用于药物靶向释放的一种新型温度敏感纳米
bamboo salt
粒的研究
重庆大学硕士学位论文
学生姓名：
指导教师：break a leg
hide是什么意思专业：生物医学工程
学科门类：工学
重庆大学生物工程学院
opps二OO八年四月
本文获重庆大学研究生科技创新基金资助（项目编号：200603Y1A0120155）
西安事变的历史意义Study on Novel Thermonsitive Nanoparticles for Targeted Drug Delivery
A Thesis Submitted to Chongqing University
in Partial Fulfillment of the Requirement for the Degree of Master of Biomedical Engineering
by
初中英语教案模板
Supervisor:
Major: Biomedical Engineering
College of Bioengineering of
Chongqing University, Chongqing, China调酒培训学校
April, 2008
abandonedThis work was supported by Chongqin g University Postgraduates’ Science & Innovation Fund (Project No. 200603Y1A0120155).
摘要
近年来，温度敏感型药物释放的研究是生物医学领域的热点课题。目前国内外主要是利用温度敏感水凝胶的溶胶-凝胶相转变特性实现药物在体内进行缓慢释放，而基于凝胶-溶胶的相转变在药物释放的
报道很少见于报道。本课题的研究目的是基于溶胶-凝胶以及凝胶-溶胶的两次相转变构建一种能在病灶部位快速释放，通过病变组织部位与正常部位的温差实现药物释放的温度敏感释放系统，为其作为靶向药物释放提供理论和应用基础。
本文首先通过开环共聚法合成并表征了温度敏感水凝胶，同时重点考察了温敏特性。然后以此温敏水凝胶为载体材料合成纳米粒并初步考察了其药剂学特性，最后重点考察了纳米粒在不同温度下的体外释放过程以及其温敏开关效应。本论文的目的是得到一种具有温敏特性的靶向给药系统。主要取得了以下几方面结果：
①以PEG1000、PEG1500、D,L-丙交酯(D,L-LA)和乙交酯(GA)为原料，利用开环共聚法得到一种温敏三嵌段共聚物PLGA-PEG-PLGA水凝胶材料。在反应时间为8h、催化剂为辛酸亚锡、反应温度为150o C，以及PEG1000与PEG1500质量比为1：1等工艺参数下，实验最终得到了相转变温度满足要求，即溶胶-凝胶温度低于体温，而凝胶-溶胶温度高于体温的温度敏感水凝胶。同时利用1H-NMR对所合成的水凝胶进行了结构表征以及分子量测定。
②对该水凝胶的温敏特性进行了考察，通过试管倒置法对其相转变过程进行了研究，当温度在室温下时，水凝胶溶液成溶胶状，而随着温度上升至体温附近时，从溶胶状转为凝胶状。当温度进一步升高时再次从凝胶状转为溶胶状。最终沉淀。当浓度从10wt%增加到25wt%，溶胶-凝胶的转变温度从39ºC
减少到24ºC，而凝胶-溶胶的转变温度从40ºC 增加到44ºC。同时利用紫外分光光度计测定最低临界温度(LCST)，大致为40.5ºC，并通过考察温度对溶胀度的影响进一步分析了LCST，其值为41ºC。两者所得的LCST基本一致，大致在40.5o C-41o C之间，该温度范围满足稍微高于体温，同时亦在人体可承受范围之内。
③以温敏材料PLGA-PEG-PLGA为囊材，对乙酰氨基酚为模型药物，通过溶剂蒸发法制备纳米粒。通过药物载药量对纳米粒的制备工艺进行优化，最终得到以丙酮为有机溶剂相、有机相/水相为1:1、聚合物在有机相中的浓度为10mg/mL，PV A浓度1%作为最佳影响因子，制备得到了载药量为6.81%，包封率为68.56%的纳米粒，粒径大小为240.6nm，电位为-27mV。同时，研究聚合物在有机相中的浓度对纳米粒的粒径大小的影响，发现两者之间具有良好的线性关系。因此，也可以通过此线性关系得到所需粒径大小的纳米粒。
领导艺术④考察了该纳米粒载体系统的体外释放行为，对释放情况进行拟合，并考察不同温度(37o C和42o C）对体外溶出度的影响。研究表明, Higuchi方程较好地拟合了纳米粒在PBS缓冲溶液中的体外释放过程，同时在42o C下药物释放速度明显高于处于37o C下时，具有明显的温敏开关效应。
本论文研究所构建的温敏药物释放系统不仅能实现药物释放在不同温度下的开关效应，而且也对局部温度靶向释放和病变组织部位定点释放提供了潜在的应用。
关键词：温度敏感，药物靶向释放，水凝胶，相变温度，纳米粒，释放性能
ABSTRACT
In recently years, thermonsitive drug carrier systems have attracted much attention in the field of biomedicine.To date, a great many rearches were focud on improving controlled-relea properties of thermonsitive hydrogel carriers bad on the sol-gel transition, whereas the rearches for targeted drug delivery during the gel-sol transition have not been found. The purpo of this study was to obtain a thermonsitive drug delivery system bad on the sol-gel and gel-sol transition, which could produce relea of the encapsulated drug only at the diad site and at controllable rates by local hyperthermia. This novel system may have potential applications in the targeted drug delivery systems.portable
In this study, thermonsitive hydrogel was synthesized by ring-opening polymerization and characterized by 1H-NMR, respectively. And, the thermonsitive properties were investigated especially. Then, thermonsitive nanoparticles were prepared and characterized bad on the thermonsitive polymer. Finally, the drug relea was investigated both at 37o C and 42o C, respectively. The goal of this study was to obtain a targeted drug delivery system, exploiting the temperature-nsitive behavior. The results of this study were as follows:
①The triblock copolymer (PLGA-PEG-PLGA) was synthesized by ring-opening polymerization of D, L-lactide and glycolide with polyethylene glycol (PEG) in the prence of stannous octoate. With veral process parameters of time, temperature PEG molecular weight, a biodegradable thermonsitive hydrogel with the effective property of pha transition temperature was obtained. The sol-gel temperature was below the normal temperature, and the gel-sol temperature above the physiological temperature. In addition, the structure and molecular weight were also characterized by 1H-NMR.
②The sol-gel transition and gel-sol transition behaviors in aqueous solution were investigated by the tube tilting method. The solution flows freely below the physiological temperature, and becomes a gel at physiological temperature, then flows freely again as temperature increas, ultimately undergoes insoluble precipitate. When the copolymer concentration incread from 15% to 25%, the sol-gel transition temperature decread from 39ºC to 24ºC and the gel-sol transition temperature incread from 40ºC to 44ºC. And, the lower critical solution temperature (LCST) was investigated by UV-spectrophotometer, about 40.5ºC. In addition, Changes on swelling
