本文選題：轉(zhuǎn)鐵蛋白受體結(jié)合肽 + 5-氟尿嘧啶��； 參考：《重慶醫(yī)科大學》2016年博士論文

【摘要】：目的腦膠質(zhì)瘤是中樞神經(jīng)系統(tǒng)發(fā)生率最高的惡性腫瘤,因血腦屏障(Blood brain barrier,BBB)的存在以及傳統(tǒng)抗腫瘤藥物對腫瘤細胞選擇性不強,導致目前腦膠質(zhì)瘤的臨床療效較差,生存期短。研究發(fā)現(xiàn),超聲微泡能無創(chuàng)、可逆開放BBB;轉(zhuǎn)鐵蛋白受體(Transferrin receptor,TfR)在腦膠質(zhì)瘤細胞膜上高表達;轉(zhuǎn)鐵蛋白受體結(jié)合肽(HAIYPRH)能與腦膠質(zhì)瘤細胞膜TfR特異性結(jié)合。本課題首次將超聲微泡和結(jié)合肽兩種不同的靶向技術(shù)聯(lián)合運用,超聲微泡介導使藥物透過BBB,在腦部定點釋放;結(jié)合肽介導使藥物對腦膠質(zhì)瘤細胞產(chǎn)生選擇性,從而實現(xiàn)高效率的腦腫瘤靶向治療。鑒于此,本課題以5-氟尿嘧啶(5-fluorouracil,5-FU)和表柔比星(Epirubicin,EPI)為工具藥,評價HAIYPRH-5-FU和HAIYPRH-EPI兩種復合物體外抗腦膠質(zhì)瘤細胞活性;同時評價HAIYPRH-5-FU復合物超聲微泡的體內(nèi)靶向性及抗腦膠質(zhì)瘤活性。方法在第一部分試驗中,以EPI為工具藥,谷氨酸為連接物,制備HAIYPRH-EPI復合物;以5-FU為工具藥,6-氨基己酸為連接物,制備HAIYPRH-5-FU復合物。在第二部分試驗中,主要明確復合物的抗腫瘤活性及其與TfR表達的相關(guān)性。首先采用流式細胞術(shù)檢測U87與LN229腦膠質(zhì)瘤細胞膜表面TfR1表達差異;然后以U87和LN229膠質(zhì)瘤細胞為研究對象,采用mtt法考察各組藥物對細胞增殖抑制作用,計算存活率評價細胞毒性,通過透射電鏡和檢測caspase3,8,9活性觀察細胞凋亡,利用epi本身的熒光特性,借助熒光顯微鏡定性和流式細胞術(shù)半定量觀察epi和haiyprh-epi細胞攝取,采用hplc-ms/ms法定量觀察5-fu和haiyprh-5-fu細胞攝取。在第三部分試驗中,我們通過正交設(shè)計優(yōu)化處方,成功制備載haiyprh-5-fu超聲微泡,測定包封率及載藥量,并進行形態(tài)觀察、穩(wěn)定性觀察、粒徑、粒度分布與電位檢測。在第四部分試驗中,主要考察載haiyprh-5-fu超聲微泡的體內(nèi)靶向性及抗腦膠質(zhì)瘤活性,采用立體定向技術(shù)建立大鼠ln229膠質(zhì)瘤模型,通過mri和he染色驗證模型制作成功,采用hplc-ms/ms法測定各組織和血液中的5-fu及haiyprh-5-fu的濃度,考察其靶向效率,并通過mri觀察復合物超聲微泡對腦膠質(zhì)瘤的抑制作用,同時比較各組大鼠的生存期和體重。結(jié)果在第一部分試驗中,我們成功制備haiyprh-epi和haiyprh-5-fu兩種復合物,質(zhì)譜鑒定分子量與預(yù)期一致,hplc測定其純度分別為99.03%和99.07%。在第二部分試驗中,流式細胞術(shù)檢測腦膠質(zhì)瘤細胞膜表面tfr1表達結(jié)果顯示:u87細胞膜表面tfr1呈低表達,而ln229細胞膜表面tfr1呈高表達;細胞毒性與細胞凋亡結(jié)果顯示:haiyprh-epi與haiyprh-5-fu對tfr呈低表達的u87細胞的細胞毒性和促凋亡活性較弱,而在tfr高表達的ln229細胞中則呈現(xiàn)明顯的細胞毒性和促凋亡活性,且細胞毒性呈劑量依賴性,外源性加入25μmtf能明顯加強復合物對ln229細胞的細胞毒性和促凋亡活性,而epi和5-fu在u87和ln229細胞中的細胞毒性和細胞凋亡活性無明顯差別,tf的加入對該類效應(yīng)也無明顯影響;細胞攝取結(jié)果與細胞毒性、細胞凋亡結(jié)果相吻合,顯示:主要依賴被動轉(zhuǎn)運入細胞的epi或5-fu在u87和ln229細胞中的攝取無明顯差別,但haiyprh-epi或haiyprh-5-fu在兩種細胞中的攝取存在顯著差異,兩種復合物在ln229細胞中的攝取明顯高于u87細胞,且外源性加入25μmtf能夠顯著加強ln229細胞對兩種復合物的攝取。在第三部分實驗中,以haiyprh-5-fu為試驗藥物,對制備影響較顯著的4個因素進行正交試驗,以包封率為指標進行評分,優(yōu)選出最佳制備處方,即聚乳酸-羥基乙酸共聚物(plga)800mg,司盤801.5ml,初乳水相體積1ml,聚乙烯醇(pva)體積45ml,并以最佳處方成功制備載haiyprh-5-fu超聲微泡。采用hplc-ms/ms法測得其包封率與載藥量分別為(45.87±0.71)%和(0.86±0.19)%;在形態(tài)及穩(wěn)定性觀察項中,凍干粉重懸于去離子水中,顯微鏡下微泡分布均勻,無粘連,7d時兩種微泡仍分布均勻,分散度較好;malvernzatasizernanozs激光粒度分析儀檢測其平均粒徑與zeta電位分別為(476.3±143.2)nm和-(12.8±5.86)mv。在第四部分試驗中,mri檢查和he染色證實大鼠腦膠質(zhì)瘤模型建立成功。荷瘤大鼠給藥并進行超聲輻照,于1h、2h、4h后測定組織分布和靶向效率,結(jié)果顯示,5-fu超聲微泡組與haiyprh-5-fu超聲微泡組均呈現(xiàn)明顯的腦部靶向性;藥物處理前后通過mri觀察腫瘤體積,結(jié)果提示,與5-fu組相比,同劑量的5-fu超聲微泡組第21d腫瘤體積明顯減小,與haiyprh-5-fu(0.5mm/kg)組相比,低(0.1mM/kg)、中(0.5mM/kg)、高(1mM/kg)濃度的HAIYPRH-5-FU超聲微泡組在第14d和第21d腫瘤體積均明顯減少,并呈劑量依賴性;各試驗組從建模第10天起開始記錄體重,與空白微泡組、5-FU(0.5mM/kg)組和HAIYPRH-5-FU(0.5mM/kg)組相比,中(0.5mM/kg)、高濃度(1mM/kg)HAIYPRH-5-FU超聲微泡組大鼠體重從第28天開始出現(xiàn)顯著性差異,且HAIYPRH-5-FU超聲微泡組濃度越大體重變化越小,呈現(xiàn)劑量依賴性;在生存曲線中,空白對照組、空白微泡組、5-FU(0.5mM/kg)組、HAIYPRH-5-FU(0.5mM/kg)組、5-FU超聲微泡(0.5mM/kg)組、低濃度HAIYPRH-5-FU超聲微泡(0.1mM/kg)組、中濃度HAIYPRH-5-FU超聲微泡(0.5mM/kg)組、高濃度HAIYPRH-5-FU超聲微泡(1mM/kg)組的中位生存期分別為26天、24天、34天、25天、45天、49天、52天和63天。結(jié)論HAIYPRH-抗腫瘤藥物復合物對TfR呈高表達的腦膠質(zhì)瘤細胞呈現(xiàn)出明顯的選擇性和抗腫瘤活性,HAIYPRH-抗腫瘤藥物復合物超聲微泡對接種TfR呈高表達的腦膠質(zhì)瘤細胞的荷瘤大鼠呈現(xiàn)出明顯的體內(nèi)靶向性和抗腫瘤活性。本課題的實施為開發(fā)新的具有臨床應(yīng)用前景的抗腫瘤藥物提供了新的理論和試驗依據(jù)。
