本文選題：MPEG-PCL + KCZ-M　； 參考：《濟(jì)南大學(xué)》2017年碩士論文

【摘要】：白色念珠菌感染能夠引起諸多感染性疾病,威脅人類的生命健康。多重耐藥真菌及生物膜的生成,導(dǎo)致真菌對(duì)抗真菌藥物的敏感性降低。如何提高抗真菌藥物的抗菌效果,已成為目前研究的熱點(diǎn)之一。酮康唑(Ketoconazole,KCZ)為唑類廣譜抗真菌藥物,對(duì)于念珠菌、各種深部真菌引起的感染均有良好治療效果,但酮康唑嚴(yán)重的肝毒性限制了其臨床應(yīng)用。減少酮康唑用藥劑量,提高其療效成為亟待解決的重要任務(wù)。姜黃素(Curcumin,CUR)是一種安全的天然化合物,已有研究表明姜黃素能夠與唑類抗真菌藥物聯(lián)合應(yīng)用提高抗白色念珠菌能力。但酮康唑與姜黃素為疏水性藥物,生物利用率低,限制了兩者在臨床方面的應(yīng)用。聚合物膠束載藥系統(tǒng)能夠克服藥物水溶性差、物理化學(xué)性質(zhì)不穩(wěn)定等問(wèn)題,在降低藥物的毒副作用同時(shí),藥物能較長(zhǎng)時(shí)間維持在有效濃度范圍內(nèi),對(duì)傳統(tǒng)抗真菌藥物的臨床研究與應(yīng)用起推動(dòng)作用,具有潛在的研究意義。本文合成不同分子量的單甲氧基聚乙二醇-聚己內(nèi)酯(Methoxy poly(ethylene glycol)-b-poly(e-caprolactone),MPEG-PCL)兩親性嵌段共聚物,結(jié)構(gòu)經(jīng)核磁共振氫譜(1H-NMR)及紅外光譜(FT-IR)進(jìn)行了確證,并經(jīng)凝膠滲透色譜(GPC)測(cè)定不同PCL鏈段聚合物分子量。薄膜水化法制備KCZ載藥膠束(KCZ-M),對(duì)影響載藥膠束包封率和載藥量的單因素進(jìn)行考察。在單因素考察結(jié)果基礎(chǔ)上,經(jīng)正交設(shè)計(jì)篩選出最佳膠束制備工藝。研究結(jié)果表明,當(dāng)MPEG/PCL重量比為1:1.7時(shí),聚合物材料70 mg,原料藥10 mg,水化溫度60°C,水化時(shí)間30 min,得到KCZ載藥納米膠束,載藥量與包封率最高,分別為85.27±1.75%、11.31±1.05%,CUR載藥納米膠束(CUR-M)的載藥量與包封率分別為91.19±0.83%、11.90±0.11%。KCZ載藥膠束的水溶性比KCZ原料藥相比提高85倍,CUR載藥膠束的水溶性比CUR原料藥提高了82900倍,水溶性得到明顯改善。采用動(dòng)態(tài)光散射技術(shù)(DLS)及透射電鏡(TEM)對(duì)酮康唑及姜黃素載藥膠束進(jìn)行了表征。酮康唑與姜黃素載藥納米膠束粒徑小且分布均勻,平均粒徑分別為44.70±1.91 nm、39.56±0.19 nm。傅里葉紅外光譜(FT-IR)、X-射線衍射(XRD)對(duì)載藥膠束進(jìn)行表征,研究發(fā)現(xiàn)KCZ與CUR成功包裹進(jìn)納米膠束,并以無(wú)定型、非結(jié)晶形式存在。動(dòng)態(tài)透析體外釋放實(shí)驗(yàn)表明,載藥膠束能控制藥物的釋放,藥物從載藥膠束中的釋放呈現(xiàn)緩慢釋放行為。KCZ-M體外釋放動(dòng)力學(xué)符合一級(jí)動(dòng)力學(xué)模型,藥物釋放速度與藥物濃度成正比。CUR-M體外釋放動(dòng)力學(xué)符合零級(jí)動(dòng)力學(xué)模型,藥物釋放量與時(shí)間成正比。采用棋盤法和抑菌圈法對(duì)姜黃素及酮康唑載藥膠束聯(lián)合用藥開(kāi)展了體外抑菌活性實(shí)驗(yàn)。實(shí)驗(yàn)結(jié)果表明,低劑量的CUR-M(1.40~22.5μg/m L)即可改善KCZ-M的抗菌活性,二者的聯(lián)合抑菌指數(shù)FICI僅為0.073,表現(xiàn)出明顯的協(xié)同抗菌作用。以白色念珠菌為實(shí)驗(yàn)對(duì)象,XTT減低法以及激光共聚焦顯微鏡法對(duì)復(fù)配制劑抑膜活性的進(jìn)一步研究表明,CUR-M可明顯提高KCZ-M的抑膜活性�？傊�,MPEG-PCL作為酮康唑-姜黃素聯(lián)合用藥的潛在藥物運(yùn)輸系統(tǒng)的研究,為其他抗真菌藥物的研究提供了新的思路,具有潛在的臨床應(yīng)用價(jià)值和發(fā)展前景。
[Abstract]:Candida albicans infection can cause many infectious diseases and threaten human life and health. The formation of multidrug-resistant fungi and biofilms leads to the reduction of fungal susceptibility to fungal drugs. How to improve the antibacterial effect of antifungal drugs has become one of the hotspots of current research. Ketoconazole (KCZ) is a broad spectrum of azolic resistance. Fungal drugs have good therapeutic effects on Candida and the infection caused by various deep fungi, but the severe liver toxicity of ketoconazole restricts its clinical application. Reducing the dose of ketoconazole and improving its efficacy have become an important task to be solved. Curcumin (Curcumin, CUR) is a safe natural compound. Lutein can be combined with azolic antifungal agents to improve the ability to resist Candida albicans. But ketoconazole and curcumin are hydrophobic drugs with low bioavailability, which limits their clinical applications. Polymer micellar drug loading systems can overcome the problems of poor solubility in water and instability in physicochemical properties, and reduce drug toxicity. At the same time, the drug can be maintained within the range of effective concentration for a long time. It plays an important role in the clinical research and application of traditional antifungal drugs, and has potential research significance. In this paper, the two affinity