【作者】 曹斌；

【导师】 万涛；

【作者基本信息】 武汉理工大学 ， 材料学， 2011， 硕士

【摘要】 近年来肝硬化及肝癌等肝病正严重威胁着人类的健康。传统的给药方式,药物难以准确到达靶部位,药物的生物利用度低且对其他正常器官有毒副作用。目前,壳聚糖作为一种新型非病毒药物载体,已引起越来越多的国家和研究机构的重视。然而,单纯的壳聚糖制备的纳米药物载体其靶向性弱,应用中略显不足。半乳糖-去唾液酸糖蛋白受体和叶酸-叶酸受体靶向是近年来倍受青睐的一种新型靶向机制,它是利用去唾液酸糖蛋白受体在肝细胞表面表达和叶酸受体在肝肿瘤部位的过度表达而在正常组织低水平表达的特性来实现目的药物的靶向输送。因此,用乳糖酸和叶酸对壳聚糖进行化学修饰,可提高药物的靶向性。1、本实验选用叶酸和半乳糖修饰壳聚糖,利用壳聚糖游离氨基上的酰化反应用两种方法制备了叶酸偶联半乳糖化壳聚糖。实验显示,叶酸偶联半乳糖化壳聚糖红外光谱图表明叶酸和半乳糖均与壳聚糖成功偶联,通过核磁图谱也得出与红外相一致的结果,此外通过核磁图谱上峰的积分强度对比计算出了叶酸偶联半乳糖化壳聚糖材料上半乳糖的接枝率；通过紫外分光光度法,检测和计算出叶酸的接枝率；通过对比两种方法得到的叶酸偶联半乳糖化壳聚糖的接枝率得出了两步法半乳糖和叶酸的接枝率均高于一步法。2、由于本文合成的是一种自然界没有的新材料,而且是用于人体的,所以本论文对所合成的新材料做了细胞毒性试验即MTT试验,选用细胞为L-929小鼠成纤维细胞,通过最新材料即叶酸偶联半乳糖化壳聚糖和壳聚糖的细胞毒性试验,得出了在实验浓度内新材料的细胞毒性小于壳聚糖,而壳聚糖为公认的可用于人体的一种天然高分子,所以本研究合成的新型材料可作为生物医用材料。3、本文通过采用离子交联反应,以TPP为交联剂,利用TPP与壳聚糖以及叶酸偶联壳半乳糖聚糖的静电作用,制备了壳聚糖纳米粒以及叶酸偶联半乳糖化壳聚糖纳米粒,并研究了各因素对纳米粒粒径的影响。通过粒度分析、扫描电镜等手段对纳米粒进行了表征。扫描电镜照片显示叶酸偶联壳聚糖纳米粒的形状规则,基本呈球形,大小分布均匀；与粒度分析结果基本相符,可作为靶向药物载体材料应用于临床。4、以5-氟脲嘧啶为模型药物,制备了稳定性良好载5-氟脲嘧啶的叶酸偶联半乳糖化壳聚糖纳米粒；分别对其包封率和载药量进行了测定,结果令人满意。更多还原

【Abstract】 Recently cirrhosis and cancer of liver serious threat people’s hearth.In traditional drug delivery mode,drugs were difficult to be transported to targeting site specifically and accurately,which caused a low bioavailability, toxicity and side effect on other normal organ. Now,chitosan as a new non-viral vectors, was paid attention to by more and more countries and research department. But the charactor of targeting of drug carrier made of chitosan only was weak and insufficient in application. Galactose--- asialoglyco protein receptor ASGPR, and folic acid---folate receptor as new targeting systems are accepted by more and more people in recently. Based on the fact that ASGRP only expreassed on the surface of liver cell and the fact that folate receptor can be overexpresed on the surface of tumor cells but scarecely expressed on normal cells, the targeting can be achieved. So using Lactobionic acid and folic acid to modify chitosan can improve the target activity.1. Lactobionic acid and folic acid was be chosed to react with amino of chitosan to modify chitosan in two different kinds of methods. Through experiment what we got was as follows:1 From FA-GC FT-IR,we know that lactobionic acid and folic acid was successful grafted to chitosan. And it was match with the result of 1HNMR. In addition through 1HNMR of FA-GC, the degree of substidution of LA was got. And the degree of substitution of FA was estimated by UV-V; Through compare reaction product of two kinds of preparation method, it was known that both the degree of substidution of FA and LA by two step mothod was higher than by one step method.2. Because what we synthetize was a new kind of material which can not be found in nature, and it will be used in human body. So, the MTT experiment need to be done to confirmed whether the new material can use in human body. Though compare the results of new material and chitosan MTT experiment, it was known that the cytotoxicity of FA-GC is less than chitosan in the chosen experiment condition. And chitosan as a kind of natural polymer was of good biocompatibility and can be used in human body. So it can be concluded that our new material can be used in human body.3. FA-GC nanoparticle was prepared by the cross-linking of TPP and FA-GC. And we discussed the effects of many factors on the properties of nanoparticle. And we characterize it with the methods of granulometer and SEM. The size of the nanoparticle from SEM pHotograpH and from granulometer was matched well. And the nanoparticle we made can be use as drug carrier.4. Fluorouracil was used as the drug model,and carring fluorouracil nano-particle drug carrier which is of good stability was prepared; And the entrapment rate and loading rate was measured. The result was satisfactory.更多还原