本文選題：物理包裹 + 膠質(zhì)母細(xì)胞瘤　； 參考：《華東師范大學(xué)》2017年碩士論文

【摘要】：近幾年我國(guó)的腫瘤新生發(fā)病率持續(xù)上升,我國(guó)癌癥新發(fā)癌癥病例占世界的1/4,在眾多癌癥類型中,膠質(zhì)母細(xì)胞瘤具有發(fā)病率高,難治愈,易復(fù)發(fā),患者生存周期短,生活質(zhì)量差等特點(diǎn)。面對(duì)如此嚴(yán)峻的形勢(shì),科研工作者需要制備并研發(fā)出新型抗腫瘤靶向納米遞藥系統(tǒng)用于癌癥的治療。人們通常用化學(xué)連接的方法將多肽等靶向配體修飾在不同納米材料表面,形成抗腫瘤靶向納米遞藥系統(tǒng)。但往往涉及到化學(xué)反應(yīng),就要考慮到反應(yīng)條件,步驟是否繁瑣,以及所用基團(tuán)是否可用,產(chǎn)物純度,反應(yīng)過程越多產(chǎn)量越低等問題。我們改變這種常用的靶向修飾方式,減少反應(yīng)步驟,將納米遞藥系統(tǒng)的制備模塊化,將具有不同功能的模塊化元件通過物理相互作用進(jìn)行組裝,避開化學(xué)合成的繁瑣,使得納米遞藥系統(tǒng)的制備更加便捷可控。首先制備功能性靶向元件,再通過物理包裹作用制備腫瘤穿透肽修飾的PGG-PTX遞藥系統(tǒng)。該系統(tǒng)包含RGERPPR多肽修飾的靶向元件,高分子聚合物及抗腫瘤藥物,此中靶向元件為二硬脂酰磷脂酰乙醇胺-聚乙二醇3400-RGERPPR(DSPE-PEG3400-RGERPPR);高分子聚合物(PGG)為聚谷氨酸骨架及骨架上的谷氨酸支鏈;抗腫瘤藥物為紫杉醇(PTX);聚谷氨酸高分子骨架和谷氨酸支鏈通過肽鍵連接,在谷氨酸支鏈末端與抗腫瘤藥物PTX通過酯鍵鍵合,形成PGG-PTX。然后PTX與靶向元件中的DSPE通過疏水相互作用,使靶向元件疏水端DSPE包裹進(jìn)入PGG-PTX中,通過物理包裹作用形成聚合物-藥物納米遞藥系統(tǒng),用于腫瘤靶向遞藥。通過動(dòng)態(tài)蒸發(fā)光散射儀、高效液相色譜儀、流式細(xì)胞儀、透射電鏡等儀器和方法對(duì)RGE-PEG-DSPE/PGG-PTX納米遞藥系統(tǒng)進(jìn)行了一系列表征。試驗(yàn)結(jié)果顯示:粒徑在100 nm左右,呈球形,分散性良好;在PBS中長(zhǎng)期保存穩(wěn)定性良好;藥物釋放緩慢;細(xì)胞攝取試驗(yàn)中通過定性定量試驗(yàn)可以看出腫瘤細(xì)胞和血管內(nèi)皮細(xì)胞均對(duì)該遞藥系統(tǒng)的攝取明顯增多,該遞藥系統(tǒng)對(duì)膠質(zhì)母細(xì)胞瘤的靶向能力較好;體外抗神經(jīng)膠質(zhì)瘤活性評(píng)價(jià)中該遞藥系統(tǒng)顯著增強(qiáng)了膠束納米藥物對(duì)神經(jīng)膠質(zhì)瘤的體外生長(zhǎng)抑制作用;通過靜脈注射給藥,利用腫瘤EPR效應(yīng)和RGERPPR介導(dǎo)作用將其靶向至腫瘤部位,此遞藥系統(tǒng)可用作腫瘤治療藥物的靶向遞送,且在治療腦膠質(zhì)瘤上獲得了良好的療效,延長(zhǎng)了 BALB/C腦膠質(zhì)瘤裸鼠的中位生存期,改善了荷瘤裸鼠的生存狀況。此遞藥系統(tǒng)可在RGERPPR的介導(dǎo)作用下用于膠質(zhì)母細(xì)胞瘤的靶向治療。為靶向納米藥物的構(gòu)建提供了新的思路和方法,同時(shí)為膠質(zhì)母細(xì)胞瘤的靶向治療提供實(shí)驗(yàn)基礎(chǔ)。因此本研究擁有重要的臨床現(xiàn)實(shí)意義和市場(chǎng)應(yīng)用價(jià)值,擁有良好的應(yīng)用前景。
[Abstract]:In recent years, the incidence of neoplasms has been rising in China, and new cancer cases in China account for one fourth of the world's total cancer cases. Among the many cancer types, glioblastoma has a high incidence rate, is difficult to cure, easy to recur, and has a short life cycle. Poor quality of life and other characteristics. Faced with such a severe situation, researchers need to prepare and develop a novel anti-tumor targeted nano-delivery system for cancer treatment. Peptides and other targeted ligands are usually modified on the surface of different nanomaterials by chemical binding to form anti-tumor targeted drug delivery system. However, chemical reactions are often involved, such as the reaction conditions, whether the steps are tedious, whether the groups used are available, the purity of the product, the lower the yield of the reaction process, and so on. We change this common targeting modification, reduce the reaction steps, modularize the preparation of nanopharmaceutical systems, assemble modular components with different functions through physical interactions, and avoid the red tape of chemical synthesis. The preparation of nano-delivery system is more convenient