[Abstract]:Objective glioma is a malignant tumor of the highest incidence in the central nervous system. The existence of Blood brain barrier (BBB) and the poor selectivity of traditional antitumor drugs on tumor cells lead to the poor clinical efficacy and short survival time of brain glioma. Transferrin receptor (TfR) is highly expressed on the glioma cell membrane, and transferrin receptor binding peptide (HAIYPRH) can be specifically associated with the TfR cell membrane of glioma cells. This subject is the first time to combine the two different target techniques of ultrasonic microbubbles and binding peptides. Ultrasound microbubbles mediate the release of drugs through BBB, binding to the brain; In view of this, 5- fluorouracil (5-fluorouracil, 5-FU) and epirubicin (Epirubicin, EPI) are used as a tool to evaluate the activity of two kinds of compound objects of HAIYPRH-5-FU and HAIYPRH-EPI against glioma cells, and evaluate HAIY at the same time. In vivo targeting and anti brain glioma activity of PRH-5-FU complex ultrasound microbubbles. Methods in the first part of the experiment, EPI was used as a tool and glutamic acid was used as a connector to prepare HAIYPRH-EPI complexes; 5-FU was used as a tool and 6- amino hexanic acid was used as a connector to prepare HAIYPRH-5-FU complex. In the second part of the experiment, the main determination of the resistance of the complex was made. Tumor activity and its correlation with TfR expression. First, flow cytometry was used to detect the difference of TfR1 expression on the surface of U87 and LN229 glioma cells. Then U87 and LN229 glioma cells were used as the research object. The inhibitory effect of the drugs on cell proliferation was investigated by MTT method and the survival rate was calculated to evaluate the cytotoxicity by transmission electron microscopy and examination. Caspase3,8,9 activity was observed to observe the apoptosis of cells. Using fluorescence characteristics of EPI itself, the uptake of EPI and haiyprh-epi cells was observed by fluorescence microscopy and flow cytometry. The uptake of 5-FU and haiyprh-5-fu cells was quantitatively observed by hplc-ms/ms. In the third part, we optimized the prescription by orthogonal design and successfully prepared the prescription. Haiyprh-5-fu ultrasound microbubbles were carried out and the encapsulation efficiency and drug loading were measured. Morphological observation, stability observation, particle size, particle size distribution and potential detection were carried out. In the fourth part, the