Direct intracellular ATP delivery for treatment of cyanide intoxication

Abstract

Cyanaide directly poisons the cellular respiratory mechanism, leading to cellular hypoxia and death. The aim of this study was to determine the effect of a newly developed direct intracellular ATP delivery technique, ATP encapsulated unilamellar fusogenic lipid vesicles (ATP-Vesicle), on rat with cyanide poisoning. Methods. ATP-Vesicle was prepared by lecithin, fusogenic agents, and sonication. There were five groups to be studied: 1, (ATP-Vesicle); 2, (lipid vesicles); 3, (ATP); 4, (saline); and 5, (lipid vesicle + ATP). Adult Sprague Dawley rats were anesthetized. The carotid artery and jugular vein were cannulated. ATP-Vesicle or other solutions were injected intraperitoneally 3 min prior to intravenous potassium cyanide (KCN) infusion (10 mg/kg/h).The survival time and dose of KCN injected were recorded. Results. The survival time and the fatal dose of KCN in rats treated with ATP-Vesicle were significantly longer (47 min) and higher (7.6 mg/kg/h) than that of other groups (Table). TABLE—ABSTRACT 82 Group ATP-vesicle Vesicle ATP Saline Vesicle + ATP Surv. T (min) 46.6 ± 4.9 ∗ 33 ± 2.8 33.4 ± 2.8 32.4 ± 2.7 27.3 ± 1.6 KCN (mg) 7.6 ± 0.8 ∗ 5.5 ± 0.5 5.6 ± 0.5 5.4 ± 0.6 4.6 ± 0.3 Note. Table n = 10; ∗ p < 0.05 as compared to other groups. Discussion. Humans may encounter cyanide in industrial chemicals, natural products, medications, combustion products, and terrorist attacks. Cyanide induced threatening symptoms resulted in permanent sequelae, and even death has been reported. We developed a new intracellular ATP delivery system, in which ATP is encapsulated in small unilemellar fusogenic lipid vesicles (ATP-Vesicle). This system can deliver ATP directly into the cytosol at sufficient rates to meet the energy demand of the cells. Our study demonstrated that animals treated with ATP-Vesicle could survive longer under higher KCN intoxication. It indicated that ATP-Vesicle could deliver ATP directly into cells to keep animals alive during chemical hypoxia induced by KCN. Our study may open a new field in the treatment of ischemic or hypoxic diseases.