【作者】 刘亮；

【导师】 张国亮；

【作者基本信息】 天津大学 ， 化学工程， 2006， 硕士

【摘要】 癌症是人类致死的主要疾病之一,目前临床上以化学疗法(化疗)为主要治疗手段。5-氟尿嘧啶(5-fluorocrail,5-FU)是目前临床上的一线抗肿瘤化疗药之一,对于大部分恶性肿瘤都有较好的治疗效果,如结肠癌、肺癌、胃癌和胰腺癌等。但由于其具有降解快(在体内仅5分钟)、毒性大和目标细胞识别性差的缺点,使5-FU存在很严重的毒副作用。因此,患者的生存质量不能得到很好的保证,使其在临床上的应用受到了很大的限制。为了增强5-FU对癌细胞靶向性及目标细胞识别选择能力,本文利用天然多聚糖普鲁兰(Pullulan)制备了5-FU的新型自组装pH敏感纳米粒载体,通过改变5-FU的制剂剂型以达到缓释、减少5-FU的毒副作用并增强其癌细胞靶向性。本文采用透析方法首先合成了乙酰化普鲁兰/磺胺地托辛(PA/SDM)化合物的自组装纳米粒子,磺胺地托辛作为pH敏感基团接枝于乙酰化的普鲁兰上,使其具备pH敏感性,进而增强其癌细胞的靶向性;同样使用透析的方法,将5-FU物理包封于自组装纳米粒中。所制备的载药自组装纳米粒通过傅立叶红外光谱仪、动态光散射仪(DLS)、扫描电镜(SEM)等手段表征其乙酰化程度、粒径分布及外观形态等。测量了5-FU的载药量和包封率并绘制了不同pH下5-FU的体外释放曲线。结果表明,自组装纳米粒的平均粒径为100nm,并有较均匀的粒径分布;通过扫描电镜照片显示,制备的纳米粒具有良好的球形度。在模拟体内环境所进行的稳定性实验表明,自组装纳米粒在pH=7.4的水溶液中具有非常良好的稳定性。而当pH降低到肿瘤细胞pH值时,自组装纳米粒会迅速聚集。使用紫外分光光度计检测5-FU的载药量及释放浓度并绘制5-FU的体外释放曲线。体外释放实验表明,该载体具有极强的pH敏感性,在pH低于6.8时,5-FU的释放速率明显增强。更多还原

【Abstract】 Cancer is a leading cause of human deaths. Chemotherapy has been a major treatment methodology for malignant tumors. 5-FU, as one of the oldest and best antineoplastic chemotherapy drugs, has been used in clinical practices for decades. 5-Fu is an active medicine against many cancers such as Colon, Breast, Stomach and Pancreas cancers. However, current practice of this chemotherapy comes with severe side effects including diarrhea, low white blood counts, low platelet counts and anemia etc. Therefore, the life quality of the patients being treated with often deteriorates within in a rather short period. The main reason is that both the target cancerous cells and normal cells are subject to none-selective expose to the drug which leads to unwanted toxic side effects.In order to improve the cancer-targeting and selective activity of antineoplastic agent, 5-fluorocracil (5-FU), a novel pH-responsive drug delivery system (DDS), pullulan acetate/sulfonamide (PA/SDM) conjugate, was synthesized by a diafiltration method. Sulfonamide was grafted to the hydrophobically modified pullulan acetate (PA) to enhance the pH sensitivity for better cancer-targeting delivery. 5-Fu was loaded into the self-assembled nanoparticles by the same method. The drug-loaded self-assembled nanoparticles were successfully obtained and characterized in terms of particle size, morphology and drug loading and release profile at various pHs. The results showed that the mean diameters of the self-assembled particles were approximately 100nm, with uniform size distribution and good sphere morphology. The nanoparticles showed good stability at pH 7.4 which is equal to the normal body fluid pH, but shrank and aggregated below pH 6.8 which is close to the pH of the tumors. The loading efficiency and concentration of released 5-FU was monitored at 269 nm on the UV/Vis spectrophotometer. The release profile was heavily pH-dependent around physiological pH, and the release rate was significantly enhanced under pH of 6.8.更多还原