本文選題：GLP-1衍生物 + γ-聚谷氨酸��； 參考：《華東師范大學(xué)》2015年碩士論文

【摘要】：糖尿病是當(dāng)今威脅人類健康的全球性疾病與難題,因而新型糖尿病治療藥物的研發(fā)是目前新藥研發(fā)中重要的一環(huán)。胰高血糖素樣肽-1(GLP-1)作為腸促將血糖素,不僅具有葡萄糖依賴性的刺激胰島素分泌和抑制胰高血糖素分泌功能,降低了低血糖的危險,還具有促進(jìn)胰島β細(xì)胞數(shù)目增加、抑制胃酸分泌和胃排空等功能,因而成為Ⅱ型糖尿病治療藥物的研究熱點。然而天然GLP-1由于二肽基肽酶Ⅳ(DPPⅣ酶)降解和腎清除等作用,體內(nèi)半衰期僅1-2min,不能直接作為臨床藥物使用。為抑制DPPⅣ酶降解,我們將GLP-1的第8位丙氨酸A替換成為甘氨酸G,并將兩分子該GLP-1衍生物通過一分子賴氨酸共價相連,形成同源二聚體體結(jié)構(gòu),形成新型GLP-1衍生物,命名DLG3312。實驗證明,DLG3312在小鼠體內(nèi)降血糖作用時間達(dá)10-12h,其活性與上市藥物利拉魯肽(Victoza)相當(dāng)。然而,DLG3312仍需一天注射一次,開發(fā)更為長效的GLP-1受體激動劑從而降低注射頻率、提高患者順應(yīng)性仍是目前的研究方向。本課題主要設(shè)計思路為：以γ-聚谷氨酸(γ-PGA)為水溶性骨架,苯丙氨酸乙酯(L-PAE)為疏水基團(tuán),制備兩性聚合物γ-PGA-PAE。γ-PGA-PAE在水中自組裝形成納米顆粒(NPs)的同時將DLG3312包裹進(jìn)入其內(nèi)部核心,形成DLG3312-納米顆粒(DLG3312-NPs),從而達(dá)到以下目的：(1)通過包裹DLG3312形成DLG3312-NPs的形式增加藥物直徑從而抵御腎小球清除作用；(2)通過納米載體外殼抑制DPPⅣ酶對DLG3312的降解,以增加體內(nèi)穩(wěn)定性；(3)通過體內(nèi)γ-谷氨酰轉(zhuǎn)肽酶(y-GTP)等酶類對載體多聚氨基酸的逐步降解達(dá)到藥物緩釋的目的；(4)通過注射給藥在動物體內(nèi)達(dá)到長效降血糖活性。本課題的研究內(nèi)容及研究結(jié)果如下：1、γ-PGA-PAE的合成首先利用枯草芽孢桿菌DL發(fā)酵制備大分子γ-PGA,再采用高溫酸解的方式將γ-PGA降解形成小分子γ-PGA,利用水溶性酰胺反應(yīng)縮合劑EDC.I將γ-PGA的羧基(-COOH)與L-PAE的氨基(-NH2)間形成肽鍵相連,形成γ-PGA-PAE。核磁共振檢測表明,得到的產(chǎn)物中既含有γ-PGA的特征峰,又含有L-PAE的特征峰,表明成功合成了兩性聚合物γ-PGA-PAE。2、納米藥物載體(NPs)的制備及表征將溶于二甲基亞砜(DMSO)中的γ-PGA-PAE滴加于水溶液中,使其在水相中自組裝,通過原子力顯微鏡和透射電鏡觀測到圓形顆粒結(jié)構(gòu),尺寸約100nm。納米粒度儀檢測結(jié)果表明顆粒平均直徑為105.9 nm,PdI系數(shù)0.078,說明制得的顆粒為單分散體系,且顆粒均一；同時測得粒子的Zeta電勢為+29.3mV,接近臨界值絕對值30 mV,而高Zeta電勢表明粒子具有較高的穩(wěn)定性。3、DLG3312-NPs的制備及表征將溶于DMSO的γ-PGA-PAE滴加于DLG3312水溶液中,使其自組裝形成顆粒,其后離心分離沉淀和上清,通過SDS-PAGE分析發(fā)現(xiàn),DLG3312溶液中DLG3312含量減少,并出現(xiàn)在顆粒沉淀中,說明y-PGA-PAE能將DLG3312包裹進(jìn)入其顆粒核心區(qū)域形成DLG3312-NPs。通過透射電鏡表征,發(fā)現(xiàn)DLG3312-NPs同樣為100nm左右的顆粒結(jié)構(gòu)；納米粒度儀檢測表明,其顆粒平均直徑為106.7nm,PdI系數(shù)為0.069,呈單分散體系,且顆粒分布均一；其Zeta電勢為+33.4mV,高于絕對值30mV,高電位使其能夠在溶液中穩(wěn)定存在。4、NPs與DLG3312-NPs制備條件優(yōu)化在探索γ-PGA分子量大小對形成的NPs的影響時發(fā)現(xiàn),不同分子量——30.0-60.OkD和265.0 kD的γ-PGA形成的NPs平均粒徑相差較小,分別為109.7nm(γ-PGA 30.0-60.0kD)和105.4nm(γ-PGA 265.0 kD),但后者顆粒分布均一,PdI系數(shù)僅為0.079,前者分布較不均一,PdI系數(shù)達(dá)0.287,提示較大分子量的γ-PGA更適于制備NPs。通過探索γ-PGA降解時間、L-PAE接入率、γ-PGA-PAE和DLG3312濃度對DLG3312包裹率的影響發(fā)現(xiàn),在γ-PGA降解9min、L-PAE接入率80%、γ-PGA-PAE濃度30mg/ml和DLG3312溶液濃度2.5mg/ml時包裹率最高,可達(dá)到78.4±2.2%。疏水基團(tuán)接入率會對兩性聚合物產(chǎn)生的顆粒理化性質(zhì)產(chǎn)生重要影響。通過調(diào)節(jié)L-PAE的投入量,合成L-PAE接入率在54.1-95.2%之間的γ-PGA-PAE,對制備的DLG3312-NPs表征發(fā)現(xiàn),其顆粒平均直徑在106-147nm范圍內(nèi)變化,L-PAE實際接入率62.5%的γ-PGA-PAE產(chǎn)生的DLG3312-NPs最穩(wěn)定、粒徑分布最為均一。5、DLG3312-NPs的短期生物學(xué)活性研究健康KM鼠、STZ誘導(dǎo)的Ⅱ型糖尿病模型鼠(STZ-T2DM小鼠)、自發(fā)性Ⅱ型糖尿病db/db小鼠的腹腔糖耐量實驗表明,DLG3312-NPs能夠顯著提高3種實驗鼠的腹腔糖耐量,并且具有一定的劑量依賴效應(yīng),表明DLG3312-NPs保留了DLG3312的生物學(xué)活性。3種實驗鼠的DLG3312-NPs單次給藥實驗表明,DLG3312-NPs的體內(nèi)活性時間可達(dá)48h,顯著延長了DLG3312的10-12h的降血糖活性時間。