Available on-demand - S.NM01.10.06
Oxime-Functionalized Nanodiamonds as a Platform for Treatment of Organophosphate Poisoning
Yevgen Karpichev1,Denys Bondar1,Pavel Starkov1,Ivo Heinmaa2,Ondrej Soukup3,Daniel Jun4,Kamil Kuca3,Vadym Mochalin5
Tallinn University of Technology1,National Institute of Chemical Physics and Biophysics2,University of Hradec Kralove3,University of Defence4,Missouri S&T5
Nanodiamonds (ND) have emerged since about a decade ago as a key platform for many developments in nanoscience and nanotechnology due to their outstanding mechanical performance, biocompatibility and unique properties. The NDs bearing biologically active fragments or immobilized on biomolecules are remarkably suitable for biomedical application . Recently, NDs were reported to affect endothelial permeability to deliver anticancer drugs [2, 3].
The main strategy to manage acute poisoning with organophosphorus agents include, either for pre-treatment or for ex-post therapy, administration of oxime AChE reactivator, along with atropine and anticonvulsant drug. The reactivators based on mono- or bis-pyridinium scaffold are not able to diffuse readily into the central nervous system to restore activity of inhibited AcChE. A challenging issue is to design a scaffold providing as high antidotal efficiency towards inhibited AcChE as quaternary oximes along with their ability to come across the blood-brain barrier (BBB).
The NDs with a surface modified with the pyridinium oxime moieties have been synthesized. Using carboxylated NDs (ND-COOH) as starting material, there was elaborated method of attaching 4-oximino pyridinium (4-PAM) fragment via variable linkers. The amino-PEG3-amine linker has been selected for studying counterion effect on the modified ND properties. Using 3-chloropropionyl chloride instead of 2-bromoethyl bromide sufficiently increases yield and purity of the final material. The FTIR, elemental analysis, and solid state NMR (13C MAS and 13C CP-MAS) confirm the structure of the substituents and conversion of ND-COOH.
Following our green chemistry approach applied recently for the synthesis of inherently biodegradable ionic liquid-derived oxime surfactants  and antidotes , the closed bottle test was adapted to estimate biodegradability of the organic material covalently attached to of the nanoparticle and therefore evaluate potential impact of the transformation products on the environment.
The MDCK assay, an example of the tight junction cell line modelling BBB, has been selected to evaluate the ability of oxime-modified NDs to diffuse from the donor compartment through the MDCK cell membrane into the acceptor compartment. An separate experiment included noncovalent loading of the quaternary oximes on the ND-COOH. Concentrations of HI-6 or 2-PAM in acceptor wells (when the cell monolayer was exposed to NDs) were not elevated in comparison to untreated cell monolayers showing that noncovalent binding is not effective enough to come across the cellular barrier, compared to covalently bound oxime-functionalized NDs.
The AcChE reactivation have been performed against three toxic OP: banned insecticide paraoxon and two CWA – sarin (GD) and VX. Our study demonstrates that, as compared to obidoxime, 800 μg/ml of Ox-ND (bromide salt) demonstrate 25-30% of its activity (taken as 0.1 mM aq. solution). For GD and paraoxon, the reactivation with 800 μg/ml is similar to that in the presence of 400 μg/ml; for VX, obidoxime reveals 3 times higher percentage of reactivation. Switching to chloride remarkably elevates the antidotal potency.
The molecular docking was applied to estimate optimal distance between the oxime moieties attached to the ND and spacer properties (length, hydrophobicity, rigidity) to get the active cite of human AcChE and act as the antidote.
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