学校代码：10385分类号： 研究生学号：1100202028 密 级：
pH响应性PEG化壳聚糖基隐形纳米胶束的制备及其释药研究 Preparetion and Drug Release Research of pH-Responsive PEGylated Chitosan-Based Nanomicelle 作者姓名： 姚文杰
指导教师： 李明春 教授
学 科： 高分子化学与物理太阳能沼气池
研究方向： 功能高分子材料
所在学院： 材料科学与工程学院
论文提交日期：二零一四年五月
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摘 要
壳聚糖和聚乙二醇(PEG)均具有良好的生物降解性、生物相容性和无毒性，在生物医药领域具有广泛的应用。本课题组曾合成出具有自组装功能的N,N-双长链烷基壳聚糖(DACS)。因此本论文以此材料为基础，通过进一步PEG化以获得具有隐形功能的新型壳聚糖基纳米胶束，并应用于药物控制释放体系。 本论文将聚乙二醇单甲醚(mPEG)经羧化后，通过酰化反应与N,N-双烷基壳聚糖结合在一起，
制得高接枝度的N,N-双烷基-3,6-O-mPEG-壳聚糖(PEDACS)，其中烷基链分别为辛基、癸基和十二烷基，mPEG的分子量分别为500和1000 Da。采用1H NMR、FTIR和EA等手段对产物的结构进行表征。
实验结果表明：PEDACS的烷基链取代度在1.90左右，mPEG的取代度在1.60左右。通过稳态荧光法测定了各个产物的临界胶束浓度(CMC)，CMC值随着烷基链的增长和mPEG分子量的减小逐渐减小。低的CMC值，有利于在体内循环被稀释时胶束的稳定存在，但由于PEDLCS-500的水溶性较差，对疏水物的增容会产生影响，所以本实验的较优产品为PEDLCS-1000，其CMC值为0.1170 mg·mL-1。载药胶束的较优投料比为酮洛芬(KP):PEDLCS-1000=0.8:1，此时载药量为34.48 %，包封率为65.78 %，粒径为155.1 nm，Zeta电位为-31.6 mv。在两种不同的pH模拟体液中发现同样的现象：随着pH值的减小，胶束的稳定性降低，胶束粒径有增大的趋势；在pH 5.5时胶束絮凝，且具有可逆性。本实验还分别考察了在pH 6.5和7.4的模拟溶液中载药胶束的药物释放行为，结果表明PEDLCS-1000载药胶束的药物释放行为具有一定的pH响应性。
mPEG接枝的N,N-双烷基壳聚糖(PEDACS)能形成粒径较小的隐形载药胶束，而且这种新型载药胶束的pH响应范围符合肿瘤细胞微环境(pH 7.2～6.0)，因此有望成为一种药物控释新材料。
关键词：两亲性壳聚糖聚乙二醇单甲醚pH响应性隐形纳米胶束
熔铜炉
I防水微动开关
Abstract
Chitosan and poly(ethylene glycol) are widely used in biomedical field. They have good biodegradability, biocompatibility and low toxicity. Our group have prepared self-assembled N,N-dialkyl chitosan (DACS). Based on DACS, a new type of PEGylated chitosan derivative was synthesized in order to prepare the stealth nano-micelles for application in the drug delivery system.
Through the acylation reaction, a series of novel chitosan amphiphilic derivatives N,N-dialkyl-3,6-O-mPEG-chitosan (PEDACS) with high degree of grafting was synthesized by grafting mPEG-COOH onto N,N-dilauryl chitosan. In addition, the alkyl chains were octyl, decyl and lauryl respectively. And the molecular weight of mPEG was 500 and 1000 Da separately. The products were charactered through the methods of 1H NMR, FTIR, EA and so on.
The experimental results showed that the degree of alkyl and mPEG substitution was about 1.90 and 1.60 respectively in the products. The Critical micelle concentration (CMC) of the products was determined by steady-state fluorescence method. The CMC value of the products would be decreased with the chain of N,N-dialkyl increasing and the molecular weight of mPEG raising. Becau
se the poor water solubility of PEDLCS-500, PEDLCS-1000 was better for further study. The CMC value of PEDLCS-1000 was 0.1170 mg•mL-1. The drug loading concent and efficiency of KP-loaded PEDLCS micelles was determined as 34.48% and 65.78 % respectively under the optimal ratio of KP and PEDLCS-1000 (0.8:1). And the KP-loaded PEDLCS micelles had an average size of 155.1 nm and zeta potential of -31.6 mV. The same phenomenons appeared in two different simulated body fluids with different pH. The stability of the micelles decreased and diameter of the micelles increased with the reduction of the pH value. When the pH value varied from 7.4 and 6.5 to 5.5, the micelles could be changed from transparent to flocculation, and the process was reversible. The drug release behaviour of drug-loaded micelles was examined at pH 6.5 and 7.4 simulated body fluid separately. It showed the release
III
behavior of drug-loaded micelles had a certain pH sensitivity.
PEDACS could form the smaller stealth micelles which achieved the long-circulating of body. And the range of pH response was rightly fit to the growth microenvironment of tumor cell (pH 7.2～6.0). It would be expected to become a new material of drug delivery system.
Keywords: Amphiphilic chitosan mPEG pH-responsive Stealth nano-micelles
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