target of haiyprh-5-fu ultrasound microbubbles and the activity of anti glioma were mainly investigated. The model of rat ln229 glioma was established by using stereotactic technique, and the model was established by using stereotactic technique. MRI and he staining verification model was made successfully. The concentration of 5-FU and haiyprh-5-fu in tissues and blood was measured by hplc-ms/ms method, and the target efficiency was investigated. The inhibitory effect of ultrasonic microbubbles on brain glioma was observed by MRI, and the survival time and weight of the rats were compared. The results were successful in the first part of the experiment. Two compounds of haiyprh-epi and haiyprh-5-fu were prepared. The molecular weight of mass spectrometry was the same as expected. The purity of HPLC was 99.03% and 99.07%. in second parts. The results of TfR1 expression on the membrane surface of brain glioma cells by flow cytometry showed that the TfR1 in the membrane surface of U87 cells was low, and the TfR1 of ln229 cell membrane was highly expressed. The results of cytotoxicity and apoptosis showed that the cytotoxicity and apoptosis activity of haiyprh-epi and haiyprh-5-fu cells with low expression of TfR were weak, but in ln229 cells with high expression of TfR, the cytotoxicity and apoptosis activity were obvious, and the cytotoxicity was dose-dependent. The exogenous addition of 25 mu MTF could obviously strengthen the compound. The cytotoxicity and apoptosis activity of ln229 cells were not significantly different from that of EPI and 5-FU in U87 and ln229 cells. The addition of TF had no obvious effect on this effect, and the results of cell uptake coincided with the cytotoxicity and apoptosis results, which showed that it mainly depended on the passive transport of EPI or 5-FU into cells. There was no significant difference in the uptake of U87 and ln229 cells, but there was a significant difference in the uptake of haiyprh-epi or haiyprh-5-fu in the two cells. The uptake of the two compounds in ln229 cells was significantly higher than that of U87 cells, and the exogenous addition of 25 mu MTF could significantly enhance the uptake of the two compounds by ln229 cells. In the third experiment, Hai Yprh-5-fu was a test drug. Orthogonal test was carried out on 4 factors which had significant influence on preparation. The optimum preparation prescription was selected by the index of encapsulation efficiency, namely, poly (PLGA) 800mg, 801.5ml, 1ml of colostrum and 45ml of polyvinyl alcohol (PVA), and the preparation of haiyprh-5-fu with the best prescription. The encapsulation efficiency and drug loading of ultrasonic microbubbles were measured by hplc-ms/ms method (45.87 + 0.71)% and (0.86 + 0.19)% respectively. In the observation items of morphology and stability, the freeze-dried powder was