Kuznetsova Darya A, Gaynanova Gulnara A, Vasilieva Elmira A, Pavlov Rais V, Zueva Irina V, Babaev Vasily M, Kuznetsov Denis M, Voloshina Alexandra D, Petrov Konstantin A, Zakharova Lucia Y, Sinyashin Oleg G
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str. 8, 420088 Kazan, Russia.
Pharmaceutics. 2022 Sep 15;14(9):1950. doi: 10.3390/pharmaceutics14091950.
One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus.
乙酰胆碱酯酶（AChE）有机磷（OPs）抑制剂中毒治疗的主要问题之一是，用作解毒剂的现有AChE复活剂穿越血脑屏障（BBB）的能力较低。在这项研究中，开发了可穿透血脑屏障并将AChE复活剂氯解磷定（2-PAM）递送至脑内的改性阳离子脂质体。脂质体基于磷脂酰胆碱和咪唑鎓表面活性剂制备。为获得在电荷、稳定性和毒性方面优化的组合物，改变了表面活性剂/脂质的摩尔比。对这些体系评估了理化参数、底物（罗丹明B、2-PAM）的释放曲线、溶血活性和引起血凝的能力。脂质体穿越血脑屏障的筛选、2-PAM药代动力学分析及体内AChE复活表明，改性脂质体可轻易进入脑内，并使对氧磷（POX）中毒大鼠脑内的AChE复活25%。首次评估了负载2-PAM的咪唑鎓脂质体减少小鼠脑内神经元死亡的能力。结果表明，静脉注射脂质体2-PAM可显著减少POX诱导的海马神经元死亡。