6、DLG3312-NPs的長期生物學(xué)活性研究兩種Ⅱ型糖尿病模型鼠——STZ-T2DM小鼠和db/db小鼠體內(nèi)的長期生物學(xué)活性研究結(jié)果基本一致：DLG3312-NPs能夠平穩(wěn)的控制兩種模型鼠的血糖處于較低的狀態(tài),并且能夠顯著降低空腹血糖、抑制飲水飲食,并呈現(xiàn)一定的劑量依賴效應(yīng)。糖化血紅蛋白(HbA1c)檢測表明,DLG3312-NPs能夠顯著降低兩種模型鼠的HbA1c水平,其中STZ-T2DM小鼠降低2.20±0.67%,db/db小鼠降低2.43±0.32%；此外,DLG3312-NPs還能夠改善兩種模型鼠的脂代謝水平。兩日給藥一次的DLG3312-NPs與一日給藥一次的DLG3312和Victoza相比：DLG3312-NPs血糖控制更為平穩(wěn),而在空腹血糖降低、飲食飲水控制、脂代謝改善等方面,DLG3312-NPs要稍優(yōu)于DLG3312和Victoza,或者兩者基本相當(dāng)。在HbA1c水平方面,DLG3312組下降1.95±0.79%(STZ-T2DM小鼠)、2.37-0.66%(db/db小鼠),Victoza組下降1.73±0.62%(db/db小鼠),表明,DLG3312-NPs血糖控制效果要略優(yōu)于DLG3312和Victoza o胰腺組織切片結(jié)果表明,DLG3312-NPs、DLG3312和Victoza均能一定程度上促進(jìn)其胰島p細(xì)胞生長,效果基本相當(dāng)。7、DLG3312-NPs對肝腎功能的影響檢測連續(xù)給藥8周的STZ-T2DM小鼠的腎功能和肝功能發(fā)現(xiàn),DLG3312-NPs給藥組各血液指標(biāo)與健康C57小鼠相比不存在差異,這表明DLG3312-NPs對肝腎功能影響小,提示DLG3312-NPs毒性低,具有良好的生物安全性。檢測連續(xù)給藥6周的db/db小鼠的肝功能和腎功能血液指標(biāo),并進(jìn)行進(jìn)行肝臟、腎臟的組織切片HE染色分析,結(jié)果同樣表明DLG3312-NPs對肝腎功能影響小,提示DLG3312-NPs具有良好的生物安全性,毒性低。綜上,本研究運用兩性聚合物γ-PGA-PAE包裹DLG3312制備了DLG3312-NPs,其平均直徑106.7nm,PdI0.069,Zeta電勢+33.4mV,通過條件優(yōu)化其包裹率可達(dá)78.4±2.2%。生物學(xué)活性研究表明：DLG3312-NPs在3種實驗鼠中體內(nèi)活性時間均可達(dá)48h,而DLG3312僅為10-12h；兩日一次給藥的DLG3312-NPs在HbA1c和空腹血糖降低、飲水進(jìn)食控制等方面要略優(yōu)于一日一次給藥的DLG3312和Victoza。目前,運用γ-PGA-PAE對GLP-1衍生物進(jìn)行納米化包裹在國內(nèi)外尚未見報道,本研究的探索性工作將為GLP-1研發(fā)成為新型的Ⅱ型糖尿病治療藥物奠定基礎(chǔ)。
[Abstract]:Diabetes is a global disease and difficult problem that threatens human health today. Therefore, the research and development of new type diabetes drugs is an important part of new drug research and development. The glucagon like peptide -1 (GLP-1) is used as an intestinal stimulating hormone, which not only has Glucose dependent stimulation of islet secretion and inhibition of glucagon secretion, but also reduces the secretion of glucagon. The risk of hypoglycemia, the increase of the number of islet beta cells, the inhibition of gastric acid secretion and gastric emptying, has become a hot spot in the study of type II diabetes. However, the natural GLP-1 is only 1-2min due to the degradation of two peptidyl peptidase IV (DPP IV) and renal clearance, which can not be used directly as a clinical drug. In order to inhibit the degradation of DPP IV enzyme, we replace the eighth bit alanine A of GLP-1 into the glycine G, and the two molecule of the GLP-1 derivative is linked together by a molecular lysine, forming a homologous two polymer structure and forming a new GLP-1 derivative. The DLG3312. experiment named DLG3312 has shown that DLG3312 in mice has a time of hypoglycemic action of 10-12h and its survival time. Sex is equivalent to the listed drug lalalu (Victoza). However, DLG3312 still needs to be injected once a day to develop a more long-acting GLP-1 receptor agonist to reduce the injection frequency and improve patient compliance. The main idea is