用于溃疡性结肠炎治疗的载姜黄素微、纳米口服给药系统研究

发布时间：2018-08-27 08:16

【摘要】：溃疡性结肠炎(Ulcerative colitis,UC)是一种病因尚不完全明确的慢性肠道疾病,属于炎症性肠病(Inflammatory bowel disease,IBD)的一种。在我国,UC的发病率呈现急剧上升趋势,由于其反复发作并且难以治愈,严重危害着社会公共健康。姜黄素(Curcumin,CUR)是一种从姜科植物根茎中提取的天然抗炎药物,由于其毒副作用小,对人体基本没有危害,而且具有抗炎、抗氧化、抗肿瘤、降血脂等多种功能,逐渐被用于UC治疗。但是,姜黄素的水溶性差和生物利用度低限制了其应用。微、纳米级别的药物递送系统能够显著提高药物的溶解度,增长药物体内循环的时间,实现药物缓释,同时药物可在炎症部位被动靶向,显著降低药物毒副作用,因此被公认为是一种有潜力的治疗策略。本文构建了载姜黄素微米和纳米载药系统用于UC治疗。研究内容分成如下两个部分:第一部分以聚乳酸-羟基乙酸共聚物(Poly(lactic-co-glycolic acid),PLGA)和pH敏感型材料丙烯酸树脂S100(Eudragit S100,ERS100)作为载体材料制备了pH敏感型载姜黄素微米粒子,ERS100和PLGA的比例分别为(1:0,2:1,1:1,1:2和0:1),分别定义为MPs-1,MPs-2,MPs-3,MPs-4和MPs-5。pH型敏感型微米粒子的粒径为1.52?1.91μm,包封率和载药量随着组成材料中PLGA含量的提高而增加,部分微米粒子的包封率超过80%。扫描电子显微镜(Scanning electron microscope,SEM)显示,MPs-4,即ERS100和PLGA的比例为1:2的微米粒子,呈现球形,并且在pH为7.2的磷酸盐缓冲溶液(Phosphate buffer saline,PBS)中,姜黄素可以快速释放。体内实验结果显示,MPs-4对葡聚糖硫酸钠(Dextran sulfate sodium,DSS)诱导的结肠炎表现出良好的治疗效果,可维持小鼠体重、结肠长度和脾重稳定,并且降低结肠组织中髓过氧化物酶(Myeloperoxidase,MPO)活性。第二部分通过乳化溶剂挥发法制备了以PLGA为载体材料的载姜黄素微米粒子和纳米粒子,从多个方面对粒子进行了理化性质的表征,同时对比研究了微米粒子和纳米粒子的体、内外抗炎效果区别。我们制备的载姜黄素微米粒子(CUR-MPs)和纳米粒子(CUR-NPs)的粒径分别约为1.7μm和270 nm,包封率超过50%,载药量为3.5%?7.0%,X射线衍射仪(X-ray diffraction,XRD)分析显示姜黄素在粒子中呈无定型分布。释放实验数据显示,微米粒子的累积释放率只达到15%,而纳米粒子的累积释放率达到50%以上。细胞实验显示,两种粒子的细胞毒性显著低于游离姜黄素,且表现出一定的抗炎性能。体内动物试验中,CUR-MPs和CUR-NPs对DSS诱导的结肠炎模型都表现出一定的抗炎作用,同时CUR-NPs在维持小鼠的体重、结肠长度和脾脏重量,降低MPO活性等方面的性能皆优于CUR-MPs。总的来说,我们的研究表明:与CUR-MPs相比,CUR-NPs具有更优的UC治疗效果。结合以上两部分研究表明,微米粒子能显著提高姜黄素对于UC的治疗效果;进一步的研究还发现,载姜黄素纳米粒子比载姜黄素微米粒子具有更优的UC治疗效果。
[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.
【学位授予单位】：西南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R574.62

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