Effect of HI-6-loaded brain-targeted metal-organic frameworks on reactivation of central nervous system enzymes.

Abstract

Organophosphate poisoning seriously endangers human life and health. Due to the existence of the blood-brain barrier, most drugs are difficult to reach the effective therapeutic concentration in the brain, thus affecting the effect of central acetylcholine esterase reactivation. The water-soluble antidote HI-6 was encapsulated in lipophilic zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, and then surface-coupled with brain-targeted RVG peptides to prepare RVG-PEG-HI-6@ZIF-8 composite nanoparticles. The BBB-penetrating capacity of RVG-PEG-HI-6@ZIF-8 was evaluated using an established in vitro model featuring BMEC-AS non-contact co-culture in a Transwell apparatus. Subsequently, the acetylcholinesterase (AChE) reactivation efficacy of the nanocomplex was assessed in a dichlorvos (DDVP)-induced poisoning mouse model following both intravenous and intranasal administration routes. The RVG-PEG-HI-6@ZIF-8 nanocomposite exhibited the following characteristics: encapsulation efficiency of (80.74 ± 0.80) %, average particle size of (177.33 ± 2.36) nm, and zeta potential of (18.9 ± 0.2) mV. Verified by in vitro and in vivo experiments, RVG-PEG-HI-6 @ ZIF-8 is superior to other control agents in targeted brain delivery. Compared with intravenous injection, intranasal administration showed a higher AChE reactivation rate (48.35 ± 4.24) %. These results good demonstrate that RVG-PEG-HI-6@ZIF-8 nanocomposites exhibit blood-brain barrier (BBB) penetration capability. Administration through the nasal-brain transport pathway can avoid the limitation of BBB and effectively enhance the reactivation of AChE in the central nervous system after organophosphate exposure.