to use gamma polyaline (gamma -PGA) as a water-soluble skeleton, ethyl phenylalanine (L-). PAE) for the hydrophobic group, the amphoteric polymer gamma -PGA-PAE. gamma -PGA-PAE was prepared by self assembly and formed nanoparticles (NPs) in water, and DLG3312 was wrapped into its inner core to form a DLG3312- nanoparticle (DLG3312-NPs), thus achieving the following purpose: (1) increasing the diameter of the drug by wrapping DLG3312 to form DLG3312-NPs to resist the kidney Pellet clearance; (2) the inhibition of DPP IV enzyme degradation by nanoscale carrier to increase the stability of DLG3312 in vivo; (3) the gradual degradation of polyamino acids through the vivo gamma glutamyl transaminopeptidase (y-GTP) and other enzymes can achieve the purpose of drug release; (4) through injection to the animal to achieve long-term hypoglycemic activity. The contents and results of the research are as follows: 1, the synthesis of gamma -PGA by Bacillus subtilis DL was first prepared by Bacillus subtilis DL, and then the gamma -PGA was degraded by high temperature acidolysis, and the carboxyl group (-COOH) of gamma -PGA and the amino group (-NH2) of L-PAE (-NH2) were formed by the water-soluble amide reaction condensation agent EDC.I. -PGA-PAE. NMR detection shows that the obtained products contain both the characteristic peaks of gamma -PGA and the characteristic peak of L-PAE, which indicates that the amphoteric polymer gamma -PGA-PAE.2 is successfully synthesized. The preparation and characterization of the nano drug carrier (NPs) are added to the aqueous solution in the two methyl sulfoxide (DMSO), so that it is in the water phase. The structure of circular particles was observed by atomic force microscope and transmission electron microscope. The average diameter of the particle size was 105.9 nm and the PdI coefficient was 0.078. The particles were monodisperse and the particles were homogeneous, and the Zeta potential of the particles was +29.3mV and the absolute value of the critical value was 30 mV. The high Zeta potential shows that the particles have high stability.3. The preparation and characterization of DLG3312-NPs are added to DLG3312 water in DLG3312 solution by DLG3312-NPs. The particles are formed by self assembly and then centrifuged to separate the precipitates and supernatants. The SDS-PAGE analysis shows that the DLG3312 content in DLG3312 solution decreases and appears in the particle precipitation. Y-PGA-PAE can form the DLG3312 package into its core region and form DLG3312-NPs. by transmission electron microscopy. It is found that DLG3312-NPs is also a particle structure of about 100nm. The nano particle size analyzer shows that the average diameter of the particles is 106.7nm, the