离子基团功能化的生物降解聚酯的高效合成及其本体性能和胶束性能研究

It’s significant to functionalize biodegradable polyesters by ions both from the viewpoint of academic research and practical application. It can improve the hydrophilicity and endows the functions to the polyesters. Conventional strategies to synthesize functional polyesters involves complex and multistep synthesis and purification process, low ionic content and narrow tuning range. In order to solve these problems, this applying project intends to efficiently and controllably introduce ionic groups with different structures and charges into the side chain of aliphatic polyesters through click chemistry strategy between carbon-carbon double bonds on fumaric acid based polyesters and mercaptans. And it can be further functionalized as it is needed. On the basis of this, the relationship between the structures and properties will be systematically investigated. The relationship between molecular structure and antibacterial activities of cationic polyesters will be studied,and relationship between molecular structure and anti-nonspecific protein adsorption of zwitterionic polyesters will also be investigated. The micelles will be prepared, and the properties of micelles and the potential application as drug carrier materials will be investigated. A novel route to functionalize polyester in high efficiency will be opened up, a series of amphiphilic polyesters with antibacterial activity and anti-nonspecific protein adsorption will be obtained, and the application of aliphatic polyesters will be widen by the execution of this project.

开展脂肪族聚酯的离子功能化改性研究可在改善其亲水性的同时赋予其功能性（抗菌性或阻抗非特异性蛋白的吸附），拓展脂肪族聚酯的应用范围，具有重要的学术意义和应用价值。针对目前离子功能化聚酯的合成存在步骤繁多、纯化复杂、离子基团含量低、可调范围窄等问题，本申请项目拟利用反式丁烯二酸基聚酯分子链中的C=C与硫醇的点击化学反应高效、可控引入多种不同结构、不同电荷的离子基团，同时还可根据设计需要进行进一步功能化修饰。并在此基础上系统研究产物的分子结构与性能的关系。对于阳离子聚酯，重点研究其分子结构与抗菌性能的关系；对于两性聚酯，重点研究其分子结构和阻抗非特异性蛋白吸附性的关系。进一步制备胶束，研究其胶束化行为，探讨其作为药物载体的潜在应用。预计通过本项目的实施，开辟出一种聚酯功能化的高效路线，得到系列两亲性、抗菌（或阻抗非特异性蛋白吸附吸附）和具有良好载药能力和缓释能力的聚酯，拓展脂肪族聚酯的应用范围。

生物降解聚酯具有良好的生物可降解性和生物相容性，在生物医学领域具有广阔的应用前景。但是生物降解聚酯的疏水性强，亲水性差，分子链中缺乏功能化的基团，使其在生物材料领域的应用受到极大的限制。如用于药物载体时由于其表面容易吸附蛋白质导致药物暴释或者释放不完全。针对目前功能化聚酯的合成存在过程复杂、条件严苛、可控性差等诸多问题，我们利用聚富马酸丁二酯（PBF）分子链上的碳碳双键实现了系列离子功能聚酯的高效合成。利用PBF的C=C的溴化和季铵化反应，实现了季铵盐阳离子聚酯的高效合成，当季铵盐的碳链长度长于8时，含量高于10%时，阳离子聚酯对大肠杆菌和金黄色葡萄球菌均具有良好的抗菌活性。进一步通过温和、高效的点击反应，合成了氨基和羧基功能化的聚酯。二者共组装的胶束，可高效负载阿霉素，并实现药物的pH触控释放，最终高效杀死癌细胞。两性离子具有超强的亲水性、优异的抗生物污染性和生物相容性，可以延长药物在体内的循环时间和作用时间。通过PBF的C=C与半胱氨酸分子上的-SH的高效点击反应引入了大量氨基酸型的两性离子（38 mol%），显著提高了聚酯的生物相容性能，当聚合物的浓度高达1000 μg/mL，细胞的成活率在91%以上。其键合的铂药前药纳米粒的释药具有pH敏感性和还原敏感性，大幅度提高了癌细胞对铂药的内吞和铂药对癌细胞A2780的毒性，并将铂药的半致死浓度下降了50%。