芳香开窍中药促进纳米粒经鼻入脑转运及其机制研究

Nowadays, brain drug targeting is the hot spot of pharmaceutical research. Intranasal delivery of nanoparticles can bypass the BBB and delivery various medicines to the brain noninvasively. However, due to the limited administration volume and the clearance action of nasal ciliary, the brain delivery ability of the nanoparticles should be further improved. Recently, the Guiding theory in traditional Chinese medicine was recognized bearing some similarity with the targeting theory. The aromatic refreshing brain guiding medicines can elevate brain concentrations of various medicines showing the targeting effect. Therefore, we suppose, the brain guiding medicines can be a novel targeting strategy based on Guiding theory of traditional Chinese medicine. The effect of brain guiding medicines on regulation of permeability of nasal membrane and the BBB, may enhace the intranasal brain delivery of nanoparticles. In the current project, we will modify PLGA nanoparticles with brain guiding medicines, borneol and β-asarone, by chemical and physical modification methods. Using Qdots as a fluorescent probe, with the add of immunofluorescence staining, fluorescence microscopy and living body imaging techniques, the mechanism and transport passway of intranasal delivered nanoparticles modified by guiding medicines were explored qualitatively and quantitatively, and the in vitro and in vivo safety of the nanoparticles were evaluated, aiming at providing theory and experiment basis for the combination of the Guiding and targeting theories. In addition, modified nanoparticles were used as brain targeting systems and loading with Pueraria Flavonid to enhance the therapeutic effects on cerebral ischemia injury, which will provide experiment basis for the application of the new targeting system.

药物的脑靶向技术是目前药剂学研究的热点。纳米粒鼻腔给药能以非侵入的方式绕过血脑屏障将多种药物递送入脑，但受到给药量的限制及鼻纤毛清除的影响，其入脑能力仍有待进一步提高。近来研究表明，中药的引经理论与西药的靶向理论有着异曲同工之妙，芳香开窍类脑部引经药可增强多种药物在脑内的浓度，体现靶向作用。因此，我们设想：脑部引经药可以作为一种基于中医引经理论的靶向策略，借助其对鼻粘膜及BBB通透性的调节作用增强纳米粒的经鼻入脑转运。本研究拟通过化学和物理修饰方法制备冰片及β-细辛醚修饰的PLGA纳米粒。以量子点为荧光探针,借助免疫荧光染色、荧光显微及活体成像技术定性定量的探讨引经药修饰促进纳米粒经鼻入脑转运的机制，明确其转运通路，并进行体内外安全性评价。为引经理论与现代靶向策略的结合提供理论基础和实验依据。此外，评价引经药修饰葛根总黄酮脑靶向纳米粒对脑缺血损伤的治疗效果，为该靶向系统的应用提供实验依据。

药物的脑靶向技术是目前药剂学研究的热点。纳米粒鼻腔给药能以非侵入的方式绕过血脑屏障将多种药物递送入脑，但受到给药量的限制及鼻纤毛清除的影响，其入脑能力仍有待进一步提高。近来研究表明，中药的引经理论与西药的靶向理论有着异曲同工之妙，芳香开窍类脑部引经药可增强多种药物在脑内的浓度，体现靶向作用。本研究选取冰片(Bo)和β-细辛醚（As）为脑部引经药的代表，修饰纳米粒，构建引经药修饰纳米递药系统,并分别以葛根总黄酮和丹参酮ⅡA为模型药物，探讨引经药修饰纳米粒增加药物脑内转运。成功合成了氨基修饰的冰片和氨基修饰β-细辛醚；分别通过化学修饰和包载法制得冰片、β-细辛醚修饰的纳米粒并对其进行表征；采用纳米系统包载香豆素-6为荧光探针，荧光显微镜观察体外血脑屏障及鼻腔细胞模型对四种修饰后纳米粒的摄取情况，并测定其摄取情况，结果证实，化学修饰法制备的冰片修饰纳米粒具有较好的脑内递送效果。16HBE细胞对于修饰纳米粒的摄取具有浓度，温度，和时间依赖性，为高尔基体和溶酶体参与的能量依赖过程，还可通过包被凹陷被内吞。制备包载葛根总黄酮和丹参酮ⅡA的引经药修饰纳米粒，体内药动学实验结果证实，经过处方优化后的引经药修饰纳米系统能显著提高药物的脑内递送效果。该研究为引经理论与现代靶向策略的结合提理论基础和实验依据。