A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate.

Introduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride ( a.k.a ., pralidoxime or 2-PAM). However, this compound does not cross the blood-brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain.
Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood-brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity.
Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase.
Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.
Competing Interests: E.H.C. and K.F.P. are two of the inventors of the described scL technology, for which several patents owned by Georgetown University have been issued. The patents have been licensed to SynerGene Therapeutics, Inc. for commercial development. K.F.P. serves as Principal Investigator for research at Georgetown University that is supported by SynerGene Therapeutics, Inc. E.H.C. owns an equity interest in SynerGene Therapeutics, Inc., and E.H.C. and A.R. serve as paid scientific consultants to SynerGene Therapeutics, Inc. S.S.K. is salaried employee of SynerGene Therapeutics, Inc. M.M. is a graduate student and M.G. an undergraduate student who were supported via a research agreement between Georgetown University and SynerGene Therapeutics, Inc. A.W. is a former paid employee of SynerGene Therapeutics, Inc. J.B.H. serves as salaried President & CEO of SynerGene Therapeutics, Inc. and owns stock in same. The authors report no other conflicts of interest in this work.
(© 2024 Pirollo et al.)