Encapsulation of oxime acetylcholinesterase reactivators: influence of physiological conditions on the stability of oxime-cucurbit[7]uril complexes

Abstract

Oxime-based acetylcholinesterase reactivators are a specific group of drugs used for the treatment of organophosphate intoxication. However, high hydrophilicity and poor blood–brain barrier penetration limit their physiological potential. Cucurbit[7]urile (CB[7]) was used in this work as a potential carrier of oxime molecules to increase their treatment effectiveness. The host–guest chemistry of CB[7] with five clinically used oximes (trimedoxime, asoxime, obidoxime, pralidoxim and methoxime) and two new pre-clinical oximes (K027 and K048) was characterized under simulated physiological conditions using titration experiments with UV-vis detection. CB[7] forms stable complexes of 1 : 1 stoichiometry with all tested oximes. The decrease of complex stability was observed at a pH above the pK_a of oxime, which limits the applicability of the complexation for oximes with pK_a below the physiological pH. The combination of physiological ionic strength and pH causes partial decrease of the complex stability. The effect of organic solvent used in the sample pretreatment step before spectral analysis of oxime–CB[7] complexes in biological samples was demonstrated. Methanol is a more suitable solvent with low effect on complex stability. Finally, the ability of mass spectrometry with electrospray ionization was demonstrated for the analysis of oxime–CB[7] complexes.