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A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate
- Publication Year :
- 2024
-
Abstract
- Kathleen F Pirollo,1 Manish Moghe,1 Miaoyin Guan,1 Antonina S Rait,1 Aibing Wang,1 Sang-Soo Kim,1,2 Esther H Chang,1 Joe B Harford2 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA; 2SynerGene Therapeutics, Inc., Potomac, MD, 20854, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Tel +1 202 687 8418, Email change@georgetown.eduIntroduction: 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 bloodâbrain 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 bloodâbrain 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 de
Details
- Database :
- OAIster
- Notes :
- text/html, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1419105840
- Document Type :
- Electronic Resource