树枝状和发散状温度敏感水凝胶的制备与性能研究

1、中南民族大学 硕士学位论文 树枝状和发散状温度敏感水凝胶的制备与性能研究 姓名：李莹 申请学位级别：硕士 专业：生物化学与分子生物学 指导教师：肖新才 2011-05 中南民族大学硕士学位论文 I 摘 要 为了减少药物在体内产生毒副作用或提高药物治疗疾病的效果， 靶向药物载 体成为当今研究的热门课题。如果把这种药物载体应用于人体，使药物只在病变 的组织部位释放，这样不仅能够有效利用药物，而且不会在其他正常部位产生毒 副作用，获得最优的治疗效果。最常用的环境感应式凝胶（载体）是 N-异丙基 丙烯酰胺（NIPAM）类高分子聚合物。因为普通 PNIPAM 水凝胶对外界刺激产 生溶胀/退溶胀的响应速率非常慢，尤其是达到最后的平衡需要几小时甚至几天 的时间；此外，普通水凝胶的机械性能较差，如较脆易碎、不易拉伸等，这些因 素在很大程度上限制了它们的应用。因此，我们需要探索制备新型温度敏感材料 的方法，来弥补温度敏感材料种类偏少的缺陷，同时探索新型复合结构凝胶的特 性和改变其对温度的敏感速度，从而建立新型的给药系统。为了增加水凝胶的反 应动力学，探索了几种策略。 1. 利用冰-融化三步合成的方法获得

2、夹心型水凝胶柱体。这种新颖的水凝胶 柱体是将线型聚（N-异丙基丙烯酰胺）链两端接枝交联型的聚（N-异丙基丙烯酰 胺） 。为了探讨引发反应途径对水凝胶温敏特性的影响，本文将 N,N-二亚甲基双 丙烯酰胺（BIS） ，过硫酸铵（APS）放入不同的层，形成夹心型凝胶 Type A 和 Type B，为了比较夹心型凝胶与普通型凝胶的不同，实验合成了 Type N 均相凝 胶，研究了凝胶柱体的溶胀/退溶胀动力学和药物释放特性。其研究结果如下： 凝胶均具有较好的温敏性，在 33时发生相变; 凝胶通过多次溶胀/退溶胀动力学测试，结果表明机械性能较高且保持良 好的完整性; 溶胀/退溶胀动力学试验表明 Type B 溶胀/退溶胀速率最大，Type N 最小; 药物释放（NaCl 溶液）测试表明：温度从低温升到高温的过程中，三种 类型的凝胶的外环境盐浓度相应的增加， Type B 增加最快、 Type A 次之， Type N 最慢。再次证明，此种方法可以提高普通类型水凝胶的反应速率； 2. 通过可逆加成-断裂链转移(RAFT)的方法合成温敏性树枝状大分子，通过 FI-IR 和 1HNMR 图谱对每一步反

3、应进行表征，对最终合成的树枝状大分子进行 温敏性测试。实验表明： 树枝状和发散状温度敏感水凝胶的制备与性能研究 II FI-IR 和 1HNMR 图谱表明每一步成功反应； 均具有较好的温敏性，苯乙烯、NIPAM 的含量影响相变温度； 变成乳白色时间较短，且恢复无色透明状态较迅速，说明将 NIPAM 接枝 于树枝状大分子能提高溶胀/退溶胀速率； 3. 原子转移自由基聚合（ATRP）的方法接枝聚（N-异丙基丙烯酰胺）于气 相球形二氧化硅（纳米级）表面，聚（N-异丙基丙烯酰胺）的链长和密度可控。 通过 FI-IR 对每一步反应进行表征，扫描电子显微镜（SEM）图显示每一步反应 的状态，最后进行温敏测试。初步试验表明：每一步反应成功，具有温敏性。还 需进一步探讨反应条件对温敏性的影响。 关键词： N-异丙基丙烯酰胺；夹心型水凝胶；水凝胶；原子转移自由基聚合 中南民族大学硕士学位论文 III ABSTRACT In order to reduce side effects of drug in the body or to improve the effectiveness of drug ag

4、ainst diseases, the targeted drug has become a hot research topic. If the drug carrier is applied to the human body, and the drug released only in the diseased tissue site, not only can effective use of drugs for optimal therapeutic effect, but also no toxic side effects would be produced in other normal parts. The most commonly used environment-sensitive hydrogels (carries) is the type of N-isopropylacrylamide (NIPAM) polymers. However, the swelling/deswelling response rate of PNIPAM hydrogels

5、to the external stimulation is very slow. Sometimes, it even takes a few hours or even several days to achieve the final balance; In addition, general hydrogels have poor mechanical properties: they are more brittle and fragile, difficult to stretch. These factors largely limit their application. Therefore, we need to explore a new preparation method of temperature-sensitive materials, to compensate for the types of temperature-sensitive materials, to explore new composite structure of the gel,

6、to change its temperature sensitive properties of the speed, and to establish new delivery systems. In order to increase the reaction kinetics of hydrogel, several strategies are explored. 1. The sandwich-typed hydrogel column is fabricated by three-step process using ice-melting synthesis. This novel hydrogel column which is featured with both ends of linear poly(N-isopropylacrylamide) chains being grafted onto cross-linked PNIPAM chain. To discuss the influence of the reaction pathway triggere

7、d to temperature sensing properties of hydrogels, this article will put N,N-Methylenebisacry- lamide(BIS), ammonium persulfate (APS) into different layers, forming sandwich-typed hydrogel of Type A and Type B. In order to compare the sandwich hydrogel with the ordinary hydrogel , the experiment synthesizes homogeneous Type N. The swelling hydrogel swelling/deswelling kinetics and drug release characteristics of the hydrogel column are studied. The results are shown as followed: Hydrogels have be

8、tter temperature sensitive, the phase transited at 33 ; Swelling-deswelling kinetics of the hydrogels are tested for several times. The results show that mechanical properties of hydrogels are still high and the integrity is 树枝状和发散状温度敏感水凝胶的制备与性能研究 IV kept; Swelling/deswelling kinetics experiments show that Type Bs swelling/ deswelling rate is the highest while Type N is the lowest; Drug release (NaCl solution) test show that the process of temperature rises from low to high, the salt concentrati

9、on of outside environment of the three types hydrogels increases correspondingly, Type B grow the most quickly, then Type A, Type N is the slowest, proving that this method can improve the reaction rate of general hydrogel; 2. Through reversible additionfragmentation chain transfer polymerization (RAFT) method, thermo-responsive dendrimer is synthesized. Each step of the reaction is charactered by FI-IR and 1HNMR spectra. And the final synthesis of dendrimers are tested by temperature sensitivity. Experiments show that: FI-IR and 1HNMR spectra show that the success of every step of the reaction; They have good temperature sensitivity. The content of styrene and NIPAM influence the phase transition temperature; They change into a milky white in a short time, and they restored the colorless rapidly, indicating that NIPAM grafted onto the dendrimer can increase the swelling / deswelling rate; 3. Through atom transfer radical polymerization (ATRP) method, poly (N

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