Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.

中文翻译：

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将肟 K027 封装到葫芦 [7] 脲中：安全性、吸收、大脑分布和再激活有效性的体内评估

基于肟的乙酰胆碱酯酶再激活剂（简称肟）再生有机磷灭活的乙酰​​胆碱酯酶并恢复其功能。较差的血脑屏障通道和从血液中快速清除限制了它们在治疗暴露于有机磷的患者中的实际应用。先前的体外结果表明进一步测试葫芦 [7] 脲作为双季铵肟的递送载体。本论文的重点是细胞毒性、体内安全性以及葫芦 [7] 脲对肟药代动力学和药效学的影响。在测试浓度下，K027 和复合物均未引起任何细胞毒性、血液生化变化或肝或肾毒性。K027 的封装增加并加速了血脑屏障的渗透。外周肟暴露也增加，支持葫芦[7] uril 保护循环肟免受快速肾清除的建议。与 K027 和封装的 K027 的体外再激活能力相当，我们未能在体内证实这一点。从理论上讲，这可能是由于分子与葫芦 [7] 脲的非特异性结合或 K027 与葫芦 [7] 脲的相互作用对于乙酰胆碱酯酶的再激活作用太强。精确的解释需要额外的计算机、体外和体内实验。这可能是由于分子与葫芦 [7] uril 的非特异性结合或 K027 与葫芦 [7] uril 的相互作用对于乙酰胆碱酯酶的重新激活太强了。精确的解释需要额外的计算机、体外和体内实验。这可能是由于分子与葫芦 [7] uril 的非特异性结合或 K027 与葫芦 [7] uril 的相互作用对于乙酰胆碱酯酶的重新激活太强了。精确的解释需要额外的计算机、体外和体内实验。