【摘要】：神經(jīng)膠質(zhì)瘤發(fā)病率高、患者存活期短，臨床現(xiàn)有手段難以將其治愈。現(xiàn)有的神經(jīng)膠質(zhì)瘤靶向分子由于在腫瘤組織中的低滲透性而無法介導靶向遞藥系統(tǒng)滲透到整個腫瘤組織。神經(jīng)氈蛋白-1（NRP-1）是一種在神經(jīng)膠質(zhì)瘤細胞和腫瘤血管內(nèi)皮細胞表面均有高表達的受體。RGERPPR多肽，NRP-1的特異性配體，是一種腫瘤穿透肽，具有穿透腫瘤血管壁和腫瘤組織的能力。本研究擬采用“NRP-1介導靶向”策略，開展RGERPPR多肽修飾的阿霉素脂質(zhì)體遞藥系統(tǒng)對神經(jīng)膠質(zhì)瘤的靶向治療研究，以期達到：通過靜脈注射給藥，脂質(zhì)體與神經(jīng)膠質(zhì)瘤血管內(nèi)皮細胞表面NRP-1受體特異性結(jié)合，穿透腫瘤血管壁，并滲透進入整個腫瘤組織內(nèi)部；在神經(jīng)膠質(zhì)瘤細胞表面NRP-1受體的介導作用下，脂質(zhì)體進入腫瘤細胞，，發(fā)揮阿霉素的抗腫瘤生長作用，實現(xiàn)對神經(jīng)膠質(zhì)瘤靶向治療的目的。 本論文首先合成了RGERPPR-PEG-DSPE并利用其制備了RGERPPR多肽修飾的脂質(zhì)體（RGE-LS），經(jīng)檢測，脂質(zhì)體平均粒徑約為90nm，分布均勻。細胞攝取實驗和近紅外活體成像實驗表明RGE-LS顯示出增加的神經(jīng)膠質(zhì)瘤細胞攝取和顱內(nèi)神經(jīng)膠質(zhì)瘤分布。細胞毒性實驗和體內(nèi)抗神經(jīng)膠質(zhì)瘤研究證明RGERPPR多肽的修飾可顯著增加阿霉素脂質(zhì)體對神經(jīng)膠質(zhì)瘤細胞的生長抑制作用，并顯著延長神經(jīng)膠質(zhì)瘤動物模型的生存時間。最后，免疫熒光染色分析實驗證明RGE-LS能夠穿透腫瘤血管和腫瘤實質(zhì)，并滲透進入整個腫瘤組織。實驗結(jié)果表明腫瘤穿透肽修飾是提高阿霉素脂質(zhì)體抗神經(jīng)膠質(zhì)瘤作用的一種有效策略。 本研究成果將為解決當前神經(jīng)膠質(zhì)瘤和其它腫瘤的主動靶向治療困境提供一種新的思路。
[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.
【學位授予單位】：上海交通大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R739.41

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