低功率聚焦超声联合微泡靶向增强脑组织药物浓度的机制

项目名称： 低功率聚焦超声联合微泡靶向增强脑组织药物浓度的机制

项目编号： No.30870723

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 医药、卫生

项目作者： 程远

作者单位： 重庆医科大学

项目金额： 31万元

中文摘要： 血脑屏障（BBB）的存在一方面阻碍有害物质进入大脑，对维持大脑内环境的稳定性起了突出贡献，但同时也阻碍大量有潜在诊断和治疗作用的因子进入，使中枢神经系统疾病的治疗更为复杂。本项目在前期工作和大量预实验基础上，首先确立了超声联合微泡开放BBB的超声参数和微泡的使用剂量,成功建立了MRI引导下超声靶向开放兔、大/小鼠BBB的动物模型,通过MRI全程动态的监测了兔BBB的开放，证实MRI引导下超声联合微泡能无创、可逆、靶向性的开放BBB，并且BBB的开放在超声照射2h后达到高峰，8h内恢复至正常水平；该方法能显著增强靶区的药物浓度，能促进外源基因在靶区神经元内有效转染；并证实BBB开放的情况下，药物的分子量对药物在靶区脑的摄入和空间分布起主要作用；还证实caveolin-1介导的跨细胞转运也可能是超声联合微泡开放BBB的机制之一。本项目的研究为超声联合微泡在CNS疾病治疗方面提供了大量新的实验依据。

中文关键词： 超声;核磁共振成像;中枢神经系统;药物传递;基因治疗

英文摘要： Owing to the existence of blood-brain barrier (BBB), this barrier system protects the the brain from foreign toxic substances and plays a major role in maintaining the stability of internal environment,but meanwhile prohibits the delivery of many potentially effective diagnostic or therapeutic agents and complicates the treatment of CNS diseases.On the basis of lots of previous work and preliminary experiments,we firstly determined the parameters of ultrasound and dose of microbubbles applied in BBB disruption and under the guidence of MRI,successfully established the experimental models of ultrasound-induced BBB disruption in rat,mouse and rabbit.Through the monitoring of MRI, it was demonstrated that under the guidence of MRI, ultrasound associated with microbubbles could open the BBB noninvasively, reversiblely and targetedly, and the extent of BBB opening reached a peak at 2h and restored to normal levels at 8h after sonication;this method could significantly enhance the drug concentration in the target region and effectively accomplish the exogenous gene transfer into neurons of the target brain;under the condition of BBB opening,the molecular weights of drugs played a key role in the quantity of brain uptake and the spatial distribution of drugs in the target region；in additon,caveolin-1-mediated transcellular transport pathway may be one of mechamisms of ultrasound-induced BBB opening.This study provided massive new experimental evidence for the treatment of CNS diseases by ultrasound and microbubbles.

英文关键词： cultrasound;MRI;central nervous system;drug delivery;gene therapy