of Methoxy poly (ethylene glycol) -b-poly (e-caprolactone), MPEG-PCL) was synthesized with different molecular weights. The block copolymer was confirmed by nuclear magnetic resonance hydrogen spectrum (1H-NMR) and infrared spectroscopy (FT-IR), and the molecular weight of different PCL chain segments was determined by gel permeation chromatography (GPC). The KCZ carrier micelles (KCZ-M) were prepared by the film hydration method. The single factor affecting the encapsulation efficiency and the drug loading of the drug loaded micelles was investigated. The basis for the single factor investigation was based on the results of single factor investigation. The optimum micelle preparation process was screened by orthogonal design. The results showed that when the weight ratio of MPEG/PCL was 1:1.7, the polymer material was 70 mg, the API was 10 mg, the hydration temperature was 60 [C], and the hydration time was 30 min, and the nano micelles loaded with KCZ were obtained. The drug loading and encapsulation rate were the highest, and were 85.27 + 1.75%, 11.31 + 1.05%, CUR carrying nano micelle (CUR-M). The drug loading and encapsulation efficiency were 91.19 + 0.83% respectively, and the water solubility of the 11.90 + 0.11%.KCZ drug micelles was 85 times higher than that of the KCZ. The water solubility of the CUR loaded micelles was 82900 times higher than that of the CUR, and the water solubility was obviously improved. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to carry out the drug micelles of ketoconazole and curcumin. The particle size of the ketoconazole and curcumin nanoparticles was small and evenly distributed, the average particle size was 44.70 + 1.91 nm, 39.56 + 0.19 nm. Fourier infrared spectroscopy (FT-IR), and X- ray diffraction (XRD) was used to characterize the drug loaded micelles. The study found that KCZ and CUR were successfully encapsulated into nanoscale micelles and existed in the form of amorphous and non crystalline form. In vitro release experiments show that drug loading micelles can control the release of drugs. The release of drugs from the drug loaded micelles shows a slow release behavior of.KCZ-M in vitro release kinetics in line with the first order kinetic model. Drug release rate and drug concentration are proportional to the.CUR-M release kinetics model, drug release and time. The antibacterial activity of curcumin and ketoconazole drug loaded micelles in vitro was carried out by chessboard method and bacteriostasis method. The experimental results showed that the low dose of CUR-M (1.40~22.5 g/m L) could improve the antibacterial activity of KCZ-M, and the combined antibacterial index of the two was only 0.073, which showed obvious synergistic antibacterial effect. White The further study on the inhibitory activity of the compound preparation by the XTT reduction method and the laser confocal microscope shows that CUR-M can obviously improve the inhibitory activity of KCZ-M. In a word, the research of MPEG-PCL as a potential drug transport system for the combination of ketoconazole and curcumin provides a new study for other antifungal drugs. The train of thought has potential clinical application value and development prospect.
【學(xué)位授予單位】：濟(jì)南大學(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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