酶催化合成多糖作为多功能药物载体的研究

Polysaccharides are widely used in drug delivery as drug carriers. Nevertheless, the synthesis of remodeled polysaccharides with multiple functional groups is still a tough task. Development on multi-function polysaccharide drug carriers has been hampered by the difficulty of the synthesis. The current proposal sought to solve the problem by employing the enzymatic approach of polysaccharide synthesis with extensive substrate recognition enabled by Endo-glycosidases and other enzymes. We plan to design and synthesize a series of carbohydrate substrates with multiple functional groups for screening and optimization on their enzymatic reactivity with various types and subfamilies of glycosidases. Starting with studies on both enzyme and substate, we ought to develop and improve the enzymatic approach for polysaccharide synthesis and preparation of novel and structure-diverse polysaccharide drug carriers. Moreover,various bioactive molecules are about to be attached to the polysaccharide via those functional groups, that will achieve the multifunctions of drug delivery, prodrug assembling,targeting release,and bioactivity improvement, and efficiently enhance therapeutic effect of the anti-tumor and other drugs.

多糖作为药物载体在药物运输中有着广泛的应用。然而，多官能团修饰的多糖在合成上是一大难点，因而制约了多功能多糖药物载体的开发。本课题利用Endo糖苷酶及其它酶的催化合成多糖的活性以及多样的底物识别能力，设计和合成一系列多官能团取代的酶底物，筛选和优化各种类型和亚型糖苷酶，从底物和酶两方面着手，发展和完善一套糖苷酶催化合成多糖的方法，用于高效便捷地制备新颖的结构多样化的多糖药物载体。并且通过官能团引入多种功能性分子，实现药物运输、前药装配、靶向释放、生物学活性优化等多种功能，有效地提高现有抗肿瘤药物及其它药物的治疗效果。

本课题围绕酶催化糖结构化合物合成方法和基于糖结构的药物运输载体两个目标开展工作，在酶催化合成方法学方面，从酶和底物两方面考察酶催化反应效率，合成了新型的类壳聚糖、聚糖、糖肽、糖蛋白等糖结构化合物；在药物输送载体的设计方面，利用穿膜肽提高药物透膜运输，利用叶酸、RGD肽、半乳糖、抗体等结构增强药物的靶向运输。针对糖结构分子在药物载体、药物靶向基团、药物分子结构优化、药物受体糖基化等方面的功能与应用，课题开展了系统的工作，取得了较好的成果，完成了预定的目标。