“门控式”介孔二氧化硅难溶性药物递送系统与定位释药的机制

Based on the previous research, for the first time, the principle of "restrict the formation of drug crystal " in which the pore structure of the carrier was specially designed contradict to the preferable growth direction of drug crystal was applied in the design and construction of serious ordered mesoporous silica carriers aiming to achieve a high loading efficiency of drug in molecular or amorphous state and simultaneously improve the physical stability of the drug by inhibiting crystalline transformation or re-aggregation of the amorphous particles through the unique morphology and rigid structure of the carrier. Moreover, "targeting ligand" and "stimulus-responsive switch" were conjugated on the surface of silica to achieve site specific drug delivery and on demand controlled release, like redox-responsive and redox/enzyme dual-stimuli responsive targeted drug delivery systems. The specific surface area and pore size analyzer, X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy are employed to investigate the correlation of structural characteristics of the carriers and the state, stability of loaded drug particles and explicitly clarify the theoretical and practical basis of this stable, efficient delivery system. Furthermore, confocal laser scan microscopy, flow cytometry, fluorescence polarization techniques will be subsequently exploited to study the mechanism of site-specific release of drug molecules or particles encapsulated in the carrier and roles the carrier played in the promoted uptake and absorption of drug. Our research will not only help to overcome scientific problems including low drug loading efficiency, instability assocaiated with high loading efficiency due to gradual aggregation and toxic side-effects of drug on normal tissues that commonly exist in delivery system for water insoluble drugs, but also provide innovative approaches for the enrichment of new formulations in the field of pharmaceutical research.

研究借鉴前期基础,首次提出以"逆药物晶形"手段构建介孔二氧化硅载体，在实现药物以分子与无定形粒子高效载药的同时，通过载体的特定形貌及刚性结构， 控制无定形粒子的转晶型或再聚集，提高药物的物理稳定性；进一步将"靶头"与"响应性开关"修饰于载药系统，分别赋予该载药系统靶向-还原敏感与靶向-酶/还原双重敏感的特性，实现载药系统向特定部位递送及定位释药的研究设想。采用比表面积及孔径分析仪、X射线衍射、X射线光电子能谱、透射电镜等技术研究载体特征与药物粒子存在形式、稳定性的关系，重点阐明高效稳定递送系统建立的理论与应用基础；采用激光共聚焦成像、流式细胞测定、荧光偏振等技术研究药物分子或粒子于特定部位释药与载体促进药物吸收的主要机制。研究为解决难溶性药物递送系统的低载药量或高载药量的"聚集"不稳定性以及降低药物对正常组织的毒副作用等科学难题，也为丰富新剂型在药剂学领域的应用提供创新性的探索思路。

研究围绕拟解决的关键科学问题，即难溶性药物递送系统的低载药量或高载药量的药物聚集不稳定性以及药物递送系统在到达治疗部位前药物的“过早”释放，增加对正常器官和组织的毒副作用，创新提出“逆晶载药”新概念，以“逆晶载药”设计的纳米骨架用于实现难溶性药物的高效装载与稳定分散，并以“生理响应性开关”修饰骨架载体，由于特定生理条件（如肿瘤环境具有较低的pH值、丰富的酶系与细胞内较高的谷胱甘肽浓度等）的改变，使难溶性药物载药系统的“开关”脱落或打开，载体释放药物，能够实现药物于特定部位的靶向递送。针对体内特定的生理条件已构建多种“门控式”二氧化硅载药系统，并分别实现①还原和酶双重敏感；②还原和敏感pH；③pH敏感和④还原和近红外（NIR）光双重敏感等多种递送系统。研究采用比表面积及孔径分析仪、X射线衍射、X射线光电子能谱、扫描电镜和透射电镜等技术对系列“门控式”载药系统进行体外表征。敏感性释药结果表明构建的“门控式”二氧化硅递送系统均能很好的减少药物到达靶部位前的提前释药。研究并对载药系统的敏感性释药机制进行验证与研究。通过对“门控式”二氧化硅递送系统的细胞毒性、靶向性的验证及体内药效学等进行评价，初步阐明敏感型递送系统增效降毒的主要机制为：“门控式”二氧化硅载药系统具有较高的装载效率，并能够减少药物到达靶部位前的提前释药，而根据病变部位的特殊生理环境实现敏感性释药，并能够增加细胞对载药体系的摄取，从而增加药物在病变部位的吸收，而减少药物在正常组织的释放，从而降低毒副作用。而当赋予“门控式”递送系统光热治疗作用时，可实现递送系统的NIR刺激响应型释药，且可使肿瘤组织的温度升高，实现化热疗的协同增效。相关研究将为最终解决药物的靶向效率差和毒副作用大的科学难题，为开发与丰富临床制剂的新品种，拓展新型递送系统在医药领域的应用，促进医药经济的发展提供创新性的探索途径。