PdI coefficient is 0.069, and the particle distribution system is uniform, and the Zeta potential is +33.4mV, Higher than the absolute value of 30mV, high potential makes it stable in the solution in the presence of.4, NPs and DLG3312-NPs preparation conditions are optimized to explore the effect of gamma -PGA molecular weight on the formation of NPs, the average particle sizes of NPs with different molecular weights, 30.0-60.OkD and 265 kD, are smaller, respectively, 109.7nm (gamma -PGA) and 105. 4nm (gamma -PGA 265 kD), but the latter particles are evenly distributed, the PdI coefficient is only 0.079, the former is not uniform, and the PdI coefficient is 0.287. It suggests that the larger molecular weight of the gamma -PGA is more suitable for the preparation of NPs. by exploring the degradation time of gamma -PGA, the L-PAE access rate, the effect of gamma -PGA-PAE and DLG3312 concentration on the DLG3312 inclusion rate. The inclusion rate is 80%, the concentration of gamma -PGA-PAE concentration 30mg/ml and DLG3312 solution concentration 2.5mg/ml is the highest, which can reach 78.4 + 2.2%. hydrophobic group access rate will have an important influence on the physical and chemical properties of the particles produced by the amphoteric polymer. By adjusting the input of L-PAE, the L-PAE access rate between 54.1-95.2% is synthesized and the DLG3312-NPs table is prepared. It was found that the average diameter of the particles changed in the range of 106-147nm. The DLG3312-NPs produced by gamma -PGA-PAE with the actual L-PAE access rate of 62.5% was the most stable, the particle size distribution was the most uniform.5. The short-term biological activity of DLG3312-NPs was studied by healthy KM mice, STZ induced type II diabetes model mice (STZ-T2DM mice), and spontaneous type II diabetes db/db mice. The intraperitoneal glucose tolerance test showed that DLG3312-NPs could significantly increase the intraperitoneal glucose tolerance of 3 experimental mice, and had a certain dose dependent effect. It showed that DLG3312-NPs retained the biological activity of DLG3312 and the DLG3312-NPs single administration experiment of.3 experimental mice showed that the activity time of DLG3312-NPs in vivo could reach 48h, and the DLG3312 was significantly prolonged. The hypoglycemic time of 10-12h,.6, and the long-term biological activity of DLG3312-NPs, the results of the long-term biological activity of two type 2 diabetes model mice - STZ-T2DM mice and db/db mice were basically the same: DLG3312-NPs could control the blood sugar of the two model rats in a lower state, and could significantly reduce the blood sugar. Low fasting blood glucose inhibited drinking water diet and showed a dose dependent