The highly toxic inorganic cyanide (CN) inhibits aerobic cellular respiration by binding to cytochrome C oxidase of the mitochondrial electron transport chain, thus it can induce histotoxic hypoxia, lactic acidosis, and ultimately death. Currently, there are two intravenously delivered therapeutic agents to combat CN intoxication available in the United States: Nithiodote™ and Cyanokit®. Dimethyl trisulfide (DMTS) is a potent sulfur donor type CN antidote that can readily transverse through the blood-brain barrier (BBB) and react with CN to form the less toxic thiocyanate. Thiocyanate can then be excreted through the urine. DMTS is used as a flavor enhancer and food additive in the food industry. It is also present in vegetables such as broccoli, cabbage, cauliflower, onion, and in the highest concentration in garlic. The ultimate goal of recent investigations is to deliver formulated DMTS via intramuscular injection to combat CN intoxication in cases of a mass scenario. The BBB penetration and the particle size distribution of the two DMTS formulations, FF-DMTS and Poly 80-DMTS, were characterized using Parallel Artificial Membrane Permeability Assay (PAMPA) and the dynamic light scattering particle analyzer Zetasizer Nano. As measured via PAMPA, FF-DMTS had a lag time of 2.00 minutes and an apparent permeability of 7.5E-6 ±2.25E-6 cm/s. The Poly 80-DMTS formulation had a lag time of 2.05 minutes and an apparent permeability of 12E-6 cm/s. The particle size for the Poly 80-DMTS formulation had a diameter of 4.275 ±2.07 nm, which contributed to 100% of the light scattered. For the FF-DMTS formulation, a particle size of a diameter of 15.77 ±6.03 nm contributed to 99% of the light scattered.

Characterization of blood-brain barrier penetration and particle size distribution of two formulations of the cyanide antidote candidate dimethyl trisulfide

ACS Spring Meeting 2021

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