基于神经毡蛋白-1介导神经胶质瘤靶向的脂质体递药系统研究

Glioblastoma shows a high incidence rate, and the life times of the patients were quite short. It is hardly to be cured by current clinical techniques. At present, the active targeting drug delivery system cannot penetrate into the whole tumor tissue due to the poor permeability of the targeting moiety in the tumor tissue. Neuropilin-1(NRP-1) is a receptor overexpressed on both glioblastoma cells and tumor endothelium. RGERPPR peptide, the specific ligand of NRP-1, is a tumor-penetrating peptide, able to penetrate through tumor vessels and tumor tissues. In this study, we will adopt the "NRP-1 mediated targeting" strategy, and study the targeted therapy of glioblastoma by using the RGERPPR-conjugated doxorubicin-loaded liposome delivery system. The study was conducted to verify our hypothesis that following intraveneous administration, the prepared liposomes specifically bind to NRP-1 on glioblastoma endothelium, penetrate through tumor vessel and into the whole tumor tissue. After that, being mediated by NRP-1 on glioblastoma cells, the prepared liposomes enter tumor cells, and the loaded doxorubicin inhibits the tumor cell growth, thereby attaining the aim of targeted therapy of glioblastoma. This study will provide a novel solution for the current dilemma of active targeted therapy of glioblastoma and other types of tumor.

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。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。

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。本研究采用“NRP-1 介导靶向”策略，开展了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。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，可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。