人参稀有皂苷-多糖双组分立方液晶载药系统的构建及促吸收机理研究

Rare ginsenosides have the low bioavailability. But in previous studies, it has shown that the rare ginsenosides and ginseng polysaccharides used together can promote the absorption of rare ginsenosides, but this application still has its limited. This research aims to construction of rare ginsenosides and polysaccharides in cubic liquid crystal. The cubic liquid crystalline carrier system has both the lipid soluble skeleton and the water soluble channels. Therefore, the ginseng polysaccharides could be loaded in the water soluble channels of cubic liquid crystalline. Both the rare ginsenosides and ginseng polysaccharides could be loaded in cubic liquid crystalline simultaneously to promote absorption. Meanwhile, the Caco-2cell model, M cell model, rat intestinal perfusion model, the bioavailability of benzo (alpha) pyrene induced A/J lung cancer mice, imaging of mouse in vivo and forth were all used to research the promoting mechanism of cubic liquid crystalline. The reasonable design was clarified by multi-models and multi-methods in order to provide the scientific basis and theoretical guidance for the promoting absorption mechanism of the cubic liquid crystalline carrier system, which load the water-soluble and lipid-soluble components at the same time.

稀有人参皂苷生物利用度较低，前期研究表明将稀有人参皂苷和人参多糖相配伍，可促进稀有人参皂苷的吸收，但是其应用仍存在一定的局限性。本项目拟构建稀有人参皂苷-多糖双组分立方液晶载药系统，利用立方液晶载药系统既具有脂溶性骨架又具有水溶性孔道的特点，将水溶性人参多糖组分溶解于水性孔道中，将两种不同性质的组分同时装载于立方液晶载药系统中，共同促进吸收。因此，本项目拟结合Caco-2细胞、M细胞模型、大鼠肠灌流模型、苯并(α)芘诱导的A/J肺癌小鼠生物利用度研究和活体成像等手段，研究立方液晶载药系统的促吸收机制，多层次多角度的阐明本项目设计的合理性，为探索立方液晶载药系统在同时提高水溶性和脂溶性组分生物利用度方面提供科学依据和理论指导。

立方液晶载药系统是由非极性脂质在含水环境中通过吸附定量的水自发的形成具有特殊内部结构的自组装闭合脂质双层“蜂窝状”并富含水层孔道结构的类凝胶相立方骨架结构，既可显著提高难溶性药物的“向水性”，促进难溶性药物溶解，促进药物跨越“静态水层”与生物膜接触，又可通过水层孔道溶解水溶性药物，可使水溶性药物和脂溶性药物均能较好的包封在载药系统中，从而促进吸收。本课题旨在研究稀有人参皂苷CK-多糖双组分立方液晶载药系统的构建、促吸收机制和抗肿瘤药效学评价，采用大数据挖掘、响应面法构建、体外吸收和抗肿瘤药效学评价等方法对稀有人参皂苷CK-多糖双组分立方液晶载药系统的构建、促吸收机制和抗肿瘤药效，进行了多层次多角度的阐述。首先通过检索PubMed、 Ovid Technologies、Embase、The Cochrane Library、万方、维普和知网等七个数据库自1990年至2015年关于人参化学预防肿瘤的文献，共纳入7,436 患者和334,544 正常人群，结果表明人参可以将肿瘤发病率降低16%。其次采用响应面“归一化”评分构建得最优人参稀有皂苷CK-多糖双组分立方液晶载药系统，并对其粒径及形态学进行表征。再其次采用Caco-2细胞模型评价其对立方液晶载药系统的摄取，结果表明立方液晶载药系统可以促进Caco-2细胞对其装载药物的摄取，通过胞饮摄取药物进入细胞质，发挥作用。最后体内外抗肿瘤药效学研究表明，稀有人参皂苷CK-多糖双组分立方液晶载药系统可以阻滞肺癌A549细胞的周期，抑制A549细胞迁移和侵袭，诱导内质网应激，促进线粒体凋亡，从而提高其在体内的抗肿瘤药效，且安全性较好。相关研究为探索立方液晶载药系统在同时提高水溶性和脂溶性组分的应用提供科学依据和理论指导。