项目名称： 基于功能化介孔二氧化硅泡沫装载蛋白类大分子药物口服纳米给药系统的构建及评价

项目编号： No.81503014

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张岩

作者单位： 沈阳大学

项目金额： 17.9万元

中文摘要： 当前生物大分子口服给药面临的生物屏障主要有肠道吸收屏障、酶屏障和粘液屏障。本课题主要针对以上三大屏障，首次构建了一种具有粘液穿透特性的新型蛋白-介孔二氧化硅泡沫（MCF）纳米给药系统，以期显著提高药物的口服生物利用度。首先，通过交联剂将重组人生长激素（rGH）与四种经典的细胞穿膜肽（CPPs）轭合，提高药物的跨膜吸收能力；然后，构建不同孔径的MCF纳米粒对上述轭合物进行负载；最后，将纳米粒表面进行PEG化修饰使其具有粘液穿透特性，大大缩短药物的吸收距离和时间，减少降解。本项目拟在对生长激素稳定化研究和载体与药物相互作用研究的基础上，揭示载体因素（不同孔径、PEG分子量和表面密度）与药物跨膜吸收及粘液穿透的关系，评价CPPs对rGH的吸收促进效率，阐明纳米粒的肠吸收机制，为无机材料装载大分子粘膜传递提供实验依据和理论参考。同时，对促进生物大分子传递系统的发展，将有重要的研究价值和实际意义。

中文关键词： 生物大分子；口服传递；无机纳米载体；细胞穿膜肽；化学轭合

英文摘要： Peroral delivery of peptide/protein drugs is generally regarded as one of the elusive tasks facing the pharmaceutical technology, and the major barriers to effective oral delivery of these molecules include the following: 1) Poor intrinsic permeability across the intestinal epithelium; 2) Rapid enzymatic degradation in the gastro- intestinal tract and 3) Difficult diffusion trapped by the mucus. In this study, a novel mucus-penetrating nanoparticles based on mesocellular silica foam (MCF) was introduced to be as the carrier of the proteins, to improve their oral bioavailability. Firstly, a model protein recombinant human growth hormone (rGH) and four cell penetrating peptides (CPPs) were conjugated by the crosslinking agent to enhance its ability across the mucosa; Sencondly, MCF nanoparticles were prepared and the conjugates were loaded; Lastly, coating particles with a high density of PEG may reduce particle-mucus adhesion, resulting a shorter time and distance for drug transport. The study mainly focus on the stability of the drugs and the interactions between nanoparticles and drugs, to explain the effect of properties of nanoparticles (pore size, Mw or surface density of PEG) on the mucus-penetrating ability and drug delivery. The absorption enhancement effect of four CPPs are compared, and their mechanism will be discussed. This research can provide the basis for carrier material of biomacromolecules and promoting the development of oral protein delivery system.

英文关键词： biomacromolecules;oral drug delivery ;inorganic nanocarrier;cell penetrating peptides;chemical conjugate