用于潰瘍性結(jié)腸炎治療的載姜黃素微、納米口服給藥系統(tǒng)研究
發(fā)布時間：2018-08-27 08:16
【摘要】：潰瘍性結(jié)腸炎(Ulcerative colitis,UC)是一種病因尚不完全明確的慢性腸道疾病,屬于炎癥性腸病(Inflammatory bowel disease,IBD)的一種。在我國,UC的發(fā)病率呈現(xiàn)急劇上升趨勢,由于其反復(fù)發(fā)作并且難以治愈,嚴(yán)重危害著社會公共健康。姜黃素(Curcumin,CUR)是一種從姜科植物根莖中提取的天然抗炎藥物,由于其毒副作用小,對人體基本沒有危害,而且具有抗炎、抗氧化、抗腫瘤、降血脂等多種功能,逐漸被用于UC治療。但是,姜黃素的水溶性差和生物利用度低限制了其應(yīng)用。微、納米級別的藥物遞送系統(tǒng)能夠顯著提高藥物的溶解度,增長藥物體內(nèi)循環(huán)的時間,實(shí)現(xiàn)藥物緩釋,同時藥物可在炎癥部位被動靶向,顯著降低藥物毒副作用,因此被公認(rèn)為是一種有潛力的治療策略。本文構(gòu)建了載姜黃素微米和納米載藥系統(tǒng)用于UC治療。研究內(nèi)容分成如下兩個部分:第一部分以聚乳酸-羥基乙酸共聚物(Poly(lactic-co-glycolic acid),PLGA)和pH敏感型材料丙烯酸樹脂S100(Eudragit S100,ERS100)作為載體材料制備了pH敏感型載姜黃素微米粒子,ERS100和PLGA的比例分別為(1:0,2:1,1:1,1:2和0:1),分別定義為MPs-1,MPs-2,MPs-3,MPs-4和MPs-5。pH型敏感型微米粒子的粒徑為1.52?1.91μm,包封率和載藥量隨著組成材料中PLGA含量的提高而增加,部分微米粒子的包封率超過80%。掃描電子顯微鏡(Scanning electron microscope,SEM)顯示,MPs-4,即ERS100和PLGA的比例為1:2的微米粒子,呈現(xiàn)球形,并且在pH為7.2的磷酸鹽緩沖溶液(Phosphate buffer saline,PBS)中,姜黃素可以快速釋放。體內(nèi)實(shí)驗(yàn)結(jié)果顯示,MPs-4對葡聚糖硫酸鈉(Dextran sulfate sodium,DSS)誘導(dǎo)的結(jié)腸炎表現(xiàn)出良好的治療效果,可維持小鼠體重、結(jié)腸長度和脾重穩(wěn)定,并且降低結(jié)腸組織中髓過氧化物酶(Myeloperoxidase,MPO)活性。第二部分通過乳化溶劑揮發(fā)法制備了以PLGA為載體材料的載姜黃素微米粒子和納米粒子,從多個方面對粒子進(jìn)行了理化性質(zhì)的表征,同時對比研究了微米粒子和納米粒子的體、內(nèi)外抗炎效果區(qū)別。我們制備的載姜黃素微米粒子(CUR-MPs)和納米粒子(CUR-NPs)的粒徑分別約為1.7μm和270 nm,包封率超過50%,載藥量為3.5%?7.0%,X射線衍射儀(X-ray diffraction,XRD)分析顯示姜黃素在粒子中呈無定型分布。釋放實(shí)驗(yàn)數(shù)據(jù)顯示,微米粒子的累積釋放率只達(dá)到15%,而納米粒子的累積釋放率達(dá)到50%以上。細(xì)胞實(shí)驗(yàn)顯示,兩種粒子的細(xì)胞毒性顯著低于游離姜黃素,且表現(xiàn)出一定的抗炎性能。體內(nèi)動物試驗(yàn)中,CUR-MPs和CUR-NPs對DSS誘導(dǎo)的結(jié)腸炎模型都表現(xiàn)出一定的抗炎作用,同時CUR-NPs在維持小鼠的體重、結(jié)腸長度和脾臟重量,降低MPO活性等方面的性能皆優(yōu)于CUR-MPs�？偟膩碚f,我們的研究表明:與CUR-MPs相比,CUR-NPs具有更優(yōu)的UC治療效果。結(jié)合以上兩部分研究表明,微米粒子能顯著提高姜黃素對于UC的治療效果;進(jìn)一步的研究還發(fā)現(xiàn),載姜黃素納米粒子比載姜黃素微米粒子具有更優(yōu)的UC治療效果。
[Abstract]:Ulcerative colitis (Ulcerative colitis,UC) is a chronic intestinal disease with unknown etiology and belongs to inflammatory bowel disease (Inflammatory bowel disease,IBD). In our country, the incidence of UC is rising sharply, because of its repeated attack and difficult to cure, it seriously endangers the public health. Curcumin (Curcumin,CUR) is a kind of natural anti-inflammatory drug extracted from rhizome of Curcumae. Because of its small toxicity and no harm to human body, curcumin (Curcumin,CUR) has many functions such as anti-inflammatory, anti-oxidation, anti-tumor and lowering blood lipids, etc., so it has been gradually used in the treatment of UC. However, curcumin's poor water solubility and low bioavailability limit its application. The drug delivery system at the micro and nanometer level can significantly improve the solubility of drugs, increase the time of internal circulation of drugs, achieve drug release slowly, and at the same time, the drugs can be passively targeted at inflammatory sites, which can significantly reduce the side effects of drugs. It is therefore recognized as a potential therapeutic strategy. In this