总葫芦素仿生胶束的构建及口服吸收机理研究

Cucurbitacins are effective constituents in traditional Chinese medicine Pedicellus Melo with liver protection and antitumor activities.But the exertion of their curative effect was restricted due to their low solubility, poor permeability and low oral bioavailability. Some viruses carrying cell-penetrating peptide have the ability to enter cells which inspired the proposer using the principle of bionics to combine the collagen cell-penetrating peptide which has penetrating ability of the membrane. Then, through taking the bionic micelles as the carrier of cucurbitacins, their turn-over capacity of transmembrane have been improved significantly. The aim of this work is to clarify the oral absorption mechanism of the cucurbitacins bionic micelle as well as to discover its applicability on improving the oral bioavailability of Chinese medicine by studying its formula optimization, assembling behavior, drug loading and drug release properties, absorption kinetics, transport process in the body and the bioavailability and efficacy as well as the safety evaluation on the gastrointestinal tract. This project will mix the field of life science and nanotechnology together to build new self-assembly carrier so as to lay the foundation for the development of cucurbitacins’s efficient oral preparation.In the meantime ,it provide new train of thought study about the modernization of TCM..

总葫芦素是中药甜瓜蒂中保肝抗癌有效成分，由于溶解性低、渗透性差，口服生物利用度很低，制约了其疗效的发挥。一些病毒因为携带了穿膜肽具有进入细胞的能力，申请人受此启示，结合仿生学原理，将前期制备的具有穿膜能力的胶原穿膜肽和胶束复合，作为总葫芦素的载体，结果跨膜转运能力大幅度提高。本项目拟通过总葫芦素仿生胶束的配方优化、组装行为、载药和释药特性、吸收动力学、体内转运过程、生物利用度和药效的相关性以及胃肠道安全性评价等方面的系统研究，阐明总葫芦素仿生胶束口服吸收机理，同时探索其在提高难吸收中药口服生物利用度方面的适用性。本研究将生命科学和纳米技术前沿领域的成果相融合，构筑新型自组装载体，以期为总葫芦素高效口服制剂的开发奠定基础，并为中药制剂现代化研究提供新的思路。

总葫芦素是一类来源于葫芦科植物甜瓜果蒂的葫芦烷型四环三萜类化合物，临床用于治疗肝炎及原发性肝癌。但因其水溶性、膜渗透性均较差，属于生物药剂学分类（BSC分类）中第四类——低溶解性、低渗透性药物，限制了其口服药效发挥与临床应用。本项目基于仿生学原理，将带正电荷的胶原穿膜肽作为纳米载体的肠道转运促进剂，介导药物的高效跨膜吸收。项目研究了总葫芦素胶原穿膜肽胶束的制备、基本理化性质，探讨了其摄取、跨膜转运及肠吸收机制，对其体内药动学、体内外药效学、口服给药安全性进行了评价。结果显示，将总葫芦素制成胶原穿膜肽纳米胶束后，Caco-2细胞摄取量、累积转运量、表观渗透系数均有显著提高, 纳米胶束的吸收以主动转运为主，其载体可有效抑制P-gp蛋白外排，转运过程需消耗能量，且网格蛋白及小窝蛋白可能是其内吞介导蛋白，分泌过程主要受浓度控制。纳米胶束在各肠段的吸收速率常数均高于总葫芦素，大鼠口服生物利用度和对HepG-2肝癌荷瘤鼠的抑瘤效果显著提高。初步安全性评价显示总葫芦素胶原穿膜肽纳米胶束口服给药安全性较好。本研究构筑了新型纳米胶束载体，为总葫芦素高效口服制剂的开发奠定了基础，并为中药制剂现代化研究提供新的思路。