【作者】 刘宗华；

【导师】 张子勇；

【作者基本信息】 暨南大学 ， 生物医学工程， 2007， 博士

【摘要】 选择天然多糖及其衍生物为基质材料，利用含有相反电荷的聚电解质之间的静电相互作用为原理，在室温和水相的温和条件下，制备了五种新型的纳米载药体系，分别为：羧甲基壳聚糖／壳聚糖纳米粒子、肝素／壳聚糖纳米粒子、羧甲基壳聚糖／磷酸化壳聚糖纳米粒子、肝素／磷酸化壳聚糖纳米粒子和磷酸化壳聚糖／DNA纳米粒子。作为前期研究的探索和比照，还制备了Ca²⁺交联的羧甲基壳聚糖凝胶珠体系。使用红外光谱、激光光散射和透射电镜等仪器对各种纳米载药体系的基本性能进行了表征，如纳米粒子复合物的形成、纳米粒子的粒径及其分布、表面电荷性能、纳米粒子的形态结构等。进一步考察了基质材料的相对分子质量、溶液浓度、溶液的加入方式、负载药物或蛋白质的浓度、存放介质的pH值和离子浓度等因素对纳米粒子的粒径及其分布、表面电荷性能、包封率和稳定性的影响。实验结果表明，天然多糖及其衍生物的相对分子质量和其溶液浓度是影响纳米粒子尺寸的重要因素。通过选择适当的相对分子质量的基材和溶液浓度，可以将纳米粒子的粒径有效地控制在100～500nm之间。药物的包封率是衡量纳米载药体系性能的重要指标。同时升高纳米体系二元组分的浓度，能够生成更多的纳米粒子，是提高纳米粒子对药物和蛋白质的包封率的有效途径。进一步研究了牛血清白蛋白纳米载药体系的释放性能和阿霉素纳米载药体系在体外条件下对HeLa细胞的抑制功能，获得了令人满意的结果。评价了磷酸化壳聚糖对质粒DNA的负载能力、保护作用和转染HeLa细胞的能力，研究结果表明，磷酸化壳聚糖是一种有效的基因载体，具有深入开发的潜力。更多还原

【Abstract】 In this study, natural polysaccharides and their derivatives were used to prepare nanoparticle drug delivery systems. The preparation was based on the static electric interaction between positive polyelectrolyte and negative polyelectrolyte and was conducted on mild conditions, i.e. at room temperature and in aqueous solutions. The obtained five nanoparticle drug delivery systems were carboxymethyl chitosan/chitosan, heparin/chitosan, carboxymethyl chitosan/phosphonic chitosan, heparin/phosphonic chitosan and phosphonic chitosan/DNA nanoparticles. In preliminary experiments, we prepared calcium-crosslinked carboxymethyl chitosan hydrogel beads.By means of IR, TEM and zeta potential analyzer etc., the physicochemical characteristics of these drug delivery systems were characterized, including the formation mechanism, the particle size, polydispersity, zeta potential and morphology of the nanoparticles. The pH and ion strength stability of nanoparticles were also evaluated. In addition, we further investigated the effects of the pH of chitosan solution, the molecular weight of chitosan, the concentration of chitosan solution and the concentration of loaded protein on the particle size, polydispersity, zeta potential, protein entrapment efficiency of the nanoparticles. As the results showed, the molecular weight and the concentration of polysaccharides were important factors to affect the size of nanoparticles. Prepared with suitable molecular weight and solution concentration of polysaccharides, the particle size ranged from 100nm to 500nm. The entrapment efficiency of drug is a key factor to evaluate drug delivery systems. We found that, increasing the concentration of both components in nanoparticles could prepare more nanoparticle carriers and hence efficiently improve the entrapment efficiency of drug.Furthermore, we investigated the effect of doxorubicin-loading nanoparticles on HeLa cells and satisfactory results were obtained. As a potential gene carrier, phosphonic chitosan were evaluated in terms of the entrapment, protection and transfection of plasmid DNA.更多还原