介孔二氧化硅用于蛋白类药物高效稳定载药的结构基础与促进口服吸收的机制

It is innovatively proposed that using mesoporous silica of different morphology to efficiently load protein drugs of different size and conformation, and subsequently improve the stability of the loaded protein during oral administration by the inhibition or retardation of the conformational change, aggregation and enzymolysis of the protein via the customized size and morphology of the mesopores in the carrier of silica. And on this basis, the size and morphology of the carrier was further adjusted thus the oral absorption of protein drugs was finally improved. Three typical kind of protein drugs were used as model. And multiple methods were employed to characterize the structure and activity of the protein loaded in or released from the carrier. Confocal laser scanning microscopy and flow cytometry were applied to study the cellular uptake and transmembrane transport of the carrier and protein drug. This research provides the theoretical foundation and an idea for the establishment of drug delivery systems basing on the specific structures of protein drugs and subsequently forming a versatile establishing mode of “protein drug-carrier-drug delivery system”. In addition, this research also provides a guidance for the solving of the unique problem that proteins are unstable due to conformational change, aggregation and enzymolysis as well as the scientific conundrum of the oral administration of protein drugs.

研究创新性地提出以不同形貌的介孔二氧化硅为载体，高效装载大小及空间结构不同的蛋白类药物，通过载体特定的介孔尺寸与孔道形貌抑制或延缓特定蛋白类药物的结构转变、聚集和酶降解，从而提高蛋白类药物的口服稳定性；进一步结合对载体粒径和粒子形貌的调控，促进蛋白类药物的口服吸收。研究以三种典型蛋白类药物为模型，采用多种手段对不同形貌载体装载或释放的蛋白类药物的空间结构及生物活性进行测定，阐明介孔二氧化硅用于蛋白类药物高效稳定载药的结构基础；采用激光共聚焦显微镜、流式细胞术等手段研究载体及药物的细胞摄取与跨膜转运，阐明载体促进蛋白类药物口服吸收的机制。研究为根据具体蛋白类药物的结构特点建立相应的给药系统，形成通用性较强的“蛋白类药物-载体-给药系统”构建模式提供理论依据与设计思路，并为解决蛋白类药物所特有的结构易改变、易聚集和易被酶降解的稳定性问题，以及蛋白类药物口服生物利用度低的科学难题提供新的借鉴。

研究围绕拟解决的关键科学问题，即目前蛋白类药物口服给药系统的设计多没有考虑蛋白类药物的具体空间结构，具有一定的盲目性，初步探索阐明了介孔二氧化硅用于蛋白类药物高效稳定载药的结构基础与促进口服吸收的机制，根据蛋白类药物的结构特点所构建的给药系统，可一定程度上解决蛋白类药物所特有的易聚集、易发生结构改变以及易被蛋白酶降解的稳定性问题，且可改善蛋白类药物的口服药效。已制备多种具有不同结构的介孔二氧化硅载体，以三种具有不同分子量/空间结构的蛋白为模型药物，对不同结构载体对不同蛋白药物的载药、释药行为，抑制蛋白被酶降解的能力，抑制蛋白结构转变、聚集的能力进行了考察，初步阐明了载体特定的介孔尺寸对蛋白类药物高效稳定载药的结构基础，以及粒径、粒子形貌对载药体系口服吸收的影响，为解决蛋白类药物口服生物利用度低的科学难题提供了探索思路，也为形成通用性较强的“蛋白类药物-载体-给药系统”构建模式，为蛋白类药物口服给药系统的建立提供了理论及科学依据。