A simple and highly effective catalytic nanozyme scavenger for organophosphorus neurotoxins
A simple and highly effective catalytic nanozyme scavenger for organophosphorus neurotoxins
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DOI：
10.1016/j.jconrel.2016.12.037
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发表时间：
2017-02-10
影响因子：
10.8
通讯作者：
Kabanov, Alexander V.
中科院分区：
文献类型：
--
作者：
Efremenko, Elena N.;Lyagin, Ilya V.;Kabanov, Alexander V.
一种基于有机磷水解酶（OPH，EC 3.1.8.1）的有毒有机磷化合物的简单且高效的催化清除剂通过六组氨酸标记的OPH（His（6）-OPH）和聚（乙二醇）-b-聚（L-谷氨酸）二嵌段共聚物的静电偶联在水溶液中产生。所得的聚离子复合物，称为纳米OPH，具有球形形态和直径从25 nm到100 nm。将His（6）-OPH并入纳米-OPH中保留了催化活性并增加了酶的稳定性，允许其在水溶液中储存超过一年。它还降低了体内对His（6）-OPH的免疫和炎症反应，如分别在Sprague道利大鼠和Balb/c小鼠中通过抗OPH IgG和细胞因子形成所确定的。与裸酶相比，纳米OPH药代动力学参数得到改善，表明大鼠静脉内（iv）给药后血液循环更长。此外，nano-OPH在肌内（im），腹膜内（ip）甚至经颊（tb）给药后具有生物利用度，并已显示出保护动物免受杀虫剂，对氧磷和战争剂VX暴露的能力。特别是，观察到对致死剂量的对氧磷的完全保护与nano-OPH给药iv和ip多达17 h，im 5.5 h和tb 2 h中毒前。进一步评估纳米OPH作为催化生物清除剂对抗有机磷化学战剂和农药是必要的。(C)2017年爱思唯尔B。V.保留所有权利。
A simple and highly efficient catalytic scavenger of poisonous organophosphorus compounds, based on organophosphorus hydrolase (OPH, EC 3.1.8.1), is produced in aqueous solution by electrostatic coupling of the hexahistidine tagged OPH (His(6)-OPH) and poly(ethylene glycol)-b-poly(L-glutamic acid) diblock copolymer. The resulting polyion complex, termed nano-OPH, has a spherical morphology and a diameter from 25 nm to 100 nm. Incorporation of His(6)-OPH in nano-OPH preserves catalytic activity and increases stability of the enzyme allowing its storage in aqueous solution for over a year. It also decreases the immune and inflammatory responses to His(6)-OPH in vivo as determined by anti-OPH IgG and cytokines formation in Sprague Dawley rats and Balb/c mice, respectively. The nano-OPH pharmacokinetic parameters are improved compared to the naked enzyme suggesting longer blood circulation after intravenous (iv) administrations in rats. Moreover, nano-OPH is bioavailable after intramuscular (im), intraperitoneal (ip) and even transbuccal (tb) administration, and has shown ability to protect animals from exposure to a pesticide, paraoxon and a warfare agent, VX. In particular, a complete protection against the lethal doses of paraoxon was observed with nano-OPH administered iv and ip as much as 17 h, im 5.5 h and tb 2 h before the intoxication. Further evaluation of nano-OPH as a catalytic bioscavenger countermeasure against organophosphorus chemical warfare agents and pesticides is warranted. (C) 2017 Elsevier B. V. All rights reserved.