本文選題：CD13 + 神經(jīng)膠質(zhì)瘤��； 參考：《華東師范大學(xué)》2017年碩士論文

【摘要】：腦膠質(zhì)瘤是一種發(fā)生于顱內(nèi)的惡性腫瘤,特別是神經(jīng)膠質(zhì)瘤在臨床上的治療效果非常的不樂(lè)觀,在膠質(zhì)瘤發(fā)病人群中,5年的存活率僅為9.8%,并且患者的生活質(zhì)量非常低。近年來(lái),研究治療腦膠質(zhì)瘤的藥物成為了醫(yī)學(xué)上的難點(diǎn)和熱點(diǎn)。目前主要通過(guò)手術(shù)以及化療和放療來(lái)治療,化療藥物主要有替莫唑胺,丙戊酸和開(kāi)普蘭等,日本學(xué)者有應(yīng)用干擾素對(duì)其進(jìn)行治療,但單純的化療對(duì)于治療效果不是特別理想。因此,研發(fā)出針對(duì)腦膠質(zhì)瘤的化療藥物是一項(xiàng)富有挑戰(zhàn)性的工作。近年來(lái),納米遞藥系統(tǒng)有了很快的發(fā)展,各種高分子納米藥物也不斷增加研發(fā)比例。主動(dòng)靶向納米藥物遞送系統(tǒng)的抗腫瘤效應(yīng)在體內(nèi)遞送中受到腫瘤血管屏障和腫瘤基質(zhì)屏障的阻礙。在這項(xiàng)研究中,為了克服兩個(gè)障礙,我們使用iNGR,一種腫瘤穿透肽,修飾脂質(zhì)體增加其在腫瘤組織中的積累和滲透。iNGR的結(jié)構(gòu)由血管回歸基序,組織穿透基序(R/KXXR/K)和蛋白酶識(shí)別位點(diǎn)組成。一方面,它可以明確地識(shí)別由膠質(zhì)瘤新生血管內(nèi)皮細(xì)胞過(guò)度表達(dá)受體CD13,特別是在病理狀態(tài)。另外,它可以在腫瘤附近通過(guò)特異性酶切割成iNGRt肽(CRNGR序列),其可以特異性穿透腫瘤血管并進(jìn)入深部腫瘤組織,并被膠質(zhì)母細(xì)胞瘤細(xì)胞內(nèi)化。該功能基于iNGRt與其受體NRP-1在腫瘤血管和膠質(zhì)細(xì)胞瘤細(xì)胞上的特異性相互作用。因此,腫瘤血管靶向和腫瘤穿透能力可能使iNGR能夠克服腫瘤血管屏障和腫瘤基質(zhì)屏障。本論文第一章節(jié)首先合成了 iNGR-DSPE-PEG目標(biāo)導(dǎo)向化合物,并制備iNGR-修飾的脂質(zhì)體(iNGR-LS),其顯示約1OOnm的粒徑,且分布均一。論文第二章通過(guò)細(xì)胞體外實(shí)驗(yàn)表明了 iNGR-LS表現(xiàn)出比未修飾的脂質(zhì)體(LS)顯著增加了 U87MG腫瘤細(xì)胞和HUVEC的細(xì)胞內(nèi)化,增加了腫瘤細(xì)胞的攝取。與普通的多柔比星脂質(zhì)體(LS/DOX)相比較,iNGR多肽修飾的DOX脂質(zhì)體(iNGR-LS/DOX)對(duì)U87MG和HUVECs細(xì)胞的毒性顯著增加。論文第三部分通過(guò)體內(nèi)成像研究證實(shí)iNGR修飾顯著增加腦膠質(zhì)瘤動(dòng)物模型中的脂質(zhì)體積累和滲透。免疫熒光染色分析證實(shí)了 iNGR-LS可以穿透腫瘤血管壁且進(jìn)入腫瘤組織。iNGR-LS/DOX 還顯示出比 LS/DOX(p0.05)更強(qiáng)的對(duì)腫瘤的生長(zhǎng)抑制作用,這應(yīng)該歸因于由iNGR介導(dǎo)的增加的腫瘤積累和穿透效果。這項(xiàng)研究證明iNGR肽修飾可能是改善脂質(zhì)體在腫瘤組織中的運(yùn)輸和增強(qiáng)其抗腫瘤效果的有效策略。
[Abstract]:Glioma is a malignant tumor occurring in the brain, especially glioma. The clinical therapeutic effect of glioma is not optimistic. The 5-year survival rate of glioma patients is only 9.8, and the quality of life of the patients is very low. In recent years, research on the treatment of glioma drugs has become a difficult and hot point in medicine. At present, it is mainly treated by surgery, chemotherapy and radiotherapy. The main chemotherapeutic drugs are temozolamide, valproic acid and Kaplan. Japanese scholars have used interferon to treat them, but chemotherapy alone is not particularly effective. Therefore, developing chemotherapeutic drugs for gliomas is a challenging task. In recent years, nanodelivery system has a rapid development, a variety of polymer nanopharmaceuticals are also increasing the proportion of research and development. The antitumor effect of active targeting nanopharmaceutical delivery system is hindered by tumor vascular barrier and tumor matrix barrier in vivo. In this study, to overcome two obstacles, we used iNGR, a tumor penetrating peptide, to modify liposomes to increase its accumulation in tumor tissues and osmotic. Tissue penetrating motifs R / K XXR / K) and protease recognition sites. On the one hand, it can clearly recognize the overexpression of CD13 receptor by glioma neovascularization endothelial cells, especially in pathological state. In addition, it can be dissected by specific enzyme in the vicinity of tumor to form iNGRt peptide CRNGR sequence. It can penetrate tumor blood vessels and enter deep tumor tissue, and be internalized by glioblastoma cells. This function is based on the specific interaction of iNGRt and its receptor NRP-1 on tumor blood vessels and glioma cells. Therefore, tumor vascular targeting and tumor penetration may enable iNGR to overcome tumor vascular barrier and tumor matrix barrier. In the first chapter of this thesis, iNGR-DSPE-PEG target oriented compounds were synthesized and iNGR- modified liposome iNGR-LSN was prepared, which showed the size of 1OOnm and its distribution was uniform. In chapter 2 the results of in vitro cell experiments showed that iNGR-LS significantly increased the cellular internalization and uptake of U87MG tumor cells and HUVEC cells as compared with the unmodified liposome LSs. Compared with the normal doxorubicin liposome LS / DOX, iNGR polypeptide modified DOX liposome (iNGR-LS / DOX) significantly increased the toxicity of iNGR-LS / DOX to U87MG and HUVECs cells. In the third part iNGR modification significantly increased the accumulation and permeability of liposome in glioma animal model by in vivo imaging. Immunofluorescence staining confirmed that iNGR-LS could penetrate the vascular wall of tumor and enter tumor tissue. INGR-LS- / DOX also showed a stronger inhibitory effect on tumor growth than LS- / DOXP0.05, which should be attributed to the increased tumor accumulation and penetrating effect mediated by iNGR. This study suggests that iNGR peptide modification may be an effective strategy for improving the transport of liposomes in tumor tissues and enhancing their antitumor effects.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R943;R96

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本文編號(hào)：1951254