paper, curcumin-loaded micrometer and nano-loaded drug delivery systems were constructed for UC therapy. The research content is divided into two parts as follows: in the first part, pH sensitive curcumin micron particles (pH) and PLGA were prepared by using poly (lactic acid-glycolic acid) copolymer (Poly (lactic-co-glycolic acid) and pH sensitive material, acrylic resin S100 (Eudragit S100 ERS100) as carrier materials. The ratios were 1: 0: 1: 1: 1: 1: 2 and 0:1, respectively, and defined as MPs-1,MPs-2,MPs-3,MPs-4 and MPs-5.pH sensitive microparticles with a particle size of 1.52 渭 m. The entrapment efficiency and drug loading increased with the increase of PLGA content. The encapsulation efficiency of some micron particles is more than 80%. Scanning electron microscopy (Scanning electron microscope,SEM) showed that MPs-4, a 1:2 micron particle with a ratio of ERS100 to PLGA, was spherical, and curcumin could be released rapidly in a pH 7.2 phosphate buffer solution (Phosphate buffer saline,PBS). The results showed that MPs-4 had a good therapeutic effect on colitis induced by sodium dextran sulfate (Dextran sulfate sodium,DSS). It could maintain the weight, colon length and spleen weight of mice and decrease the activity of myeloperoxidase (Myeloperoxidase,MPO) in colon tissue. In the second part, curcumin loaded micron particles and nanoparticles with PLGA as carrier were prepared by emulsified solvent volatilization method. The physicochemical properties of the particles were characterized from many aspects. At the same time, the bodies of micron particles and nanoparticles were compared and studied. Internal and external anti-inflammatory effects are different. The encapsulation efficiency of curcumin micron particles (CUR-MPs) and nano-particles (CUR-NPs) were about 1.7 渭 m and 270 nm, respectively, and the entrapment efficiency of curcumin was over 50 渭 m. The results of X-ray diffraction (X-ray diffraction,XRD) analysis showed that curcumin was amorphous in the particles. The experimental data show that the cumulative release rate of micron particles is only 15%, while the cumulative release rate of nanoparticles is more than 50%. Cell experiments showed that the cytotoxicity of the two particles was significantly lower than that of free curcumin and showed certain anti-inflammatory properties. In vivo animal experiments, CUR-MPs and CUR-NPs showed some anti-inflammatory effects on DSS induced colitis model, and CUR-NPs was superior to CUR-MPs. in maintaining weight, colon length, spleen weight and reducing MPO activity in mice. In general, our study shows that CUR-NPs are more effective than CUR-MPs in the treatment of UC. Combined with the above two parts of the study, micron particles can significantly improve the therapeutic effect of curcumin on UC, further research also found that curcumin nanoparticles have better therapeutic effect than curcumin micron particles.
