多功能纳米晶体的设计及跨过粘液屏障和抑制p-糖蛋白外排的研究

Nanocrystals have an incomparable advantage over other formulations in the field of bioavailability improvement of poorly water soluble drugs. However, little is know about the absorption machanism of nanocrystals, and little attention has been paid to the mucus barrier, which is the first barrier for the absorption of nanocrystals from gastrointestinal (GI) tract. The conventional nanocrystals also have limitations in the bioavailability improvement of poorly soluble drugs with p-glycoprotein mediated efflux, which classified as BCS IV drugs. This project will provide a new thought to solve these problems by functional surface modification of nanocrystals using polymers. Advanced techniques will be taken from cellular,tissue and in vivo level to investigate the effects of the functional polymers on surface properties of nanocrystals,and the effects GI mucus permeation p-glycoprotein inhibition ability of nanocrystals on the drug absorption. A novel nanocrystal drug delivery system with mucus barrier permeation and p-glycoprotein efflux inhibition ability will be designed by surface modification of nanocrystals.To our knowledge,so far,this new drug delivery system has not been reported. The results of this project will provide an unique insight into the absorption machanism of nanocrystals though GI tract, and the oral absorption improvement of BCS IV drug with poorly water solubility and p-glycoprotein mediated efflux.

当前，纳米晶体在提高难溶性药物口服吸收方面具有独特的优势。然而，其口服吸收机理尚不明确，粘液层阻滞对纳米晶体口服吸收的屏障作用尚未得到足够重视。此外，普通纳米晶体在提高具有被p-糖蛋白外排的难溶性药物（BCS IV类）口服吸收的能力受到限制。本项目提出采用功能性聚合物对纳米晶体表面进行修饰，设计一种新型的多功能纳米晶体给药系统。该纳米晶体具有粘膜穿透和抑制p-糖蛋白外排的功能。采用先进的技术从细胞、组织和整体动物水平，探讨和评价功能型纳米晶体对粘液屏障的穿透、p-糖蛋白药泵的抑制，以及最终体内药物动力学。关于纳米晶体多功能表面修饰，并将其应用于BCS IV类药物的研究，国内外尚未见报道。本项目的实施将为纳米晶体的口服吸收机理提供新的见解；为提高BCS IV类药物口服生物利用度的研究提供新的思路。

本课题针对难溶性药物纳米晶消化道给药面临的各种生物屏障（粘液屏障和上皮细胞屏障）系统开展了以下几方面的工作：①以环孢素A为模型药物，采用聚合物改善药物溶解特性，设计过饱和给药系统，研究过饱度影响药物在消化道内结晶析出对药物吸收的影响；②针对消化道粘液屏障，以环孢素A为模型药物设计粘液穿透型和粘液粘附型药物纳米载体，探讨粘液屏障对纳米载体吸收的影响；③针对消化道上皮细胞屏障，以伊曲康唑为模型药物，设计配基修饰的主动转运纳米晶，对纳米晶在消化道内的命运进行深入探讨；④针对上皮细胞屏障，以沙奎那韦为模型药物，对纳米晶体表面进行脂质修饰，探讨其在胞内的转运机制。本研究发现：①对于聚合物胶束给药体系，如果过饱和度过高，环孢素A析出结晶，过低则药物分子受困于胶束核心难以释放，因此设计过饱和给药系统时，需对过饱和度进行优化，选择适宜的过饱和度更加有助于药物吸收；②粘液穿透型纳米载体比粘液粘附型纳米载体在胃肠液中具有更好的稳定性，其良好的粘液穿透能力对环孢素A的吸收具有促进作用；③在克服上皮细胞屏障的研究中，凝集素修饰的伊曲康唑纳米晶能粘附在上皮细胞表面，部分晶体能通过消化道特殊的细胞（杯状细胞）实现良好的跨膜转运和药物吸收；④表面进行脂质修饰的沙奎那韦纳米晶同未修饰的纳米晶相比更易于入胞，并通过胞内特殊的转运途径避免p-糖蛋白的外排作用。