Lipid Nano-Vehicles for Cyanide Antagonism: A Mini-Review
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Industrial use of cyanide makes it a common intoxicant in such settings but it is increasingly being encountered in cases of domestic fires due to the burgeoning use of novel synthetics in production processes. Since time is of crucial importance in treating cyanide intoxication, it is essential to use antidotes which are rapid-acting and facile to administer. With this in mind, our group has focused its research efforts towards identifying potential sulphur donors which perform better than those already available. Furthermore, we have focused on improving delivery kinetics of putative antidotes by using biologically relevant lipid nano-vehicles like liposomes and micelles. This review provides a vista to the development and evaluation of such formulations both in vitro and in vivo.
Keywords: Cyanide antagonism, In vitro/in vivo efficacy, Parenteral, Sulphur donor, Liposome, Micelle, Nanoparticle
Apart from intentional use as a chemical warfare agent, cyanide (CN) intoxication is frequently observed in domestic fires . One possible reason for this is the increased use of newly developed synthetics in production of household equipage . Accordingly, increased levels of CN have been observed in nearly two-thirds of fire-related deaths making the case for the use of CN antidotes in the treatment of such patients . Available antidotes include Nithiodote (comprised of a combination of sodium thiosulfate and sodium nitrite) and Cyanokit (hydroxocobalamin) each with its attendant limitations. The primary limitation of Cyanokit is that it requires a high injection volume (>200 ml). The major limitation of sodium nitrite is the formation of excess methemoglobin in certain individuals even at the recommended doses, resulting in methemoglobinemia. Furthermore, the antidotal activity of sodium thiosulfate has limitations due to its small volume of distribution, short biological half-life and high rhodanese dependence . These drawbacks initiate the necessity of developing either alternative antidotes or alternative vehicles for existing antidotes which offer more attractive pharmacodynamic/pharmacokinetic parameters. Within this context, our research group has worked in both directions and identified new CN antagonists as well as novel lipid carriers for the antagonists. The following review summarizes the results of our studies in these endeavors.
Development of new sulphur donors
Efforts directed towards the discovery of novel sulphur donors that demonstrated better reactivity and lipophilicity resulted in the identification of the garlic component dimethyl trisulfide (DMTS) [5,6]. Experiments verifying the potential of DMTS as a CN antagonist were published by Rockwood  in which the authors demonstrated that DMTS converts CN to non-toxic thiocyanate more efficiently than sodium thiosulfate, the component of the existing therapy Nithiodote. Further, the in vivo antidotal efficacies of DMTS were evaluated in a mouse model of CN toxicity. Intramuscular administration of DMTS showed a threefold higher antidotal potency than an equivalent intramuscular dose of sodium thiosulfate.
DMTS is a pale-yellow liquid which is soluble in organic solvents but insoluble in aqueous solvents . This makes it imperative to find appropriate solvent/carrier systems to deliver DMTS in vivo.
Development of nano-vehicles for DMTS
Preliminary approaches to improve in vivo delivery and efficacy of DMTS adapted the use of liposomes as an extension of previous studies which had investigated the efficacies of liposomal encapsulation and co-encapsulation of cyanide antidotes in different combinations . Accordingly, liposomes prepared by using combination of selected lipids were evaluated with regard to their encapsulation efficiency of DMTS with and without Rhodanese as well as thiosulfate. The optimized liposomal preparations were also used in proof-of-concept studies in a mice model of CN toxicity . Results from these experiments demonstrated that DMTS was an effective sulphur donor both in the presence and absence of Rhodanese. This stand-alone efficacy of DMTS as sulphur donor led us to cast about for alternate approaches of packaging DMTS for in vivo delivery.
Accordingly, we decided to test micelles as putative carriers of DMTS. Micelles are spherical structures composed of a hydrophobic core and a hydrophilic corona with sizes ranging from 5 - 50 nm and earlier have been used for delivering anticancer drugs with success . In our studies, micelles were prepared by hydrating polyethylene glycol phosphatidylethanolamine (PEG-PE) block co-polymers with a mixture of DMTS and distilled water. This encapsulation method allowed for a maximal injectable dose of DMTS of 12.5 mg/kg. Intramuscular administration of this formulation allowed mice to tolerate twice the LD50 of CN .
Our experiments have shown the value of DMTS as an efficient antidote for CN toxicity. Moreover, demonstration of the antidotal properties when injected intramuscularly makes it even more attractive as it obviates the need for trained personnel to administer CN countermeasures intravenously. However, its volatile property represents a limiting factor in the applicability of neat DMTS in extant clinical settings. To surmount this difficulty our research efforts are now focused on investigating formulations of DMTS which would ensure storage stability of DMTS and simultaneously improve its pharmacodynamic/pharmacokinetic properties. The cyanide antidote development with the sulphur donor DMTS is an intense and ongoing project nationwide. Efforts are focused on developing newer formulations in order to enhance bioavailability, antidotal efficacy, pharmacokinetics, pharmacodynamics properties, achieving rapid onset of action and making it available for other than intramuscular administration.
- Graham J, Traylor J (2021) Cyanide Toxicity. In: Stat Pearls. Treasure Island (FL): Stat Pearls Publishing. Available online at: https://www.ncbi.nlm.nih.gov/books/NBK507796/
- Borron SW (2006) Recognition and treatment of acute cyanide poisoning. J Emerg Nurs 32(4 Suppl): S12-S18.
- Anseeuw K, Delvau N, Burillo-Putze G, De Iaco F, Geldner G, et al. (2013) Cyanide poisoning by fire smoke inhalation: a European expert consensus. Eur J Emerg Med 20(1): 2-9.
- Petrikovics I, Kiss L, Chou CE, Ebrahimpour A, Kovács K, et al. (2019) Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives, Toxicol Mech Method 29(6): 438-444.
- Petrikovics I, Rockwood GA, Baskin SI (2015a) Dimethyl trisulfide as a potential cyanide antidote. Pending US Patent Application, 14/685,008.
- Petrikovics I, Kovacs K (2015b) Formulations of dimethyl trisulfide as a cyanide antidote. Pending US Patent Application, 14/685,014.
- Rockwood GA, Thompson DE, Petrikovics I (2016) Dimethyl trisulfide: A novel cyanide countermeasure. Toxicol Ind Health 32(12): 2009-2016.
- Ayala‐Zavala JF, González‐Aguilar GA, Del‐Toro‐Sánchez L (2009) Enhancing Safety and Aroma Appealing of Fresh‐Cut Fruits and Vegetables Using the Antimicrobial and Aromatic Power of Essential Oils. J Food Sci 74: R84-R91.
- Petrikovics I, Budai M, Baskin SI, Rockwood GA, Childress J, et al. (2009) Characterization of liposomal vesicles encapsulating rhodanese for cyanide antagonism. Drug Deliv 16(6): 312-319.
- Petrikovics I, Jayanna P, Childress J, Budai M, Martin S, et al. (2011) Optimization of liposomal lipid composition for a new, reactive sulphur donor, and in vivo efficacy studies on mice to antagonize cyanide intoxication. J Drug Deliv 2011: 928626.
- Torchilin VP (2005) Lipid-core micelles for targeted drug delivery. Curr Drug Deliv 2(4): 319-327.
- Kovacs K, Jayanna PK, Duke A, Winner B, Negrito M, et al. (2016) A Lipid Base Formulation for Intramuscular Administration of a Novel Sulphur Donor for Cyanide Antagonism. Curr Drug Deliv 13(8): 1351-1357.