本文選題：口服 + 胰島素�。� 參考：《浙江理工大學(xué)》2017年碩士論文

【摘要】：近年來,糖尿病成為了全球范圍內(nèi)的一種疾病,它會(huì)對人體健康系統(tǒng)造成巨大的損害和沉重的負(fù)擔(dān)。據(jù)統(tǒng)計(jì),2015年全球成年人中有4.15億患有糖尿病,按照這種趨勢,到2040年預(yù)計(jì)將達(dá)到6.42億,這意味著每十個(gè)人里面就有一個(gè)患有糖尿病。聚合物基納米藥物載體用于藥物負(fù)載及其可控釋放的應(yīng)用研究受到人們的密切關(guān)注。此外,通過目標(biāo)聚合物的口服給藥,不僅可以增強(qiáng)智能響應(yīng),還可以減少注射的痛苦,同時(shí)具有高效、持續(xù)緩釋的優(yōu)點(diǎn)。苯硼酸及其衍生物能與糖類相互作用,形成共價(jià)復(fù)合物。因此,引入苯硼酸修飾到聚合物藥物載體,研究口服利用后的胰島素釋放,具有重要的研究意義。本論文采用三種不同的方法制備了含苯硼酸修飾葡萄糖敏感口服胰島素載體,并對其藥物釋放性能進(jìn)行了研究。具體來說,主要包括以下三個(gè)部分:1.結(jié)合RAFT聚合與酶法酯交換方法制備苯硼酸修飾葡萄糖敏感的熒光共聚物。這種兩親性的共聚物膠束可以自組裝成球形膠束,通過核磁(1H NMR)、紅外(FT-IR)、透射電鏡(TEM)和動(dòng)態(tài)光散射(DLS)對其進(jìn)行表征。使用熒光光譜儀和激光共聚焦顯微鏡(CLSM)對其熒光特性進(jìn)行了研究。由于其兩親性和葡萄糖敏感的特性,作為胰島素載體用以包覆胰島素。在體外模擬葡萄糖進(jìn)行了胰島素釋放研究。此外,該藥物載體具有較低的細(xì)胞毒性和較好的抗蛋白穩(wěn)定性。釋放前后的胰島素經(jīng)圓二色譜(CD)對比分析,表明釋放的胰島素的二級結(jié)構(gòu)沒有損傷。這種苯硼酸修飾葡萄糖敏感的熒光聚合物膠束在胰島素傳遞治療糖尿病方面有望成為有效的載體材料。2.近些年,口服遞送胰島素的研究已經(jīng)引起人們極大的關(guān)注。本章采用低溫乳化聚合的方法,首先設(shè)計(jì)制備了苯硼酸修飾葡萄糖敏感聚合物納米顆粒,并研究了其對Caco-2細(xì)胞的細(xì)胞毒性及抗蛋白穩(wěn)定性,胰島素在體外模擬pH和葡萄糖刺激釋放也進(jìn)行了研究。為了增強(qiáng)口服胰島素的利用率,采用透明質(zhì)酸的交聯(lián)構(gòu)建3D水凝膠體系,將負(fù)載胰島素的聚合物納米顆粒包封其中,以克服吸收屏障和減少運(yùn)送傳遞過程中的胰島素的損失。通過糖尿病小鼠口服給藥研究,發(fā)現(xiàn)對該種水凝膠體系具有長時(shí)間的口服降血糖效果和更高的藥物利用率。3.為了克服口服遞送胰島素的吸收屏障,采用羧化殼聚糖接枝聚合的方法,將腸上皮細(xì)胞特異性吸收的L-纈氨酸加入體系,制備具有靶向作用的苯硼酸修飾葡萄糖敏感的聚合物。研究發(fā)現(xiàn)對HT-29細(xì)胞有較低的毒性和較好的抗蛋白穩(wěn)定性。胰島素在體外模擬pH和葡萄糖刺激釋放也進(jìn)行了研究。在包含胃蛋白酶的模擬胃液中和包含胰蛋白酶的模擬腸液中對胰島素的化學(xué)穩(wěn)定性進(jìn)行了研究。通過激光共聚焦顯微鏡觀察了HT-29細(xì)胞對聚合物納米顆粒的轉(zhuǎn)運(yùn)行為。進(jìn)一步通過糖尿病小鼠口服給藥研究了作為胰島素運(yùn)送載體的優(yōu)勢,表明該L-纈氨酸修飾的基于殼聚糖的納米顆粒在口服胰島素的應(yīng)用中有著巨大的潛力。
[Abstract]:In recent years, diabetes has become a global disease, which can cause huge damage and heavy burden on human health systems. According to statistics, 415 million of the world's adults in 2015 were suffering from diabetes, which is expected to reach 642 million by 2040, which means that one in every ten people is suffering from diabetes. The application of polymer based nanoscale drug carriers to drug loading and controlled release is closely concerned. In addition, oral administration of the target polymer can not only enhance the intelligent response, but also reduce the pain of the injection, at the same time, it has the advantage of high efficiency and continuous slow release. Therefore, the introduction of boric acid to polymer drug carriers and the study of the release of insulin after oral use is of great significance. In this paper, three different methods were used to prepare the oral glucose sensitive oral insulin carrier containing benzyl boric acid, and the drug release performance was studied. It mainly includes the following three parts: 1. the preparation of benzboric acid modified glucose sensitive fluorescent copolymers with RAFT polymerization and enzymatic