类病毒结构高分子纳米载体介导高效口服递送GLP-1多肽类似物

Protein/peptide drugs possessing high potency and specificity, and good safety play an important role in the treatment of metabolic disorders, autoimmunity and cancer. Due to these advantages of multiple dosing, non-invasive administration and good patient compliance, oral delivery is the most accepted mode of administration. However, multiple biological barriers in gastrointestinal(GI) tract lead to a very low oral bioavailability of protein/peptide drugs. Oral delivery of protein/peptide drugs is still an important challenge in the field of pharmaceutical industry. In this project, glucagon-like peptide 1 (GLP-1) analogue Liraglutide was chosen as a model drug. Inspired by structure features of hydrophilic glycosylated protein on the surface of virus, the polycationic protamine and polyanionic polysaccharides were used as drug carriers. Depending on the electrostatic and/or hydrophobic effects between polyelectrolyte carriers and peptide drug, biomimetic virus-like polymeric nanoparticles with similarity of structure and composition, particle size, surface charge and targeting ligand were produced and screened by flash nano-complexation platform in controlled and high throughput manners. The virus-mimicking nanoparticle can meet specific environment protection and controlled release of peptide drugs in GI tract, and overcome mucus layer and intestinal epithelial barriers, and then achieve high-efficient oral delivery of Liraglutide via enterohepatic circulation of bile acids for a hypoglycemic effect in vivo. We anticipate to provide new strategies or methods for the development of new oral delivery nanosystems.

蛋白/多肽药物具有活性高、特异性强和安全性好的优点，在治疗代谢障碍、自身免疫及癌症疾病中发挥重要作用。口服给药是最为广大患者接收的给药途径，具有服用便利、非侵入性、依顺性高等特点。然而，胃肠道多重生物屏障导致蛋白/多肽药物口服生物利用度极低，实现它们的口服递送至今仍是医药领域亟待攻克的重要挑战。本项目以胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽为药物模型，提出以聚阳离子鱼精蛋白和聚阴离子多糖类聚电解质为载体材料，模拟病毒表面亲水性糖基化蛋白结构，调控载体与药物之间静电和/或疏水作用，利用质量可控的快速纳米复合技术高通量制备和筛选仿生类病毒结构与组成、颗粒尺寸、表面电荷和靶向配体特点的高分子纳米载体，满足在胃肠道特定环境的药物保护和可控释放，同时克服粘液层和小肠上皮细胞吸收屏障，依靠胆酸肠肝循环系统实现高效口服递送利拉鲁肽治疗2型糖尿病，旨在为新型纳米口服递送系统的发展提供新策略或方法。

本项目设计和制备了用于口服递送多肽/蛋白药物的纳米载体体系，优化了纳米颗粒的制备方法以及理化性质，进行了口服递送机制和体内应用研究。在研究中，我们成功获得了一种靶向ASBT转运体，并且利用胆酸肠肝循环通路介导口服药物递送的高分子纳米载体，优化了颗粒组成比例、尺寸和稳定性，证实可以跨过小肠上皮细胞吸收屏障，实现高效口服递送多肽药物。发展了单宁酸/壳聚糖纳米载体实现了GLP-1多肽药物口服输送，并且表现出高的口服生物利用度。获得了高效递送蛋白药物的新型载体材料和肠道局部酶疗法的纳米给药体系。通过本项目的实施，共发表标注基金的论文8篇，申请中国发明专利2项，实用新型专利1项。以上研究为发展生物大分子药物递送载体和高效口服递送系统提供了借鉴方法，也为本课题组在口服药物递送系统开发方面奠定了坚实基础。