Intracellular ATP Delivery Using Highly Fusogenic Liposomes

Healthy cells must maintain a high content of adenosine triphosphate (ATP) because almost all energy-requiring processes in cells are driven, either directly or indirectly, by hydrolysis of ATP. During ischemia or hypoxia, reduced blood flow or disturbed oxygen supply results in the disrupted balance of energy production and utilization, and depletion of high-energy phosphates is the fundamental cause of cell damage. Direct intravenous infusion of high-energy phosphates, such as adenosine triphosphate (ATP), has not produced a consistent result because strongly charged molecules like ATP normally cannot pass the cell membrane in sufficient quantities to satisfy tissue metabolic requirements. Furthermore, the half-life of free ATP in blood circulation is very short, limiting its efficacy as a bioenergetic substrate. We have developed a new technique for intracellular delivery of high-energy phosphate into normal or ischemic cells by using specially formulated, highly fusogenic, unilamellar lipid vesicles that contain magnesium-ATP. In vitro studies indicated a rapid fusion with the endothelial cells, protection of endothelial cells, and cardiomyocytes during ischemia. In vivo studies have shown enhanced full-thickness skin wound healing in various animal models. This technique has the potential to reduce or eliminate many detrimental effects caused by ischemia or hypoxia.