transesterification. The two Pro copolymer micelles can be self assembled into spherical micelles and are characterized by NMR (1H NMR), infrared (FT-IR), TEM and DLS. Fluorescence spectrometers and laser confocal microscopy (CLSM) have studied their fluorescence characteristics. Due to their two affinity and glucose sensitive properties, they are used as insulin carriers to encapsulate insulin. The insulin release of glucose in vitro is studied in vitro. In addition, the drug carrier has lower cytotoxicity and better anti protein stability. A comparative analysis of the insulin before and after the release by circular two chromatography (CD) shows that the two grade structure of the released insulin is not damaged. This kind of benzyl boric acid modified glucose sensitive fluorescent polymer micelles is expected to become an effective carrier material for insulin delivery in the treatment of diabetes. In recent years, the study of oral delivery of insulin has been cited. In this chapter, we designed and prepared the phallic acid modified glucose sensitive polymer nanoparticles in this chapter, and studied the cytotoxicity and anti protein stability of Caco-2 cells. In order to enhance the oral islet, the insulin in vitro simulated pH and glucose stimulation release. The 3D hydrogel system was constructed by cross-linking of hyaluronic acid. The polymer nanoparticles loaded with insulin were encapsulated to overcome the absorption barrier and reduce the loss of insulin during delivery. Oral administration of diabetic mice showed that the hydrogel system had a long time of oral hypoglycemia. The effect and higher drug utilization rate.3., in order to overcome the absorption barrier of oral insulin delivery, uses carboxyl Chitosan Graft polymerization, adding L- valine, which is specifically absorbed by intestinal epithelial cells, and preparing the polymer sensitive to glucose with benzyl boric acid, which has a targeting effect. The study found that there is a lower toxicity to HT-29 cells. Sex and good anti protein stability. Insulin stimulated release of pH and glucose in vitro was also studied. The chemical stability of insulin was studied in simulated gastric juice containing pepsin neutralization and in simulated intestinal fluid containing trypsin. The effect of HT-29 cells on polymer nanoparticles was observed by laser confocal microscopy. The transport behavior of the particles was further studied by oral administration of the diabetic mice as an insulin carrier, indicating that the L- valine modified nanoparticles based on chitosan have great potential in the application of oral insulin.
【學(xué)位授予單位】：浙江理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：TQ467.32

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