可降解聚乙二醇纳米空心球的设计、合成及性能研究

Polymeric hollow nanospheres have advantage over polymeric micelles in the application of drug delivery as they have more capacity and better stability. This topic is proposed on the basis of our previous work of multi-stimuli responsive poly(ether amine)s (PEAs). We design the prepared process of PEG hollow nanopheres: first, PEAs are synthesized by nucleophilic addition/ring-opening reaction, which contain poly(ethylene oxide) (PEO) side chains and coumarin units; secondly,different hydrophobic side chains are grafted to PEAs through esterification; sequentially, the shell cross-linked nanopaticles are obtained by the photo-crosslinking of coumarin units; finally, the hydrophobic cores are removed through hydrolysis. The size of the cavities is controlled by the hydrophobic side chains. The degradation of these hollow nanospheres is studied as the depolymerization of coumarin's photodimer. Their swelling behavior is studied under different conditions of various pH,temperature and ionic strength by using UV-vis, DLS,TEM. The drug release experiment is carring out to investigate the capability of the hollow nanospheres as drug carriers. These PEG hollow nanospheres is expected high biocompatibility and hydrophilicity, sharp stimuli responsiveness, good degradability.

在药物传输方面，聚合物纳米空心球与传统聚合物胶束相比，具有更大的载药能力及分散稳定性。本项目在前期对多重刺激响应性聚醚胺的研究基础上，拟通过亲核加成/开环反应，合成侧链为PEG、主链含香豆素成分的聚醚胺，经酯化引入不同的疏水侧链，制备两亲性接枝聚醚胺。该聚醚胺在水中自组装形成胶束或囊泡，经光交联胶束中间层、水解去除胶束内核，得到聚乙二醇纳米空心球。在制备过程中，通过引入不同的疏水侧链控制空心球腔体的大小；利用香豆素基团的可逆光响应特性，研究该空心球的降解能力；用UV-vis、DLS、TEM研究其在不同pH、温度和离子强度环境中的溶胀行为；负载药物，研究不同大小空心球的载药能力及在不同环境条件下的体外释放行为。使用该设计方案可制备出性能优异的聚合物纳米空心球：具有良好的生物相容性和亲水性、快速的环境刺激响应性、可降解性等。该工作将为药物的高效安全靶向可控释放提供新型载体。

在药物传输方面，交联的聚合物纳米空心球与传统聚合物胶束相比，具有更大的载药能力及分散稳定性。聚乙二醇（PEG）具有良好的亲水性，并可延长药物在体内的循环时间。将两者结合，研究开发出一种光可逆交联的聚乙二醇纳米空心球，用于药物的安全、可控、缓慢释放。本项通过亲核加成/开环反应，合成侧链为PEG、主链含香豆素成分的聚醚胺。聚醚胺主链中含有具有pH响应性的叔胺基团，为药物的靶向释放提供基础；同时，大分子主链上的羟基基团可进一步功能化，为自模板形成空心结构创造条件。通过酯化，在聚醚胺分子链上引入疏水侧链，制备两亲性接枝聚醚胺。该聚醚胺直接分散在水中自组装形成胶束，经光交联胶束中间层、再水解去除胶束的疏水内核，得到交联的聚乙二醇纳米空心球。以阿霉素DOX为模型药物，研究交联与未交联、空心化与未空心化的聚乙二醇纳米颗粒的载药能力、生物相容性及在不同环境条件下的体外释放行为。研究结果表明：在所研究的几种聚乙二醇纳米颗粒中，空心化的载药率最高，交联后的聚乙二醇纳米颗粒药物释放速率明显低于未交联的聚合物纳米空心球，所研究的聚乙二醇纳米颗粒的药物都具有pH响应性；细胞毒性测试显示出这些纳米颗粒都具有良好的生物相容性；光解聚试验证明在适当光波长照射下，交联的空心球可以顺利降解，并快速释放药物。