基于蛋白聚糖仿生的糖聚肽水凝胶的合成及其生物医学应用研究

The unique brush structure of natural proteoglycan, which is composed of a core protein and densely grafted glycosaminoglycans, plays a crucial role in its physicochemical properties and biological functions. Based on the designing route of construction of biomimetic polymer materials using natural amino acid and saccharides as the basic units, this project proposes to synthesize glycopolypeptide brush copolymers, which are composed of a polypeptide backbone and densely grafted mono-saccharide or polysaccharide, through opening polymerization and "click" grafting method. Glycopolypeptide hydrogels are to be developed via the enzymatic crosslinking of the phenol groups in the copolymers. The influence of the chemical components and structure of the glycopolypeptide on the morphology and self-assembly behaviors of the copolymer will be studied. By using the glycopolypeptide hydrogels as 3D scaffolds for cell culture, the mechanism of the regulation of cellular behaviors by the mono-saccharide through the receptor-mediated effects is to be clarified, the effects of the brush structure of the glycopolypeptide densely grafted with polysaccharide on the physicochemical and biological properties of the hydrogels will be analyzed. The relationships between the composition, structure and properties of the glycopolypeptide copolymers and hydrogels will be discovered, which can provide important theoretic and experimental data for further disclosing the relationship between the molecular structure and functions of natural proteoglycan. Moreover, this project can also lay the foundation for development of biomimetic synthesis and the preparation of new type of biomimetic hydrogel scaffolds.

天然蛋白聚糖以核心蛋白质为主链、密集接枝的糖胺聚糖为侧链的独特刷型分子结构对于其物理化学性质及生物学功能具有至关重要的作用。本项目基于以天然氨基酸和糖分子作为基本结构单元构建仿生高分子材料的设计思路，通过开环聚合和“点击”接枝的方式，合成以聚氨基酸为主链，单糖或多糖密集接枝的糖聚肽刷型共聚物。并通过酶催化交联共聚物中的苯酚修饰基团，制备糖聚肽仿生水凝胶。考察糖聚肽共聚物化学组成和结构对于共聚物形貌与自组装行为的影响。以糖聚肽水凝胶作为细胞三维培养支架材料，阐明侧链单糖分子通过细胞表面受体调节细胞行为的作用机制，分析多糖接枝的糖聚肽刷型分子结构对于水凝胶物理、化学及生物学性质的影响。阐明糖聚肽共聚物和水凝胶组成、结构与性质之间的相互关系，为进一步揭示天然蛋白聚糖独特的分子结构与功能的关系提供重要的理论和实验依据。同时，也为发展仿生合成新技术和开发新型水凝胶仿生支架材料奠定坚实的基础。

蛋白聚糖等活性高分子物质包含多肽主链及糖分子等生物活性分子侧链这一独特结构，是构成生命体细胞外基质的核心成分，在支撑细胞生长与调控细胞行为方面发挥着至关重要的作用；同时，该类结构也为生物活性高分子的仿生合成提供了天然的分子模型。本项目基于以天然L-氨基酸和糖分子作为基本组成构建仿生高分子材料的设计思路，通过α-氨基酸-N-羧基环内酸酐单体开环聚合、侧链“点击”修饰、缩合反应等方法，合成以聚肽为主链，糖分子、活性多肽、生物响应基团等为侧基的新型糖聚肽和功能聚肽共聚物。进一步通过酶催化交联共聚物中的苯酚修饰基团，制备了糖聚肽、生物响应及生物活性聚肽等一系列仿生水凝胶。以这些仿生水凝胶作为细胞三维培养支架材料，阐明了水凝胶物理性质、生物活性等性质变化对于调控细胞行为的作用机制。研究了不同糖分子接枝的糖聚肽对于水凝胶物理性质、生物降解行为及诱导宿主体内免疫响应方面的影响规律，为揭示生物材料通过受体调节体内免疫细胞行为提供了实验依据。本项目相关研究成果共发表SCI论文14篇，其中IF>5.0的论文6篇，申请中国发明专利3项。项目期间，项目负责人受邀在国内和国际学术会议作邀请报告9次，培养博士生2名、硕士生3名。