Adam Carie and Jonathan Rois-Doria contributed equally to this work.
The specific treatment of cyanide (CN) intoxication means the use of scavengers (e.g., methemoglobin former sodium nitrite (SN) or cobalt compounds or cyanohydrin formers, hydroxocabalamin (Cyanokit has been approved in the US), cobinamide [1], and/or the conversion of CN to the less toxic thiocyanate (SCN) with exogenously administered GSK343 sulfane sulfur and sulfurtransferase enzymes [2–4]. Rhodanese (Rh) is the best characterized multifunctional, mitochondrial sulfurtransferase [5–8] catalyzing the transfer

of a sulfane sulfur atom from a donor molecule to cyanide. Determining the exact role of nitrite in cyanide antagonism is not clearly Inhibitors,research,lifescience,medical understood yet. Earlier studies were focusing on the methemoglobin-forming effect of nitrite that act as a scavenger by forming a relative stable complex Inhibitors,research,lifescience,medical of cyanomethemoglobin [3, 4]. Very recent studies are focusing on the mitochondria-linked mechanism of nitrite as a nitric oxide donor [9–11]. Extensive researches are also focusing on developing effective sulfur-containing Inhibitors,research,lifescience,medical compounds serving as sulfur donors for reacting with CN with or without Rh. Thiosulfate (TS) is the classical sulfur compound found to participate in the

enzyme reaction [3, 4, 12]. However, TS has limited ability to reach the endogenous Rh enzyme because of a nearly exclusive extracellular distribution [13]. Baskin et al., reported results on the efficacy of various sulfur donors demonstrating that altering the chemical substituent Inhibitors,research,lifescience,medical of the longer chain sulfide modified the ability of the candidate molecule to protect against CN toxicity [14]. Earlier investigations were focused on administration of free Rh and the sulfur donor (SD) directly into the bloodstream [15–18]. Unfortunately, the free Rh enzyme was rapidly destroyed

by the body’s immune system, which makes the efficacy Inhibitors,research,lifescience,medical of this approach quite limited. To overcome the limitations for the circulating free Rh, micro- or nanosized carrier systems among others sterically stabilized unilamellar liposomes of ~100–150nm diameter are in either the focus of recent encapsulation efforts [19]. The encapsulation of Rh with a sulfur compound into liposomes—the so-called coencapsulation—can offer further advantages. Over stability enhancement for Rh the coencapsulation can provide better overall conversion of CN, since the basis component for enzyme reaction, the sulfur donor no longer has to penetrate the liposome membrane. The lipid composition has a significant impact on the encapsulation efficiency of the Rh and/or sulfur compound and on the in vivo stability and antidotal effect of the carrier system [19]. Thus, optimization of the liposomal composition is an inevitable step in the design of novel antidotal systems. Present work deals with a new lipophilic sulfur-containing compound, developed at the US Army Medical Research Institute of Chemical Defense, called DTO.