Currently available antidotes against toxic organophosphorus compounds suffer from poor permeability across the blood-brain barrier (BBB) and due to this, are limited in their ability to restore the inhibited acetylcholinesterase (AChE) in the central nervous system (CNS). We designed functionalized detonation nanodiamond nanocarrier platforms to transport quaternary oxime antidotes into CNS. We showed that the nanodiamonds with covalently attached 4-oximinopyridinium moiety, cross the layer of Madin-Darby Canine Kidney (MDCK) cells, the surrogate BBB model, and demonstrate a dose-independent reactivation in vitro towards human AChE inhibited by nerve agents GB and VX, and pesticide paraoxon. Confocal microscopy visualization of tight junctions and actin cytoskeleton in MDCK and Human Umbilical Vein Endothelial Cells (HUVEC) revealed temporary disruption of tight junctions at higher nanoparticle concentrations without compromising cell viability or cytoskeletal integrity. Although reactivation was modest, the nanodiamond platform showed promise for delivering quaternary oxime to the central nervous system (CNS) in vitro. The results reveal the potential of detonation nanodiamonds as a promising delivery platform for charged therapeutic agents to CNS aimed to enhance treatment outcomes in organophosphorus poisoning.

Biomedical Research Center University Hospital Hradec Kralove 581 Sokolska 50005 Hradec Kralove Czech Republic

Biomedical Research Center University Hospital Hradec Kralove 581 Sokolska 50005 Hradec Kralove Czech Republic; Department of Toxicology and Military Pharmacy Military Faculty of Medicine University of Defense 1575 Trebesska 50001 Hradec Kralove Czech Republic

Centre for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove 62 Rokitanskeho 50 003 Hradec Kralove Czech Republic

Department of Chemistry and Biotechnology Tallinn University of Technology 15 Akadeemia Rd 12618 Tallinn Estonia

Department of Chemistry Missouri University of Science and Technology Rolla MO 65409 USA; Department of Materials Science and Engineering Missouri University of Science and Technology Rolla MO 65409 USA

Department of Toxicology and Military Pharmacy Military Faculty of Medicine University of Defense 1575 Trebesska 50001 Hradec Kralove Czech Republic

National Institute of Chemical Physics and Biophysics 23 Akadeemia Rd 12618 Tallinn Estonia

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