纳米化酰胺磷定对梭曼中毒小鼠乙酰胆碱酯酶的重活化作用  

Reactivation of nanoparticulated HI-6 on acetylcholinesterase activity in soman poisoned mice

作　　者：王飞剑[1] 杨军[1] 程凤[1] 李万华[1] 聂志勇[1] 骆媛[1] 隋昕[1] 魏朝[1] 郑志兵[1] 王永安[1] 房彤宇[1] 

机构地区：[1]军事医学科学院毒物药物研究所军事毒理与生化药理研究室,北京100850

出　　处：《中国药理学与毒理学杂志》2014年第2期255-261,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家新药创制重大专项(2011ZXJ09102-05C);国家新药创制重大专项(2011ZXJ09305);全军医学科技"十二五"重大项目(AWS11C004);全军医学科技"十二五"重点项目(BWS12J042);总后青年培育基金(13QNPQ152)~~

摘　　要：目的：评价比较基于不同载药模式的纳米化酰胺磷定（HI-6）对梭曼中毒小鼠外周及中枢乙酰胆碱酯酶（AChE）的重活化作用。方法制备以人血清白蛋白纳米粒（HSA NP）为载体挂载 HI-6（HSA-HI-6 NP）、聚乳酸-羟基乙酸纳米粒（PLGA NP）为载体包裹 HI-6（PLGA-HI-6 NP）及纳米多孔硅球（MSN）为载体吸附 HI-6（MSN-HI-6）的3种纳米化 HI-6。电镜进行物理表征；测定体外释药速率。观察梭曼染毒（120μg·kg -1，sc）小鼠 iv 给予含恒量 HI-622 mg·kg -1的3种纳米化 HI-6对外周及中枢中毒 AChE 的重活化作用。结果3种纳米载体均符合纳米药物基本特征。体外释药速率为 HI-6＞HSA-HI-6 NP ＞MSN-HI-6＞PLGA-HI-6 NP。对中毒小鼠全血 AChE 的重活化作用结果显示给予 HSA-HI-6 NP，MSN-HI-6及HI-6组中毒小鼠全血 AChE 的重活化率在20％～30％，组间比较无显著差异；但均显著高于 PLGA-HI-6 NP（6．2％）给药组（P ＜0．01）；在中毒小鼠脑 AChE 的重活化作用结果中，HSA-HI-6 NP 组重活化率（15．3％）显著高于 PLGA-HI-6 NP（3．3％）组及 HI-6组（6．3％）（P＜0．01）；MSN-HI-6组（10．2％）则仅显著高于 PLGA-HI-6 NP（3．3％）给药组（P ＜0．01）。结论不同载药模式的纳米化 HI-6对外周及中枢中毒AChE 的重活化效率存在显著差异，HSA-HI-6 NP 对外周及中枢中毒 AChE 均具较高重活化作用。OBJECTIVE Based on different drug loading models,three types of nanoparticulated HI-6 were prepared and their reactivations on inhibited acetylcholinesterase （AChE）in peripheral and central nervous syste ms were evaluated and compared in so man-intoxicated mice.METHODS Three kinds of nano-reactivators including HI-6 loaded human serum albunin nanoparticle （HSA-HI-6 NP）,HI-6 absorptive mesoporous silica nanoparticle（MSN-HI-6）,polylactico-glycolic acid nanoparticle coated HI-6 （PLGA-HI-6 NP）were prepared.The characteristic of all blank nanocarriers was observed through elec-tron microscope.HI-6 release rate of nano-reactivators was also determined in vitro.Then the reactiva-tion rate of nano-reactivators at a constant HI-6 dosage（22 mg·kg -1 ）on so man-inhabited AChE both in blood and brain was assessed the so man intoxicated mice（120 μg·kg -1 ,sc）.RESULTS All the syn-thetic nanocarriers met the de mand for nanodrug use in vivo.The rate of HI-6 release of nano-reactiva-tors was HI-6 〉HSA-HI-6 NPs 〉MSN-HI-6 〉PLGA-HI-6 NP in vitro.On the reactivations of so man-inhibited mice blood AChE,the free HI-6 and HSA-HI-6 NPs,as well as MSN-HI-6 showed co mparable reactivation rates（20% -30%）but were greater than that of PLGA-HI-6 NPs （6.2%）（P 〈0.01 ）. However on the reactivations of so man-inhibited mice brain AChE,the reactivation rate of HSA-HI-6 NP （15.3%）was significantly higher than that of PLGA-HI-6 NP（3.3%）and free HI-6（6.3）（P〈0.01 ）.In addition,MSN-HI-6 group had a significant reactivation rate compared to PLGA-HI-6 NPs（P 〈0.01 ）. But there was no statistic difference between MSN-HI-6 and free HI-6.CONCLUSION The reactivation potency changed obviously with different drug loading models and HSA-HI-6 NPs had the most potent reactivation on so man-inhibited AChE in both blood and brain.

关 键 词：神经性毒剂 乙酰胆碱酯酶 纳米化HI-6 重活化作用 

分 类 号：R595.4[医药卫生—内科学]