超分子生物降解有机原位凝胶协同释药传递系统的构建机理及其应用基础研究

The project is the following research of the NSFC (30772670) named "self-assembly of organic situ injectable implant gel long-acting delivery system". The previous study found that organic in situ gel had the advantages of good drug loading capacity and smooth subcutaneous drug release property, which indicated it might be a potential carrier. However, there are a few of scientific problems that have not been resolved: firstly, we have not gained the relationship between the gelling process, the gel properties, in vivo degradation rate of the carrier and gelator structure parameters. Second, we have not obtained the mechanism based on which we can control the biological degradation of drugs by the gelator structure to avoid the too fast or too slow drug release rate that result in burst release or carrier degradation lag problems respectively. If the above problems were to be answered, the theory and application of in situ organic gel would come to a new era. The present project will synthesis or organize a series of amino acid derivative gelator to analysis of gelation, the drug release and in vitro/vivo biodegradation character, the structure parameters of the gelator achieved by chemical databases, and obtain the correlation equations between the gel characters and those parameters, and eventually seek out the internal relationship of the gel structures and properties. Therefore, we can design a preferred gel having the specifically structure parameters account for ideal properties based on the above equations or relationships. As long as we achieve the mechanism, we will finally obtain a "chemical switch" to control gel function. In this project, the supramolecular structure of the gel and gelation mechanism will also be analysis from molecular level.

本项目是基金"自组装有机原位注射植入凝胶长效传递系统的研究"的连续申请。研究中发现有机原位凝胶载药量大，皮下释药平稳，展示出强大的载体功能。然而尚有科学问题未能得到解决：第一，胶凝过程、凝胶性质和载体的体内降解速率与凝胶因子的结构参数的内在联系是什么？第二，如何从凝胶因子结构角度解决载体生物降解过快或过慢，造成突释或载体降解滞后的不同步问题？若这些本质问题得到回答，有机原位凝胶的理论和应用研究水平都将跃升一个新台阶。本申请拟合成或整理系列氨基酸衍生物类凝胶因子，研究它们的胶凝、载药释药和体内外生物降解性质；通过化学数据库获取凝胶因子的结构参数，建立性质与参数相关方程，得到性质与参数的内在联系规律。若期待构建特性的凝胶，可依据方程计算出凝胶因子的预测结构参数，设计符合参数要求的凝胶因子，使凝胶因子的结构特征成为控制凝胶功能的"化学开关"。同时还从分子层面研究凝胶的超分子结构和胶凝机理。

本课题以组织相容性好，生物可降解的氨基酸衍生物类凝胶因子为研究主体，研究其胶凝、载药释药和体内外降解性质，探究凝胶性质与凝胶因子结构之间的关系，以期为设计和寻找载药量大、控释能力强和释药与降解同步的有机原位凝胶提供理论依据。.以氨基酸为母体，与脂肪酸进行酰化反应，合成了十种凝胶因子。通过考察其最小胶凝浓度，探究凝胶因子结构与胶凝能力之间的关系，结果表明，氨基酸手性碳原子的空间位阻的增加会削弱其胶凝能力，而氢键位点的增加和脂肪酸端碳链长度的增长则会使凝胶因子胶凝能力增强。考察凝胶因子在有机溶剂中的胶凝情况，发现溶剂形成氢键能力越强、极性越大越不利于凝胶的形成。.空白凝胶的相转变温度与凝胶因子浓度正相关。凝胶因子浓度相同时，胶凝能力越强，其屈服值越大，弹性模量（G'）和粘性模量（G''）较大，意味着具有更好的机械强度。胶凝能力越强的凝胶因子达到最短胶凝时间的浓度越低。.与体内降解相比，凝胶体外降解缓慢，当降解液中加入脂肪酶后可明显加快。HPLC-ELSD法可以定量凝胶降解过程中的凝胶因子和油相，深入考察控制降解的关键因素。结果表明，凝胶因子是控制降解的关键因素。探索了pH，油相种类和脂肪酶对降解速率的影响。将空白凝胶皮下植入体内，发现凝胶的体内降解与凝胶因子种类和浓度有关，可通过二者来调节凝胶的降解行为。大鼠皮下注射有机凝胶组织切片表明，在注射初期无急性炎症反应出现，整个愈合过程中表现为较低的炎症反应，提示凝胶具有良好的体内外生物相容性。.研究药物的加入对凝胶系列性质的影响及释药规律。含有氢键的药物加入凝胶后最小胶凝浓度增加，抗凝剂用量减少；相转变温度降低，热力学稳定性变差、流变学参数G' 和G''明显降低、机械强度均减弱。同时随着药物成氢键能力的增强和药量的增加，这种影响越显著，制剂设计时需要充分考虑药物方面的影响。.以坎地沙坦酯为模型药物，制备载药凝胶，进行体内外释药行为研究，探讨原位凝胶的长效缓释释药性质和规律。结果表明体外缓释作用明显，可累计缓释释放药物达15天。凝胶因子的结构，浓度、药物量及抗凝剂用量均影响药物的释放速率。药物的体内释药主要是由扩散和溶蚀双重机制控制的。.本文得到了凝胶因子的结构和凝胶性质之间的关系及影响凝胶降解和释放行为的因素进行了考察，为凝胶制剂的设计和进一步优化提供了科学依据。