基于蛋白- - 多肽特异性结合的抗癌药物小分子水凝胶的制备及其应用

Hydrogels are an ideal biomaterials for tissue engineering and controlled drug delivery.Typically, hydrogels possess three dimensional fiber networks with water molecules encapsulated.In this proposal, we propose a novel method to prepare three dimensional fiber networks for molecular hydrogelations.We plan to use specific protein-peptide interactions to enhance the inter-fiber interactions, thus leading to more cross-linking points between self-assembled fibers and molecular hydrogelations. In our hydrogel systems, the self-assembled nanofibers are formed by peptide conjugates of anti-cancer drugs, which is different to other delivery systems with anti-cancer drugs physically incorporated or covalently bound to networks of hydrogels.Therefore, the drug loading contents in our hydrogel systems are very high and there is no burst effects of drug release.In this study, we will monitor the in vitro drug release, in vivo anti-tumor effects, and in vivo pharmacokinetics in mice models. We believed that our injectable hydrogel systems could be developped into a novel kind of delivery systems for controlled release of anti-cancer drugs and for cancer chemotherapy.

水凝胶是一类理想的组织工程与药物控释材料。它由三维网络结构包裹着水而成。本课题提出了一种新型的形成三维网络结构小分子水凝胶的方法，即使用蛋白-多肽特异性结合提高自组装结构之间的结合力并增加自组装结构之间的交联点，从而形成稳定的具有三维网络结构的小分子水凝胶。本课题先设计与合成抗癌药物的多肽衍生物，该衍生物在水中能自组装形成纳米纤维，然后利用构建的融合蛋白（ULD-TIP-1）将纤维交联形成小分子水凝胶。与其它药物控释体系不同，本课题设计的小分子水凝胶内部的骨架（三维网络结构）是由抗癌药物的多肽衍生物组成，抗癌药物的多肽衍生物既作为载体也作为控释对象。因此，这类药物控释体系具有药物包载率高、防止药物暴释的特点，是一类新型的药物控释体系。课题组将同时开展该类药物控释体系的体外释放行为、体内抗肿瘤效果、体内药物代谢动力学等工作，目的是制备一类可注射的、抗癌效果优越的新型抗癌药物小分子水凝胶。

课题组在一年的执行期内成功的利用蛋白质固有的巯基与生物相容性很好的四臂聚乙二醇-马来酸酐交联形成多功能可注射的蛋白质水凝胶。同时，我们证实了该蛋白质水凝胶不仅适合小鼠胚胎成纤维细胞的三维培养，还可以根据需要控制所包裹药物的释放速率。课题组还制备了两类复合水凝胶并研究了复合水凝胶作为酶的固定化载体的应用。在本项目的资助下，课题组发表了2篇SCI收录论文。