suspended in the deionized water. The microbubbles were evenly distributed under the microscope without adhesion, and the two kinds of microbubbles were still evenly distributed, and the dispersion degree was better at 7d, and the malvernzatasizernanozs laser particle size fraction was better. The average particle size and zeta potential were measured by (476.3 + 143.2) nm and - (12.8 + 5.86) mv. respectively in fourth parts. MRI examination and he staining proved that the rat glioma model was established successfully. The tumor bearing rats were given and irradiated by ultrasound, and the tissue distribution and target efficiency were measured after 1h, 2h, 4h, and the results showed that 5-FU ultrasound microbubbles and haiy were found. The prh-5-fu ultrasound microbubble group showed obvious brain targeting, and the tumor volume was observed by MRI before and after the drug treatment. The results suggested that the volume of 21d tumor in the same dose 5-FU ultrasound microbubble group decreased significantly, and compared with the haiyprh-5-fu (0.5mm/kg) group, the low (0.1mM/kg), middle (0.5mM/kg), and high (1mM/kg) concentration of HAIYPRH-5-FU ultrasound microscale was compared with the haiyprh-5-fu (0.5mm/kg) group. The volume of the tumor in the group 14d and 21d decreased significantly and was dose-dependent. The body weight of the experimental groups began to be recorded from the tenth day of modeling, compared with the blank microbubble group, the 5-FU (0.5mM/kg) group and the HAIYPRH-5-FU (0.5mM/kg) group, and the weight of the rats in the high concentration (1mM/kg) HAIYPRH-5-FU ultrasonic microbubble group began to appear from twenty-eighth days. Difference, and the greater the concentration of HAIYPRH-5-FU ultrasound microbubbles, the smaller the weight change, the more dose dependence; in the survival curve, the blank control group, the blank microbubble group, the 5-FU (0.5mM/kg) group, the HAIYPRH-5-FU (0.5mM/kg) group, the 5-FU ultrasound microbubble (0.5mM/kg) group, the low concentration HAIYPRH-5-FU ultrasonic microbubble group (0.1mM/kg), and the middle concentration HAIYPRH-5-FU ultrasonic microbubbles (0.5 MM/kg group, the median survival time of the high concentration HAIYPRH-5-FU ultrasound microbubbles (1mM/kg) group was 26 days, 24 days, 34 days, 25 days, 45 days, 49 days, 52 days and 63 days. Conclusion the HAIYPRH- antitumor drug complex showed obvious selectivity and antitumor activity to the high expression of TfR glioma cells, HAIYPRH- antitumor drug complex ultrasound microbubbles. The tumor bearing rats inoculated with high expression of TfR glioma cells showed significant in vivo targeting and antitumor activity. The implementation of this topic provides a new theoretical and experimental basis for the development of new antitumor drugs with clinical applications.

