Optimization of Liposomal Lipid Composition for a New, Reactive Sulfur Donor, and In Vivo Efficacy Studies on Mice to Antagonize Cyanide Intoxication

Abstract EN

Present studies have focused on a novel cyanide antidotal system, on the coencapsulation of a new sulfur donor DTO with rhodanese within sterically stabilized liposomes.

The optimal lipid composition for coencapsulation of DTO with rhodanese is the combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, cholesterol, cationic lipid (DOTAP), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] ammonium salt (with molar ratios of 82.7 : 9.2 : 3.0 : 5.1).

With the optimized compositions, prophylactic and therapeutic in vivo efficacy studies were carried out in a mice model.

When DTO was coencapsulated with rhodanese and thiosulfate the prophylactic antidotal protection was 4.9×LD50.

Maximum antidotal protection against cyanide intoxication (15×LD50) was achieved with coencapsulated rhodanese and DTO/thiosulfate in combination with sodium nitrite.

When applied therapeutically, 100% survival rate (6/6) was achieved at 20 mg/kg cyanide doses with the encapsulated DTO-rhodanese-thiosulfate antidotal systems with and without sodium nitrite.

These data are indicating that the appropriately formulated DTO is a promising sulfur donor for cyanide antagonism.