PAMAM Dendrim衍生物合成及其作为吸收促进剂对中药有效成分促吸收作用、安全性及机理研究

It is well known that the druggability and absorption of some active ingredients of Traditional Chinese Medicine (TCM), including water soluble sent and fat soluble constituents, is very poor. The low bioavailability and druggability of these drugs is mainly due to the complexity of the TCM composition, their diversity of the physical and chemical properties, their poor dissolution velocity. The outmoded Formulation and their excipients were contributed either. Therefore, many approaches have been examined to overcome this problem. Of all these approaches, the use of absorption enhancers has been shown to improve the absorption of western drugs as the most convenient and effective way. In the present study, therefore, PAMAM Dendrimer Derivatives(PDDs) with various functional groups were newly synthesized, the absorption-enhancing effects of PDDs on the oral absorption of three different types of active ingredients of TCM (Saponin，Flavones and Alkaloid) were examined by the in vivo and in vitro absorption methods. The toxicity and mechanism study were also determined by some analysis chemical method. The relationship between the physical and chemical properties of PDDs and the active ingredients of TCM were studied either. Finally, we plan to find out ideal absorption enhancers, which can increase the druggability and bioavailability of the active ingredients of TCM from oral administration sites. They would improve the development of formulation and excipient of TCM, and increase the clinical value of TCM.

中药因成分复杂，剂型、辅料落后，致使其口服生物利用度很低，有效成分不能充分利用，造成中药资源大量浪费，也增加了患者负担。吸收促进剂可以有效提高中药有效成分的生物利用度和成药性，已在西药研究中广泛应用。本项目首先以树状高分子聚合物（PAMAM Dendrimer）为模板、经化学修饰得到的一系列衍生物（PAMAM Dendrimer Derivatives，PPDs）为口服吸收促进剂，以吸收特性各具代表性的中药有效成分——皂苷，黄酮，生物碱为模型药物，从体内及体外两种角度全面研究其对中药有效成分的吸收促进作用及安全性，从动物、细胞到分子不同水平，系统研究吸收促进剂的机制，及其与中药有效成分理化性质之间的关系，寻找PDDs对不同类型中药有效成分的促吸收规律。新型吸收促进剂PPDs的引入，不仅可以提高中药有效成分成药性、生物利用度，更可以促进中药制剂及辅料的发展，提高中药临床价值。

中药因成分复杂，剂型、辅料落后，致使其口服生物利用度很低，有效成分不能充分利用，造成中药资源大量浪费，也增加了患者负担。吸收促进剂可以有效提高中药有效成分的生物利用度和成药性，已在西药研究中广泛应用。本项目首先以树状高分子聚合物（PAMAM dendrimer）为模板，对PAMAM dendrimer外围的氨基进行一系列的修饰改造，选择具有不同分支结构及分子量的乙二醇对PAMAM进行修饰，包括树枝状乙二醇基元及线形乙二醇链段构建PAMAM衍生物库（PAMAM Dendrimer Derivatives，PPDs）。以吸收特性各具代表性的中药有效成分——皂苷，黄酮，生物碱为模型药物，从体内及体外两种角度全面研究其对中药有效成分的吸收促进作用及安全性，从动物、细胞到分子不同水平，系统研究吸收促进剂的机制，及其与中药有效成分理化性质之间的关系，寻找PDDs对不同类型中药有效成分的促吸收规律。本项目共制备成分支状及线形PAMAM衍生物7种，这些衍生物具有很好的生物安全性，对于细胞的毒性相较于PAMAM显著降低。对于不同种类的中药具有很好的吸收促进作用。此外，项目组成员积极拓展，将PAMAM衍生物用于装载难溶性天然药物，构建纳米给药体系。目前共发表文章10篇，其中SCI论文9篇。培养硕士研究生10名。