to study the targeted treatment of glioma by RGERPPR polypeptide modified doxorubicin liposome delivery system, in order to achieve: intravenous administration, The liposome binds specifically to the NRP-1 receptor on the surface of glioma vascular endothelial cells, penetrates the vascular wall of the tumor and penetrates into the whole tumor tissue, and is mediated by the NRP-1 receptor on the surface of glioma cells. Liposomes enter into tumor cells and play the role of adriamycin in the treatment of glioma. RGERPPR-PEG-DSPE was first synthesized and RGERPPR polypeptide modified liposomes (RGE-LS) were prepared by RGERPPR-PEG-DSPE. The average particle size of RGERPPR-PEG-DSPE was about 90 nm. Cell uptake and near infrared imaging showed that RGE-LS showed increased uptake of glioma cells and distribution of intracranial gliomas. Cytotoxicity tests and in vivo antiglioma studies showed that the modification of RGERPPR peptide could significantly increase the growth inhibition of glioma cells induced by adriamycin liposome and prolong the survival time of glioma animal model. Finally, immunofluorescence staining results show that RGE-LS can penetrate tumor blood vessels and tumor parenchyma and penetrate into the whole tumor tissue. The results show that tumor penetrating peptide modification is an effective strategy to improve the antiglioma effect of adriamycin liposome. The results of this study will provide a new way to solve the problem of active target therapy for gliomas and other tumors.
【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R739.41

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