Petrikovics I, McGuinn W D, Sylvester D, Yuzapavik P, Jiang J, Way J L, Papahadjopoulos D, Hong K, Yin R, Cheng T C, DeFrank J J
Department of Medical Pharmacology and Toxicology, Texas A&M University, College of Medicine, College Station 77843-1114, USA.
Drug Deliv. 2000 Apr-Jun;7(2):83-9. doi: 10.1080/107175400266641.
This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.
本研究描述了一种新的有机磷（OP）解毒治疗方法，即将一种OP水解酶——OPA水解酶（OPAA）包裹在空间稳定脂质体中。重组OPAA酶源自交替单胞菌菌株JD6。它对多种OP化合物具有广泛的底物特异性：二异丙基氟磷酸酯（DFP）以及神经毒剂梭曼和沙林。通过机械分散法制备了包裹OPAA的脂质体（SL）。使用氟离子选择性电极通过跟踪氟离子浓度的增加来测定（SL）对DFP的水解情况。包裹在载体脂质体中的OPAA能迅速水解DFP，DFP的水解速率与加入溶液中的（SL）量成正比。不含酶的脂质体载体不能水解DFP。该反应呈线性，水解速率在底物方面为一级反应。这种酶载体系统为重组OP代谢酶OPAA提供了一个可生物降解的保护环境，从而延长了体内酶的浓度。这些研究表明，通过将包裹在（SL）中的OPAA添加到解磷定和阿托品中，可显著增强对OP中毒的保护作用。
