以穿心莲药效组分为模型药物的“三位一体”智能化胶束-微粒系统的构建及促口服吸收机制研究

Poor water solubility and low oral bioavailability are challenges in fat-soluble effective components in Chinese traditional medicines, and seriously limit clinical effects. Andrographis diterpene lactone, the main active components separated from Andrographis paniculata, is one of the typical representative. Polymeric micelles are adopted to increase oral absorption efficiency of insoluble components of traditional Chinese medicine by improving pharmacokinetic properties, but are still subjected to three oral absorption barriers which are stability in gastrointestinal tract, mucus permeability and transmembrane transport efficiency, respectively. To overcome oral absorption barriers of micelles and more efficiently improve the oral absorption of liposoluble components, a pH-dependent, easily mucus penetration and oligopeptide transporters (PEPT-1) targeted trinity-intelligent micelle – microparticle system is prepared with andrographis diterpene lactone as model drugs. This system dissolves and releases micelles in intestine, then complete micelles are easy to penetrate mucus and targeted transport across intestinal epithelia cells, ultimately to enter blood circulation and exert pharmacological efficacy. Pharmaceutics, pharmacokinetics and molecular biology are integrated used in this project, to evaluate the mechanism of micellar targeting and transmembrane transport, clarify the release and in vivo absorption process of particles, and study the increment of anti-tumor efficacy mechanism in cells- organization –animal level. In consequence, this project provides promising approaches to promote oral bioavailability of insoluble components of traditional Chinese medicine.

中药中脂溶性药效成分普遍存在着溶解性差、口服生物利用度低的问题。穿心莲的药效组分二萜内酯类成分就是其中的一类典型代表，严重影响其临床疗效的发挥。胶束具备改善难溶性中药组分的药动学性质而提高口服吸收的优势，但胶束口服吸收仍受三大屏障（胃肠道稳定性、粘液渗透性和跨膜转运效率）的限制。为克服胶束口服吸收屏障、更高效地改善脂溶性成分的口服吸收，本课题以穿心莲二萜内酯组分为模型药物，构建pH依赖、易粘液渗透和寡肽转运蛋白（PEPT-1）靶向的“三位一体”智能化胶束-微粒系统。该系统在小肠溶蚀释放胶束，以完整的胶束形态渗透粘液层，靶向肠上皮细胞而提高跨膜转运效率，进入血液循环而发挥药效。课题综合运用药剂学、药动学和分子生物学等技术手段，在细胞-组织-动物水平上，系统评价胶束的靶向性与跨膜转运机制，阐明微粒的释放规律、体内吸收过程及提高药效作用的机制。以期为提升难溶性中药组分口服生物利用度开辟新的途径。

为改善中药脂溶性药效成分溶解度低、口服吸收差的问题，本课题构建了胃稳定性好、粘液渗透性高和肠上皮细胞靶向的纳米制剂，改善药物的溶解度、增加肠上皮细胞跨膜转运效率、提高药物的口服吸收，进而提高药物疗效。本课题综合运用合成化学、中药药剂学、细胞生物学和药理学等技术和方法，构建功能性的纳米制剂，并对所构建制剂的跨膜转运机制、体内药动和药效等方面进行系统评价。首先，我们采用化学合成法合成了缬氨酸-聚乙二醇维生素E琥珀酸酯（Val-TPGS）和苯丙氨酸-聚乙二醇维生素E琥珀酸酯（Phe-TPGS），以其载体制备了稳定性高的纳米胶束（Val-PMs和Phe-PMs），并从体外细胞和体内动物明确所构建制剂的口服吸收机制。结果显示，所构建的制剂其粒径较小、胃中稳定性高且具有较好的贮存稳定性；其能渗透穿过粘液层、靶向肠上皮细胞表面的PepT1转运蛋白，显著增加肠上皮细胞粘附和摄取，然后通过胞吞、胞转的跨膜转运途径和淋巴转运途径；与TP-PMs相比，所构建的靶向制剂能更显著地提高所装载药物的口服吸收，Val-PMs和Phe-PMs的AUC是TP-PMs的近3.5倍，并更好地提高药物的抗炎疗效。本研究构建了一种显著增加脂溶性药效成分口服吸收的纳米制剂，并阐明了其口服吸收机制，为开发肠上皮细胞靶向中药纳米制剂以增加药物的口服吸收奠定了工作基础，同时为研究和开发更高效地口服制剂的奠定基础，并为口服制剂的研发也提供了方向。本项目在研究期间，参加5次国内学术交流；在文章发表方面，资助发表论文11篇，其中SCI论文7篇，中文核心2篇；申请专利1项。在学生培养方面，协助培养3名硕士研究生和3名博士研究生。