中国组织工程研究

中国组织工程研究 ›› 2016, Vol. 20 ›› Issue (5): 688-693.doi: 10.3969/j.issn.2095-4344.2016.05.014

• 心脏及血管损伤动物模型 Animal models of heart and vascular damage • 上一篇    下一篇

升麻苷H-1利用鼻腔嗅觉区鼻-脑通道进行鼻脑靶向给药的可行性

武密山1，赵素芝2，高维娟3，王 茹1，韩红伟1，师旭亮1   

  1. 1河北中医学院基础医学院方剂学教研室，河北省石家庄市 050200；2石家庄市长安区胜北社区卫生服务中心，河北省石家庄市 050041；3河北省心脑血管病中医药防治重点实验室，河北省石家庄市  050091
  • 收稿日期:2015-11-07 出版日期:2016-01-29 发布日期:2016-01-29
  • 作者简介:武密山，男，1966年生，1998年河北医科大学毕业，博士，教授，博士生导师，主要从事补肾化痰活血方药治疗心脑血管病的作用机制研究。
  • 基金资助:
    国家自然科学基金资助项目(81073074，30472200)；河北省自然科学基金资助项目(H2013206005)；河北省高等学校科学技术研究重点项目(ZD2015053)；河北省高等学校高层次人才科学研究项目(GCC2014013)

Feasibility of nasal brain targeted drug delivery through the nose-brain channel in the nasal olfactory region using cimicifugoside H-1

Wu Mi-shan1, Zhao Su-zhi2, Gao Wei-juan3, Wang Ru1, Han Hong-wei1, Shi Xu-liang1   

  1. 1Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei Province, China; 2Changan District Shengbei Community Health Center of Shijiazhuang, Shijiazhuang 050041, Hebei Province, China; 3Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050091, Hebei Province, China
  • Received:2015-11-07 Online:2016-01-29 Published:2016-01-29
  • About author:Wu Mi-shan, M.D., Professor, Doctoral supervisor, Department of Formulaology, Basic Medicine College, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei Province, China
  • Supported by:

    the National Natural Science Foundation of China, No. 81073074, 30472200; the Natural Science Foundation of Hebei Province, No. H2013206005; the Major Scientific Research Project of Hebei Provincial Higher Education Schools, No. ZD2015053; the High-Level Personnel of Institutions of Higher Learning in Hebei Province (Scientific Research Project) No. GCC2014013

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摘要：

文章快速阅读：

文题释义：

脑靶向药物递送：根据生物体的生理学、病理学和分子生物学特性，借助受体、载体与配体、抗体的作用，将药物选择性地递送至脑靶细胞的一种递药系统。理想的脑靶向给药系统应该有3个要素：即定位蓄积、控释、无毒且可生物降解。根据脑靶向机制，将药物脑靶向系统分为两大类型：生物学脑靶向给药系统和化学脑靶向给药系统。生物学脑靶向给药系统主要是以抗体为基础，包括单克隆抗体识别，寻找新的潜在靶向体以及基因治疗；化学脑靶向给药系统即通过化学合成反应、化学修饰合成药物的非活性衍生物，使药物与特殊设计的“载体”以共价键的方式相连，到达脑靶向组织、细胞，利用酶断开共价键，释放出活性药物。
鼻腔给药入脑途径：①经鼻腔呼吸区黏膜毛细血管吸收，经血液循环透过血脑屏障。②药物通过嗅黏膜上皮或嗅神经进入嗅球或脑脊液，此通路依赖嗅黏膜下层与蛛网膜下隙相通的解剖结构，转运到脑组织中。

 

背景：近些年研究表明，鼻腔给药作为脑靶向给药的途径之一，可有效使通过其他给药途径不易透过血脑屏障的药物绕过血脑屏障，靶向递送到脑部，为治疗中枢神经系统疾病提供一种极有发展前景的给药途径。
目的：研究大鼠鼻腔给药及静脉注射升麻苷H-1的药代动力学和脑靶向性归经的组织分布特性，探索升麻苷H-1利用鼻腔嗅觉区的鼻-脑通道进行鼻脑靶向给药的可行性。
方法：鼻腔给药及静脉注射给予升麻苷H-1后，检测各时间点血浆和主要的归经组织器官(肺、脾、胃、大肠、肝、肾、脑、大脑、小脑、脑脊液、嗅球、嗅区等)药物浓度，绘制药-时曲线，用DAS程序拟合房室模型并计算药代动力学参数。

结果与结论：①升麻苷H-1 吸收迅速，分布广泛。在主要的归经器官中，肺、脑药物浓度分布均远高于其他脏器组织。②升麻苷H-1鼻腔给药后经以下吸收通路直接转运入脑：鼻腔嗅黏膜吸收进入蛛网膜下腔的嗅球，然后相继进入嗅区、脑脊液大脑、小脑等部位，嗅球是药物分子经鼻腔入脑的必经之路。③与静脉注射给药相比，升麻苷H-1鼻腔给药具有明显的肺、脑靶向性。  

ORCID: 0000-0003-3959-9906(武密山)

关键词: 实验动物, 心肺损伤与修复动物模型, 升麻苷H-1, 鼻腔给药, 脑靶向归经, 示踪剂, 定量分布, 药代动力学, 国家自然科学基金

Abstract:

BACKGROUND: Recent studies have suggested that intranasal administration is one of the ways to target drug 
delivery, and can effectively make the drug that cannot pass through the blood brain barrier by other pathways to bypass the blood brain barrier, resulting in targeted delivery to the brain. It provides a promising route for the treatment of central nervous system diseases.
OBJECTIVE: To study the pharmacokinetic and brain-targeted channel-tropism tissue distribution character of cimicifugoside H-1 after nasal and intravenous administration in plasma and tissues in rats, in order to evaluate the feasibility of developing brain-targeted nasal delivery system of cimicifugoside H-1 by the passage between nose and brain in nasal olfactory area.
METHODS: After intravenous injection and nasal administration of cimicifugoside H-1, the drug concentrations of plasma and channel-tropism organs (lung, spleen, stomach, large intestine, liver, kidney, brain, brain, cerebellum, cerebrospinal fluid, olfactory bulb and olfactory region) were detected. Drug-time curve was drawn. DAS program was used to select apartment model and pharmacokinetics parameters.
RESULTS AND CONCLUSION: (1) The pharmacokinetics characters of cimicifugoside H-1 are rapidly absorbed and extensively distribution. Among major channel-tropism organs, drug concentrations were higher in the lung and brain than in the other organs. (2) Cimicifugoside H-1 could be straightly transported into brain by the intranasal administration. The molecule through olfactory mucosa in nasal cavity entered into olfactory bulb in arachno-hypostegal cavity, and then entered into olfactory region, cerebrospinal fluid, cerebrum and cerebellum gradually. Olfactory bulb was the only way for drug molecule to go through nasal cavity into brain. (3) Compared with the intravenous injection, cimicifugoside H-1 through the intranasal administration has a significant channel-tropism of lung and brain targeting.