effect. Glycosylated hemoglobin (HbA1c) detection showed that DLG3312-NPs could significantly reduce the HbA1c level of two model mice, of which STZ-T2DM mice decreased by 2.20 + 0.67% and db/db mice were 2.43 + 0.32%, and DLG3312-NPs could also improve lipid metabolism in two model mice. Level. The one time DLG3312-NPs was compared with one day DLG3312 and Victoza: DLG3312-NPs blood glucose control was more stable, and DLG3312-NPs was slightly better than DLG3312 and Victoza in the decline of fasting blood glucose, drinking water control, and lipid metabolism, or the same. In HbA1c level, the DLG3312 group dropped 1.. 95 + 0.79% (STZ-T2DM mice), 2.37-0.66% (db/db mice), and Victoza group decreased by 1.73 + 0.62% (db/db mice). The results showed that the effect of DLG3312-NPs on blood glucose control was slightly better than that of DLG3312 and Victoza o pancreatic tissue sections. The results showed that DLG3312-NPs, DLG3312 and Victoza could promote the growth of the pancreatic islet cells to a certain extent. The effect of s on the function of liver and kidney detected the renal function and liver function of STZ-T2DM mice after 8 weeks of continuous administration. The blood indexes of DLG3312-NPs administration group were not different from those of healthy C57 mice, which showed that DLG3312-NPs had little effect on liver and kidney function, suggesting that DLG3312-NPs was low toxicity and had good biological safety. The detection of D in D was d. B/db mice liver function and renal function blood index, and carry on the liver, kidney tissue section HE staining analysis, the result also shows that DLG3312-NPs has little effect on liver and kidney function, suggesting that DLG3312-NPs has good biological safety and low toxicity. In summary, this study used two sex polymer gamma -PGA-PAE to package DLG3312 to prepare DLG3312-NPs, The average diameter of 106.7nm, PdI0.069, and Zeta potential +33.4mV was optimized. The biological activity of the inclusion rate of 78.4 + 2.2%. was optimized by conditions. The results showed that the activity time of DLG3312-NPs in the 3 experimental mice could reach 48h, and DLG3312 was only 10-12h; the DLG3312-NPs of the two day administration was reduced to HbA1c and fasting blood glucose, and the drinking water feeding control and so on. DLG3312 and Victoza. are superior to one day, and the use of gamma -PGA-PAE to encapsulate GLP-1 derivatives has not been reported at home and abroad. The exploratory work of this study will lay the foundation for the research and development of GLP-1 as a new type of type 2 diabetes treatment drug.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：TQ460.1;TB383.1

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