Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, Kazan 420088, Russia.
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), Rouen, France.
J Control Release. 2018 Nov 28;290:102-111. doi: 10.1016/j.jconrel.2018.10.010. Epub 2018 Oct 9.
A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160 nm and negative zeta potential (-30 to -25 mV) were stable for a period of 10 months at 4 °C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8 × LD) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.
一种针对有机磷中毒的新型脑保护方法是基于双重递送两种肟的联合治疗开发的。氯化羟肟酸（2-PAM）和一种新型重活化剂，6-（5-（6,7-二甲氧基-3,4-二氢异喹啉-2（1H）-基）戊基）-3-羟基吡啶甲酰肟（3-HPA），已被载入固体脂质纳米粒（SLNs）中，以提供两种肟的独特释放曲线和系统半衰期。为了增加两种肟的治疗时间窗，设计了具有两个不同隔室的 SLNs 来分别装载各自的药物。具有 100 至 160nm 之间的水动力学直径和负 zeta 电位（-30 至-25mV）的载肟 SLNs 在 4°C 下稳定 10 个月。与游离 3-HPA 和游离 2-PAM 相比，SLNs 在血液中表现出更长的循环时间。载肟 SLNs 适合静脉（iv）给药。用 3-HPA 负载的 SLNs 和 2-PAM+3-HPA 负载的 SLNs 以 3-HPA 和 2-PAM 5mg/kg 的剂量对 0.8×LD 的对氧磷中毒大鼠进行治疗。在给予 3-HPA-SLNs 后 5 小时内，脑 AChE 再激活率缓慢达到 30%。对于两种肟的联合治疗，观察到时间依赖性加性和再激活率增加至 35%。
