碳纳米角增加难溶性药物透膜性及口服吸收机理的研究

Enhancing the oral bioavailability of poorly soluble drugs have always been a great challenge to pharmaceutical researchers. Nanocarriers can significantly improve oral bioavailability of poorly soluble drugs. However, there are usually many problems with them such as low encapsulation efficiency, easy leakage and less nanocarrier material type. Single-walled carbon nanohorns (SWNHs), a new type of nanocarrier material, has unique structural properties with cone sharp and hollow structure. SWNHs has many merits such as large surface area, good stability and easy functionalization, and so on. SWNHs has a great application potential. But, so far there is no report about SWNHs being used as drug delivery system for poorly soluble drugs. In this study SWNHs will be used as drug nanovector for poorly soluble drugs, to elucidate the possibility of SWNHs enhancing the oral bioavailability of insoluble drugs and explore the related mechanisms. We will choose paclitaxel and atorvastatin calcium as model insoluble drugs, to construct SWNHs drug delivery systems. The Madin–Darby canine kidney (MDCK) cell line and caco2 cell line will be used as epithelial cell models in this study. To illuminate the transport route and transport disciplines of SWNHs, the location and dynamic transport of SWNHs across epithelial cell monolayer will be monitored by various modern analytical techniques such as fluorescence probe tracer imaging method, Raman imaging and transmission election microscopy. The oral bioavailability of SWNHs drug delivery systems will be studied in animals. Multispectral Optoacoustic Tomography (MSOT) will be used to explore the problems of the dynamic distribution, transport process, in vivo residence time of SWNHs drug delivery systems and whether they can transport across gastrointestinal tract into blood, to uncover the relevant mechanisms of SWNHs enhancing oral absorption of poorly soluble drugs. It is of great scientific significance. Some pre-study has been conducted already.

促进难溶药口服吸收是药剂学领域的研究难点和热点。纳米载体能显著增加难溶药口服吸收，但常有载药量低、易渗漏、载体种类少等问题。单壁碳纳米角SWNHs是一种新型纳米载体材料，有特殊管锥形和中空结构，比表面积大、稳定性好，易功能化，应用潜力大，但尚未见其促进难溶药口服吸收的报道。本研究拟用SWNHs包载难溶药，阐明其增加难溶药口服吸收的可行性及其作用机理等科学问题。拟用紫杉醇和阿托伐他汀钙为模型，构建SWNHs载药系统，以MDCK及Caco2细胞单层模拟胃肠道上皮，用荧光探针示踪、拉曼成像、透射电镜等方法研究SWNHs在细胞内的动态转运和定位，阐明其跨上皮细胞膜的转运途径与规律；研究SWNHs载药系统在动物体内口服生物利用度，用MSOT多光谱光声成像技术研究SWNHs的体内动态分布、转运过程、滞留时间和跨胃肠道入血问题，揭示其促进难溶药口服吸收的作用机理，有重要科学意义。本研究有较好工作基础。

促进难溶药口服吸收是药剂学领域的研究难点和热点。纳米载体能显著增加难溶药口服吸收，但常有载药量低、易渗漏、载体种类少等问题。单壁碳纳米角（SWCNHs）是一种新型纳米载体材料，具有独特的管锥形和球形聚集体结构，表面积大，理化性质独特，用作药物载体有特殊优势。但迄今还未见SWCNHs用于促进难溶药物口服吸收的报道，也未见其口服后体内外的转运过程和转运规律等作用机理的报道。本课题首先以MDCK细胞为胃肠道极性上皮细胞模型，研究了SWCNHs与极性细胞的相互作用及其在极性上皮的渗透性。采用SWCNHs制备了氧化型的SWCNHox并构建了FITC-BSA修饰的SWCNHox，采用透射电镜、荧光示踪成像等方法研究了SWCNHs在细胞内的动态转运和定位，阐明了其跨上皮细胞膜的转运途径与规律。本课题进一步用MSOT多光谱光声成像技术研究了SWCNHs的体内动态分布、转运过程、滞留时间和跨胃肠道入血问题，揭示其促难溶药口服吸收的作用机理。为验证SWCNHs能促进难溶药口服吸收，本课题选用缬沙坦和索拉非尼为模型药，构建并评价了SWCNHs载药系统。细胞水平的研究结果表明，SWCNHs有很强的细胞粘附特性，部分能被MDCK细胞摄取并转运通过MDCK细胞单层，网格蛋白介导的内吞作用、巨胞饮作用等多个途径介导了SWCNHs的摄取和跨膜转运。体内研究结果表明SWCNHox口服后仅限于在胃肠道内分布,且在胃部滞留长达8h以上，在肠道内滞留长达36h以上，在检测水平下没有发现SWCNHox纳米粒子跨越胃肠道屏障进入血液系统，且在肝、脾、肾脏内均没有检测到SWCNHox的光声信号。处方优化后，SWCNHs装载缬沙坦和索拉非尼难溶药所得的载药系统粒径在纳米尺度，分散性好，改善了难溶药物的体外释放。总之，本课题在体内外水平研究了SWCNHs载体与胃肠道上皮的相互作用、跨膜转运规律和机制以及该载体口服后的体内命运，并将其装载难溶药进行了载药系统的处方优化、体外释放等研究，综合研究表明SWCNHs具有用作口服给药新材料的前景，有重要科学意义。

内容获取失败，请点击重试