基于介孔碳支撑磷脂双分子层的难溶性药物口服纳米给药系统的构建及其性能研究

The objective of this study was to develop a novel drug delivery system (DDS) based on mesoporous carbon nanoparticles supported lipid bilayers (MCN-SLB), intended to be orally administered, able to combine the excellent properties of mesoporous carbon nanoparticles and liposomes, improve the oral bioavailability of poorly water-soluble drugs. Paclitaxel, furosemide, lovastatin and nimodipine were selected as model drugs and loaded into carriers using different loading methods. The physicochemical properties of the drug carriers and drug-loaded composites were systematically studied using scanning electron microscopy, transmission electron microscopy, atomic force microscope, specific surface area analysis, zeta potential measurement, differential scanning calorimetry, thermogravimetric analysis, High-performance liquid chromatography, X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction measurements, etc. The effects of composition, porous structure, particle size and surface properties (morphology, functional groups and zeta potential) of this novel DDS and the drug loading methods on the aqueous solubility, stability and in vitro sustained release behavior of the model drugs were investigated and the possible mechanisms were confirmed. Moreover, the effects of MCN-SLB on drug transport across human intestinal epithelial cells, paracellular permeability and intestinal lymphatic drug transport as well as its bioadhesive properties were investigated using various established models (such as in vitro Caco-2 cell monolayers and in vivo animal models) and techniques (such as laser confocal scanning microscopy and flow cytometry measurements). The critical factors responsible for enhanced intestinal absorption of poorly water-soluble drugs and the possible mechanisms were clarification. Furthermore, in vivo pharmacokinetic studies were conducted to confirm the increase in oral bioavailability. In addition, safety evaluation of MSN-SLB was also conducted. The optimal design of this novel DDS and the exploration of its potential mechanisms of improvement of oral bioavailability of poorly water-soluble drugs (at the molecular, cellular, and in vivo levels) in this study will help the design of a widely used oral DDS for improving solubility and bioavailability of poorly water-soluble drugs.

拟构建一种基于介孔碳支撑磷脂双分子层的新型纳米给药系统，协同发挥介孔碳纳米粒和脂质体作为口服药物载体的优势同时弥补各自缺陷，以期提高难溶性药物的口服生物利用度。以紫杉醇、洛伐他汀等为模型药，采用电镜测试、比表面积测试、电位测试、热分析、色谱分析及X–射线衍射分析等技术，从微观层次阐明该给药系统的组成、结构、尺寸、表面性质及载药方法等对于增加药物水溶性、储存稳定性及调节释药行为等方面的作用机理；进一步通过Caco-2细胞单层膜等模型及应用流式细胞仪、共聚焦显微镜等技术，从载体提高药物跨肠上皮细胞转运、调节细胞旁路通透性、促进药物经肠淋巴转运及生物黏附性等方面，揭示该给药系统促进药物肠吸收的关键因素与机理；同时以在体动物进行生物利用度及安全性评价。该给药系统的优化设计及在分子、细胞和整体水平上对其提高药物生物利用度等机制的探索，将为开发一种通用性较强的难溶性药物口服给药系统奠定新的基础。

本研究拟构建一种基于介孔碳支撑磷脂双分子层的新型纳米给药系统，协同发挥介孔碳纳米粒和脂质体作为口服药物载体的优势同时弥补各自缺陷，以期用于改善难溶性药物的口服吸收。本研究分别构建了介孔碳/磷脂膜纳米复合物（MCN-SLB）、羧甲基壳聚糖/磷脂膜/介孔碳纳米复合物（CCS-MCN-SLB）及具有多“核”单“壳”结构的普朗尼克修饰性多囊脂质体/介孔碳纳米递药系统(f-MVL/MCN)，并以尼莫地平、多西紫杉醇、吉非替尼等为模型药对该类给药系统进行评价。采用透射电镜测试、扫描电镜测试、比表面积测试、热分析、色谱分析及X–射线衍射分析等技术，从微观层次阐明该系统的组成、结构、表面特性及载药方法等对于增加药物水溶性、储存稳定性及调节释药行为等方面的机制；通过Caco-2细胞模型采用激光共聚焦显微等技术，从载体提高药物跨肠上皮细胞传递及增加生物黏附性等方面，揭示该给药系统促进药物肠道吸收的关键因素；同时以在体动物进行生物利用度评价。结果表明，该类载药系统具有较高的载药量及缓释特性，通过对其表面进行羧甲基壳聚糖优势，可使其具有pH敏感的释药能力和提高的生物粘附性。此外，融合普朗尼克修饰性多囊脂质体与介孔碳纳米粒构建具有多“核”单“壳”的纳米递药系统，更有助于调控药物的释药行为。本研究通过对介孔碳纳米粒支撑磷脂双分子层的纳米给药系统的可控构建，以及从分子、细胞和整体水平上研究和阐明其提高难溶性药物口服吸收的作用机制，丰富了介孔材料促进难溶性药物口服吸收机制的研究，进而为开发一种通用性较强且适用于改善难溶性药物口服吸收的给药系统奠定新的基础。