丹参酮IIA-冰片分子药对PEG化脂质纳米载体的构建及其协同促口服吸收/脑转运特性的研究

The transport ability of drugs to the gastrointestinal barrier and blood brain barrier is one of the key issues for the treatment of brain diseases via oral administration. According to the basic theories of traditional Chinese medicine, borneol (BO) is called an “upper guiding drug”, which can guide other components in the herbal formulas to the brain. However, the tradition decoction pieces compatibility, without a targeted design for the absorption and distribution, leads to poorly bioavailability, uncertain brain targeting efficiency and limited therapeutic effects. In this project, we choose Tanshinone IIA(Tan-IIA) and BO molecule herb pair with anti-cerebral ischemia effect as research object to prepare Tan-IIA-BO-PEGylated nanostructured lipid carrier(Tan-IIA-BO-pNLC). The drug delivery system, with high physiology stability, can absorb by gastrointestinal tract as whole particles, improve the biopharmaceutical properties of the two drugs and enhance the oral brain targeting efficiency with the aid of the high membrane penetration ability of BO and pNLC. The cell model and in situ rat intestinal perfusion model are utilized to illuminate the principle of the drug delivery system for enhancing the permeability through biological membranes. Meanwhile, combined with pharmacokinetics and tissue distribution to clarify the mechanism of Tan-IIA-BO-pNLC for promoting the oral brain targeting safely and effectively. On this basis, the protective effects of drug delivery systems against cerebral ischemia are studied to clarify the characteristics and rules of Tan-IIA-BO-pNLC for oral brain drug delivery. The project can offer the theoretical and experimental guidance for the development of excellent oral brain targeting drug delivery system with obvious characteristics of chinese traditional medicine.

药物透过胃肠道和血脑屏障的转运是口服给药治疗脑部疾病的关键问题。中医方剂伍以冰片“开窍醒神”、“引药上行”的作用促进口服药物的脑部递送。但仅以饮片配伍给药，缺乏药物在体内的吸收、分布的靶点设计，导致药物生物利用度低，脑部递药效率不稳定，疗效发挥受到极大限制。本项目以具有相使配伍特性的丹参酮IIA-冰片抗脑缺血分子药对为研究对象，通过构建高生理稳定性的PEG化脂质纳米载体，改善药物的生物药剂学性质，促进递药体系以完整粒子形式经胃肠道吸收进入体内，协同冰片和载体的促膜透作用，提高药物口服吸收/脑转运效率。利用细胞模型和大鼠在体肠灌流模型，探索递药体系的促膜透转运机理，并结合药物药动学和组织分布特性，阐明体系安全、有效改善药物口服脑靶向特性的机制，进一步通过抗脑缺血实验，揭示体系在脑靶向转运和药效协同方面的特征和规律，为构建具有中医药特色的高效口服脑靶向给药体系提供理论和实验依据。

药物的脑内转运是脑部疾病治疗的瓶颈问题。冰片与PEG化纳米脂质载体可发挥协同作用，通过抑制P-糖蛋白，降低与单核吞噬细胞系统的亲和力，诱导生物膜屏障超微结构可逆性改变等方式，调节胃肠道粘膜及血脑屏障的通透性，发挥给药系统长循环及脑靶向的特性，促进药物口服转运入脑，提高药物口服吸收/脑转运效率。本项目以难溶性的中药有效单体-丹参酮IIA为模型药物，筛选了与药物相容性好的辅料，采用乳化蒸发-低温固化法制备了冰片修饰的丹参酮IIAPEG化纳米脂质载体（Bo-Tan-IIA-pNLC）。通过正交试验优化处方，并对最优处方所制备的纳米脂质载体的理化性质、体内促吸收机制及体内药代动力学及其脑靶向特性进行了深入的研究。研究结果表明，优化制备的Bo-Tan-IIA-pNLC粒径分布均匀，包封率较高，稳定性较好，且具有明显的体外缓释特征。大鼠在体肠循环实验表明，Bo-Tan-IIA-pNLC能够促进制剂的肠道吸收，且其吸收呈现出一级动力学特征，表明制备的纳米脂质载体在机体内的转运机制为被动扩散。小鼠体内药动学及脑靶向研究表明，与丹参酮IIA相比，Bo-Tan-IIA-pNLC能够显著增加药物的体内吸收，提高药物的口服生物利用度，脑靶向效率也有大幅提升。冰片修饰的PEG化纳米脂质载体，可以有效的提高丹参酮IIA的口服生物利用度，改善药物的脑靶向特性，达到了协同促进药物的口服吸收/脑转运的效果，为进一步构建中药高效口服脑靶向给药体系提供了理论依据和实验基础。