and controllable. First, functional target elements were prepared, and then the tumor penetrating peptide modified PGG-PTX delivery system was prepared by physical encapsulation. The system consists of RGERPPR polypeptide modified target elements, polymer polymers and antitumor drugs, in which the target elements are DSPE-PEG3400-RGERPPRN, which are DSPE-PEG3400-RGERPPRA, and the polyglutamic acid backbone and its branched chains on the framework of poly (glutamic acid), the target elements of the system are DSPE-PEG3400-RGERPPRA. The antitumor drug was paclitaxel, the polyglutamic acid polymer skeleton and the glutamic acid branched chain were connected by peptide bond, and the end of the glutamic acid branched chain was bonded with the antitumor drug PTX through ester bond to form PGG-PTX. Then the PTX and the DSPE in the target element interact with each other through hydrophobic interaction, and the hydrophobic end DSPE of the target element is encapsulated into the PGG-PTX, and the polymer-drug delivery system is formed by physical encapsulation, which can be used for tumor targeting delivery. The RGE-PEG-DSPE/PGG-PTX nano-drug delivery system was characterized by means of dynamic evaporative light scattering, high performance liquid chromatography, flow cytometry and transmission electron microscope. The results showed that the particle size was about 100nm, spherical and dispersive, the stability of PBS was good, the drug release was slow. In the cell uptake test, it can be seen that both tumor cells and vascular endothelial cells have significantly increased uptake of the drug delivery system, and the drug delivery system has a better targeting ability to glioblastoma. In the evaluation of anti-glioma activity in vitro, the drug delivery system significantly enhanced the inhibitory effect of micellar nanopharmaceuticals on the growth of gliomas in vitro, which was targeted to the tumor site by intravenous administration of EPR and RGERPPR mediated action. The delivery system can be used as the target delivery of tumor therapy drugs, and it has a good effect on the treatment of brain glioma, prolongs the median survival time of BALB/C glioma nude mice, and improves the survival condition of nude mice bearing tumor. The drug delivery system can be used in targeted treatment of glioblastoma mediated by RGERPPR. It provides new ideas and methods for the construction of targeted nanopharmaceuticals and provides experimental basis for targeted treatment of glioblastoma. Therefore, this study has important clinical significance and market application value, and has a good application prospects.
【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
【分類號(hào)】：R943

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相關(guān)期刊論文 前2條

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本文編號(hào)：1897862