【學(xué)位授予單位】：西南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R574.62
本文編號：2206656
[Abstract]:Ulcerative colitis (Ulcerative colitis,UC) is a chronic intestinal disease with unknown etiology and belongs to inflammatory bowel disease (Inflammatory bowel disease,IBD). In our country, the incidence of UC is rising sharply, because of its repeated attack and difficult to cure, it seriously endangers the public health. Curcumin (Curcumin,CUR) is a kind of natural anti-inflammatory drug extracted from rhizome of Curcumae. Because of its small toxicity and no harm to human body, curcumin (Curcumin,CUR) has many functions such as anti-inflammatory, anti-oxidation, anti-tumor and lowering blood lipids, etc., so it has been gradually used in the treatment of UC. However, curcumin's poor water solubility and low bioavailability limit its application. The drug delivery system at the micro and nanometer level can significantly improve the solubility of drugs, increase the time of internal circulation of drugs, achieve drug release slowly, and at the same time, the drugs can be passively targeted at inflammatory sites, which can significantly reduce the side effects of drugs. It is therefore recognized as a potential therapeutic strategy. In this paper, curcumin-loaded micrometer and nano-loaded drug delivery systems were constructed for UC therapy. The research content is divided into two parts as follows: in the first part, pH sensitive curcumin micron particles (pH) and PLGA were prepared by using poly (lactic acid-glycolic acid) copolymer (Poly (lactic-co-glycolic acid) and pH sensitive material, acrylic resin S100 (Eudragit S100 ERS100) as carrier materials. The ratios were 1: 0: 1: 1: 1: 1: 2 and 0:1, respectively, and defined as MPs-1,MPs-2,MPs-3,MPs-4 and MPs-5.pH sensitive microparticles with a particle size of 1.52 渭 m. The entrapment efficiency and drug loading increased with the increase of PLGA content. The encapsulation efficiency of some micron particles is more than 80%. Scanning electron microscopy (Scanning electron microscope,SEM) showed that MPs-4, a 1:2 micron particle with a ratio of ERS100 to PLGA, was spherical, and curcumin could be released rapidly in a pH 7.2 phosphate buffer solution (Phosphate buffer saline,PBS). The results showed that MPs-4 had a good therapeutic effect on colitis induced by sodium dextran sulfate (Dextran sulfate sodium,DSS). It could maintain the weight, colon length and spleen weight of mice and decrease the activity of myeloperoxidase (Myeloperoxidase,MPO) in colon tissue. In the second part, curcumin loaded micron particles and nanoparticles with PLGA as carrier were prepared by emulsified solvent volatilization method. The physicochemical properties of the particles were characterized from many aspects. At the same time, the bodies of micron particles and nanoparticles were compared and studied. Internal and external anti-inflammatory effects are different. The encapsulation efficiency of curcumin micron particles (CUR-MPs) and nano-particles (CUR-NPs) were about 1.7 渭 m and 270 nm, respectively, and the entrapment efficiency of curcumin was over 50 渭 m. The results of X-ray diffraction (X-ray diffraction,XRD) analysis showed that curcumin was amorphous in the particles. The experimental data show that the cumulative release rate of micron particles is only 15%, while the cumulative release rate of nanoparticles is more than 50%. Cell experiments showed that the cytotoxicity of the two particles was significantly lower than that of free curcumin and showed certain anti-inflammatory properties. In vivo animal experiments, CUR-MPs and CUR-NPs showed some anti-inflammatory effects on DSS induced colitis model, and CUR-NPs was superior to CUR-MPs. in maintaining weight, colon length, spleen weight and reducing MPO activity in mice. In general, our study shows that CUR-NPs are more effective than CUR-MPs in the treatment of UC. Combined with the above two parts of the study, micron particles can significantly improve the therapeutic effect of curcumin on UC, further research also found that curcumin nanoparticles have better therapeutic effect than curcumin micron particles.
【學(xué)位授予單位】：西南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R574.62
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