【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R96

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2 鄒爭春 朱廣平;腦膠質(zhì)瘤診斷有望從“有創(chuàng)”到“無創(chuàng)”[N];中國醫(yī)藥報;2013年

3 張獻懷;我國腦膠質(zhì)瘤研究獲新進展[N];大眾科技報;2007年

4 本報通訊員 張獻懷;對腦膠質(zhì)瘤進行局部強力“打擊”[N];大眾科技報;2007年

5 張獻懷;腦膠質(zhì)瘤別急著手術(shù)[N];健康時報;2007年

6 張獻懷;科學家提出對腦膠質(zhì)瘤應(yīng)進行局部強力打擊[N];科技日報;2007年

7 金源;中關(guān)村生命科學園構(gòu)建國家生物醫(yī)藥基地[N];中國醫(yī)藥報;2006年

8 張獻懷;對腦膠質(zhì)瘤應(yīng)進行局部強力打擊[N];中國醫(yī)藥報;2007年

9 健康時報特約記者 朱立明;切腦膠質(zhì)瘤用超聲引導[N];健康時報;2007年

10 通訊員 張獻懷;腦膠質(zhì)瘤臨床研究與治療獲新進展[N];大眾科技報;2009年

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2 王耀伍;FOXC2在腦膠質(zhì)瘤中表達并與其他腫瘤標記物相關(guān)性研究及其臨床病理意義[D];河北醫(yī)科大學;2015年

3 吳秀偉;Rab27a對人腦膠質(zhì)瘤細胞生物活性的影響及其在老年腦膠質(zhì)瘤中的臨床應(yīng)用[D];安徽醫(yī)科大學;2014年

4 魏曉麗;穩(wěn)定性多肽介導跨屏障膜的腦膠質(zhì)瘤雙重靶向遞藥系統(tǒng)研究[D];復旦大學;2014年

5 韓海玲;腦膠質(zhì)瘤靶向納米藥物及其與放療聯(lián)用的實驗研究[D];吉林大學;2016年

6 楊沛;分子病理指導下的腦膠質(zhì)瘤分子分型及綜合治療研究[D];首都醫(yī)科大學;2016年

7 秦國強;EFEMP1 rs3791679單核苷酸多態(tài)性與腦膠質(zhì)瘤易感性的關(guān)聯(lián)性研究[D];南方醫(yī)科大學;2016年

8 張燦;靶向干擾Diaph1表達對腦膠質(zhì)瘤細胞增殖、凋亡、遷移的影響及分子機制的研究[D];上海大學;2016年

9 邵靈敏;腦膠質(zhì)瘤中調(diào)控LRIG1表達的微小RNA篩選及機制研究[D];武漢大學;2015年

10 余維;腦膠質(zhì)瘤初治及配對復發(fā)標本分子特征差異分析[D];浙江大學;2017年

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1 孫文博;酪氨酸激酶2（DDR2）和血管內(nèi)皮細胞生長因子（VEGF）在腦膠質(zhì)瘤中的表達及相關(guān)性研究[D];河北醫(yī)科大學;2015年

2 姚冉;孕烷X受體在腦膠質(zhì)瘤中的臨床意義[D];新鄉(xiāng)醫(yī)學院;2015年

3 趙江華;腦膠質(zhì)瘤預(yù)后的影響因素分析[D];山西醫(yī)科大學;2015年

4 朱瀟鵬;不同級別腦膠質(zhì)瘤中差異microRNA的表達譜研究[D];第三軍醫(yī)大學;2015年

5 李政;膠質(zhì)瘤MGMT的表達及意義[D];四川醫(yī)科大學;2015年

6 張忠民;IL-6與NF-κB在人腦膠質(zhì)瘤中的表達及相關(guān)性研究[D];佳木斯大學;2015年

7 胡全銀;多肽介導的腦膠質(zhì)瘤靶向遞藥策略研究[D];復旦大學;2014年

8 張娜娜;miR-103/195/15b調(diào)控SALL4抑制腦膠質(zhì)瘤細胞增殖及侵襲作用的研究[D];哈爾濱工業(yè)大學;2015年

9 孫恒翠;~1H-MRS在亞急性腦梗死與低級別腦膠質(zhì)瘤鑒別診斷中的應(yīng)用價值[D];山東大學;2015年

10 潘俊辰;異常表達長鏈非編碼RNA在腦膠質(zhì)瘤中的功能研究[D];南京醫(yī)科大學;2015年

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