离子液体中ATRP法改性纤维素及其药物控释的研究

发布时间：2019-03-04 20:28

【摘要】：纤维素以其良好的生物相容性、可生物降解性等优点,在生物医药领域中有着广泛的应用。通过对纤维素进行接枝改性,在其结构中引入pH敏感性基团,可使得到的纤维素聚合物胶束能够根据人体不同部位的pH特点,实现对其所负载药物的靶向释放,提高药物的生物利用度,减小药物对人体的毒副作用。因此,本研究以纤维素的良好溶剂离子液体为反应介质,并结合原子转移自由基聚合(ATRP)反应过程活性可控的技术优点,在纤维素分子中均匀地接枝了不同的pH敏感性分子,以期更好地实现pH响应性纤维素聚合物胶束在不同生理环境下对药物的缓、控释效果。本研究在离子液体氯化-1-烯丙基-3-甲基咪唑([AMIM]Cl)中,通过ATRP法在微晶纤维素分子骨架上分别均匀地接枝了聚4-乙烯基吡啶和聚甲基丙烯酸叔丁酯分子,并通过聚甲基丙烯酸叔丁酯水解为聚甲基丙烯酸,分别得到了具有pH响应性的弱碱性MCC-g-P4VP和弱酸性MCC-g-PMAA聚合物分子,优化了两种产物的合成工艺条件。通过FT-IR、1H NMR,确定了产物的分子结构;GPC测得聚合物的侧链分子的分子量分布窄,大小均匀。采用表面张力法,测得MCC-g-P4VP和MCC-g-PMAA聚合物胶束均具有较小的临界胶束浓度(CMC),稳定性较好;通过TEM、DLS和UV-Vis对两种聚合物自组装胶束的粒径、形貌及pH响应性进行了研究,结果表明:两种聚合物可自组装成球状结构胶束,胶束的流体力学直径小于200纳米、粒径分布均匀。两种聚合物胶束在不同pH条件下的粒径及透光率均表现出了相应的转变,具有良好的pH响应性。分别以亲水性的罗丹明B(Rh B)和疏水性的阿司匹林(ASP)为模型药物,对MCC-g-P4VP和MCC-g-PMAA胶束的药物包覆性能及在不同pH条件下的药物控释性能进行了分析,并结合动力学模型对比分析了两种聚合物胶束在不同pH条件下对水溶性不同药物的释放机制,结果表明:MCC-g-P4VP胶束对两种药物具有良好的包覆性能,载药后胶束具有核-壳状的球形结构,载药胶束在酸性条件下的累积药物释放量大于碱性条件,且在酸性条件下的体外药物释放符合一级动力学方程,在中性和碱性条件的药物释放符合Ritger-Pappas方程;MCC-g-PMAA载药胶束在碱性条件下的累积药物释放量大于酸性条件,表现出了良好的药物控释性能,药物释放动力学方程拟合结果表明,酸性和中性条件下,MCC-g-PMAA胶束对两种药物的释放符合扩散和溶蚀相结合的机制;碱性条件下对两种药物的释放为扩散机制。
[Abstract]:Cellulose has been widely used in the field of biomedicine because of its good biocompatibility and biodegradability. Through the graft modification of cellulose and the introduction of pH sensitive groups into its structure, the cellulose polymer micelles can achieve the targeted release of the drugs loaded on the cellulose micelles according to the characteristics of pH in different parts of the human body. Improve the bioavailability of drugs, reduce the toxic side effects of drugs on the human body. Therefore, in this study, ionic liquids, a good solvent of cellulose, were used as reaction medium, and combined with the advantages of controllable activity of atom transfer radical polymerization (ATRP) reaction process, different pH sensitive molecules were evenly grafted into cellulose molecules. In order to realize the slow and controlled release effect of pH responsive cellulose polymer micelles in different physiological environment. In this paper, poly (4-vinylpyridine) and poly (tert-butyl methacrylate) were grafted uniformly on the framework of microcrystalline cellulose by ATRP method in ionic liquid chloride-1-allyl-3-methylimidazole ([AMIM] Cl). Through hydrolysis of poly (tert-butyl methacrylate) to poly (methacrylic acid), weak basic MCC-g-P4VP and weak acid MCC-g-PMAA polymers with pH response were obtained respectively. The synthesis conditions of the two products were optimized. The molecular structure of the product was determined by FT-IR,1H NMR, and the molecular weight distribution of the side chain molecule of the polymer was narrow and uniform by GPC. By using surface tension method, it was found that both MCC-g-P4VP and MCC-g-PMAA micelles had better stability of (CMC), with lower critical micelle concentration. The particle size, morphology and pH response of two kinds of self-assembled micelles were studied by TEM,DLS and UV-Vis. The results showed that the two polymers could be self-assembled into spherical micelles, and the diameter of micelles was less than 200nm, and the diameter of micelles was less than 200nm. The particle size distribution is uniform. The particle size and transmittance of the two kinds of polymer micelles under different pH conditions showed corresponding changes and had good pH response. Using Rhodamine B (Rh B) and hydrophobic aspirin (ASP) as model drugs, the drug-coated properties of MCC-g-P4VP and MCC-g-PMAA micelles and their controlled-release properties under different pH conditions were analyzed. The release mechanism of two kinds of polymer micelles to water-soluble and different drugs under different pH conditions was compared and analyzed with kinetic model. The results showed that MCC-g-P4VP micelles had good coating properties for two kinds of drugs. The drug-loaded micelles have a spherical core-shell structure. The cumulative drug release of drug-loaded micelles in acidic condition is larger than that in alkaline condition, and the drug release in vitro accords with the first-order kinetic equation under acidic conditions. The drug release in neutral and alkaline conditions was in accordance with the Ritger-Pappas equation. The cumulative drug release of MCC-g-PMAA micelles in alkaline condition was higher than that in acidic condition, and showed a good controlled release performance. The results of drug release kinetics equation fitting showed that under acidic and neutral conditions, the drug release rate of micelles was higher than that of acidic micelles. The release of MCC-g-PMAA micelles to the two drugs was consistent with the mechanism of diffusion and dissolution. The release of the two drugs under alkaline conditions is a diffusion mechanism.
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O636.11;TQ460.1

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