【作者】 刘志景；

【导师】 朱诚身；

【作者基本信息】 郑州大学 ， 材料学， 2010， 硕士

【摘要】 纳米凝胶具有独特的优势：尺寸可调(从几十纳米到几百纳米)、大的比表面积(可连接多化合价的生物分子)、内部网络结构(有助与生物分子的内部结合)。因此纳米凝胶可作为靶向药物释放载体来物理包封生物活性分子,如药物、蛋白质、碳水化合物和DNA,实现其体外可控释放。在生物医学工程、药物应用和生物材料科学方面,越来越多的研究人员开始设计和制备纳米凝胶,其中最受人关注的是温度、pH敏感纳米凝胶。而采用简单工艺制备粒径可控的纳米凝胶成为其难点。本工作以N-异丙基丙烯酰胺(NIPAM)为温敏性聚合单体,丙烯酸(AA)和具有良好生物相容性的壳聚糖(CS)为pH敏感性聚合单体,采用无皂乳液聚合法(SFEP)制备了一系列温度、pH敏感纳米凝胶。研究了纳米凝胶的粒径和分布及其溶胀和释药性能。主要研究内容和结论如下：(1)采用SFEP制备的PNIPAM、P(NIPAM-co-AA)、P(NIPAM-co-AA)/CS纳米凝胶球形完整,粒径可控制在200nm以下且分散均匀；连续式比间歇式SFEP合成纳米凝胶的粒径要小,分散更均匀；调节共聚单体AA和CS的加入量,可使共聚凝胶的LCST提高到具有临床意义的37℃以上。(2)随交联剂含量的增加,PNIPAM纳米凝胶的粒径逐渐减小,溶胀性能变差；随乳化剂的增加,凝胶的粒径明显变小,但其溶胀率变化不大；采用SFEP制备纳米凝胶,交联剂和乳化剂的适宜用量分别为单体物质量的8%和0.4%。(3)随共聚单体AA含量的增加,P(NIPAM-co-AA)纳米凝胶的粒径逐渐增大,pH敏感性越来越明显；溶胀速率随着pH的增大而增大,在酸性介质中具有明显的温度敏感性,随着介质pH值的增大,凝胶的相转变温度越来越不明显；载药NL-a(7%)、NZ-a(7%)纳米凝胶的释药性受温度和pH的影响,37℃时的最大释药量大于25℃时的最大释药量,模拟胃液中的释药率明显小于模拟肠液中的释药率。(4) P(NIPAM-co-AA)/CS纳米凝胶的粒径随AA/CS含量的增加而增大；在偏中性介质中溶胀速率最小,在碱性介质中其溶胀速率最大；在模拟体温和肠液环境中,载药N-as(20%)纳米凝胶的药物释放量较小,而且随着时间的延长释药率持续稳定。这种双敏纳米凝胶有望在生物医药领域发挥重要作用。更多还原

【Abstract】 The design and preparation of nanogels have attracted a great deal of interest in biomedical engineering, pharmaceutical applications, and biomaterials science because of their tunable advantage. Nanogels have tunable size from nanometers to several micrometers and a large surface area for multivalent bioconjugation. They also have an interior network for the incorporation of biorelated molecules. Physical entrapment of bioactive molecules such as drugs, proteins, carbohydrates, and DNA in the polymeric network, as well as their in vitro release behavior, have been extensively investigated as targeted drug delivery carriers for biomedical applications.N-isopropylacrylamide (NIPAM) was choosed as a temperature-sensitive monomer, acrylic acid (AA) and chitosan (CS) of biocompatibility as pH-sensitive monomers, a series of temperature-and pH-sensitive nanogels were prepared by surfactant-free emulsion polymerization (SFEP). The paricle size and distribution, swelling properties and drug release of nanogels were studied. The main contents and conclusions are as follows:(1) The nanogels of PNIPAM, P(NIPAM-co-AA), P(NIPAM-co-AA)/CS obtained by SFEP have perfect spherical structure and uniform distribution of particle size. The particle size of nanogels prepared by continuous SFEP is smaller and more homogeneous than intermittent SFEP, and it be controlled smaller than 200nm.(2) With a designed concentration of monomer, when the size and the swelling ratio of nanogels PNIPAM decrease with the content of crosslinking agent (MBA) increasing. Under the same polymerization conditions, the size of nanogels becomes significantly smaller with the content of sodium dodecyl sulfate (SDS) increase, but the swelling ratio changed little. The appropriate amount of crosslinking agent and emulsifier monomer amount of substance are 8% and 0.4% by SFEP.(3) The particle size of P(NIPAM-co-AA) nanogels became bigger with the increasing of the AA comonomer content. The swelling rate in acidic medium was slow, and increased with the increase of pH, went to maximum in alkaline medium. pH sensitivity of P(NIPAM-co-AA) hydrogels was more and more obvious with the increase of the AA monomer proportion. Nanogels have obvious temperature sensitivity in acidic media, the phase transition temperature becoming less distinct with the medium pH value increases. P(NIPAM-co-AA) nanogels NL-a (7%) and NZ-a (7%) which containing aspirin have temperature and pH sensitivity, Their maximum release were greater at 37℃than at 25℃. The release rate was significantly lower in simulated gastric juice than in the simulated intestinal fluid at 37℃.(4) The surface of P(NIPAM-co-AA)/CS gels was not smooth any more, nano-particle size became bigger with the comonomer AA/CS content increases. The swelling rate of P(NIPAM-co-AA)/CS gels was fast in acidic medium, slower in the neutral medium, fastest in the alkaline medium. At body temperature and intestinal fluid in the simulation environment, the drug release of N-as (20%) nanogel was less, and maintained with a stable release rate. This Double-Sensitive Nanogel is expected to play an important role in biomedical application.更多还原