CO2诱导纳米乳液介质内中药纳米结构脂质载体的绿色组装、微结构调控与构效关系

As a novel drug delivery system, nanostructured lipid carriers (NLCs) can improve the bioavailability and achieve sustained-releasing for lipophilic or poorly soluble compounds purified from Chinese traditional medicine. With solid/liquid mixing lipids as the carriers, butenolides as model drugs, the nanostructured lipid carriers loading drugs were assembled in the nanoemulsions induced by supercritical/compressed CO2 used as soft templates, providing a novel approach for microstructure control of nanostructured lipid carriers loading drugs with a green technology. Combining the measurement on line and mesoscale simulation with dissipative particle dynamics simulation, the dynamical microstructures and self-assembly process of NLCs loading drugs were studied, so as to illuminate the mechanism of microstructure control by modifying the procedure parameters of the soft templates. The multi-layer microstructure system was construed by combination of the dynamical microstructures and static microstructures. The relationships of microstructure and pharmaceutical activities including the drug loading efficiency, release property, stability, bioavailability, and the anti-tumor effects in vitro were summarized. According to the key ideas of product engineering, the evolution of self-assembly behaviour, microstructures and pharmaceutical activities of NLCs loading drugs in the nanoemulsion induced by CO2 are revealed, looking forward to providing the theory basis for drug delivery system of NCLs design in the complex colloidal medium induce by CO2 fluids.

纳米结构脂质载体 (Nanostructured Lipid Carriers, NLCs)可提高难溶中药成分生物利用度，并具有缓释作用，是一种新型中药传递系统。以固/液混合脂质为载体，白术内酯为模型中药，以超临界/压缩CO2诱导的纳米乳为软模板，为载药NLCs的绿色可控组装，实现微结构精细调控提供了一条新途径。采用超临界在线实验表征与DPD介观模拟结合的方法，研究载药NLCs动态微结构与组装动力学过程, 阐释组装过程调控载药NLCs微结构机制。获取载药NLCs产品静态结构信息，构筑NLCs的动态与静态结构相结合的多层次微结构信息，研究微结构与载药NLCs的载药性能、药物释放性能、稳定性、生物利用度、体外生物活性等药学效能之间的构效关系。按化学产品工程理念，揭示CO2诱导纳米乳介质中载药NLCs组装行为、结构与药学效能的关系规律，为复杂流体作用下胶体多相体系构建纳米脂质载体提供理论支撑。

以固/液混合脂质为载体，白藜芦醇为模型药物，利用超临界/压缩CO2诱导磷脂形成的O/W 型纳米乳液（CIN）为软模板，调控模板内药物/脂质载体的共沉析过程，使溶剂去除、药物包封、纳米粒沉析均在CO2流体中连续完成，实现了白藜芦醇纳米结构脂质载体（RES-NLC）的绿色组装。与经典制备方法相比，CIN组装RES-NLC无溶剂残留，提高了RES-NLC的载药性能，并保证其在纳米尺度均匀分布。对纳米粒的脂质载体表面与基质进行修饰，所构建的纳米粒具有体外缓释与pH敏感性释放、体内肝靶向分布与长循环的药学性能，提升了白藜芦醇的抗氧化作用，并具有抑制肝癌HepG2细胞增殖作用。构筑静态与动态结构结合的纳米粒微观结构，揭示了CIN过程参数/微结构/药学效能之间的关联关系。所构建的NLC脂质载体具有α亚稳晶型与β稳态晶型共存的同质多晶结构，脂质基质包含晶格缺陷，白藜芦醇以无定形态富集在晶格缺陷中，形成核-壳式的纳米粒微观结构，提升了纳米粒的生物功效，显示了其在肿瘤靶向的纳米药物传递系统的应用潜力。