糖基化改性食品添加剂作为新型潜在中药辅料的机制与性能研究

Traditional Chinese Medicine(TCM) modernization requires the emergence of novel excipients. Our preliminary experiments showed that three new excipients, which have been prepared via the biotransformation of food additives with flavonoid or terpene skeleton, exhibited the self-association behavior in water and significantly improved the absorption and brain distribution of poorly water-soluble drugs. Through the international collaboration with Chiba University in Japan, we aim to 1) prepare series of novel transglycosylated products with different glucose levels or link position after the enzyme modification of more food additives; 2) depict the three dimensional structure by varies of techniques including NMR, DLS,SEM, PXRD and TEM to make clear the correlation between the molecular structure and the release behavior of the model drug; 3) investigate the effect of excipients on the absorption and tissue distribution of the model flavonoid drugs, and screen the excipients with tissue-targeting potential; 4) find out the interaction between excipients with important drug transporters. This project is in itself a cross subject study widely supported by TCM pharmaceutics, biology and food chemistry. Our research will be greatly helpful for the development of novel multifunctional excipients toward TCM delivery in pharmaceutical industry.

目前符合中药成分特性的新辅料较为缺乏，制约了中药的现代化。课题组前期通过对具有黄酮或萜类骨架的食品添加剂进行糖基化，成功得到三种新型辅料，均可在水中形成不同形态的纳米胶束，极显著改善了难溶性药物的吸收和分布，并具有一定的脑靶向功能。本项目将继续与日本千叶大学合作，1）进一步对食品添加剂进行糖基化，采用电喷雾质谱联用技术快速识别转化产物，色谱法分离制备具有不同骨架结构、糖基数目和连接位置的糖基化辅料；2）运用脉冲梯度场和固液核磁共振技术，配合激光散射、扫描电镜、PXRD和透射电镜等手段，从分子水平阐明载体-药物分子空间构像与载药体系释药规律的相关性；3）考察辅料对各类黄酮药物体内吸收和组织分布的影响，关注具有靶向特征的辅料；4）揭示糖基化辅料与重要转运蛋白之间的相互作用机制。本项研究属于中药学、生物学和食品化学的交叉，研究结果将提供一类符合中药成分特性的新型辅料。

目前符合中药成分特性的新辅料较为缺乏，制约了中药的现代化研究。在这个国家自然科学基金的资助下，本项目获得了以下四个方面的成果：1）通过对甜菊苷、罗汉果苷、橙皮苷等多种食品添加剂的生物转化，得到了一系列糖苷类辅料，并发现其中的Hsp-G、Rut-G、St-2G、St-G、 MOG-V和RUB都是极具潜力的药用辅料；2）本项目主要运用核磁共振（NOE效应、弛豫时间、自扩散系数和耦合常数等）技术，系统研究了该类辅料的自组装性质及三维结构、载药特性、辅料结构与稳定性的关系等，结果表明，该类辅料在水中的自组装结构大大促进了难溶性药物的体内吸收；3）课题组还首次发现，该类辅料能促进药物在肝脏部位的蓄积，表现一定的肝靶向能力；4）本项目在完成原有计划的同时，进一步拓宽研究，构建了药物-糖苷类辅料-PVP（胆酸盐）三元给药系统，获得了较强的稳定性、更高的溶出和口服吸收。本研究不仅开发出数个增溶性强、毒性低、具有肝脏靶向性能的糖苷类辅料，更为进一步研发符合中药成分特性的辅料提供了重要的理论依据。