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Radioprotection by Mitochondria Targeted Nitroxides

Detailed Technology Description

None

*Abstract

Ionizing irradiation induces apoptosis of cells, tissues, and organs causing significant toxicity. A central step in the mechanism of irradiation apoptosis is damage to the mitochondria through the action of free radicals and reactive intermediates of peroxidase complexes of cytochrome c with a mitochondria-specific phospholipid, cardiolipin, at the level of the mitochondrial membrane. Nitroxides are a class of compounds which act as electron and radical scavengers and can decrease irradiation toxicity in some tissue culture and animal model systems. However, a central problem in efficient use of nitroxides is the problem of biodistribution. Getting enough nitroxides to a subcellular level of the mitochondria often requires employment of a very high concentration and can produce significant toxicity of the drug itself. Targeting of nitroxides has been shown to increase attached drug delivery to mitochondria and improve therapeutic efficacy in the use of nitroxides in amelioration of hemorrhagic shock. The inventors have discovered that mitochondria targeted nitroxides are a highly effective counter measure against ionizing irradiation damage. In cells in culture, tissues of a mouse model system, mitochondria targeted nitroxides have shown significant protection against ionizing irradiation induced damage. Furthermore, in cell culture studies and in vivo models, the molecular mechanism of action of mitochondria targeted nitroxides has been shown to be at the level of inhibition of oxidation of a mitochondria-specific phospholipid, cardiolipin, by cytochrome c/cardiolipin complexes. This protection of cardiolipin against oxidation is critical to maintenance of intact mitochondrial function and prevention of apoptosis.Applications1) Radioprotectants when administered prior to exposure2) Mitigators, if administered after exposure3) Protects tissues against total body irradiation4) Therapeutic agents to protect normal tissues against irradiation damage and necrosis during radiotherapyAdvantages1) Allows a larger dose of anti-tumor irradiationRelated TechnologyID 1198-Gramicidin S based Mitochondrial Targeting AgentsPCT Patent Application filed

*Principal Investigator

Name: Natalia Belikova, Postdoctoral Associate

Department: GSPH-Environmental/Occupational Health

Name: Michael Epperly, Associate Professor

Department: Med-Radiation Oncology

Name: Joel Greenberger, Professor & Chairman

Department: Med-Radiation Oncology

Name: Jian Jiang

Department: GSPH-Environmental/Occupational Health

Name: Valerian Kagan, Professor and Vice Chairman

Department: GSPH-Environmental/Occupational Health

Name: Joshua Pierce, student

Department: A&S-Graduate Office

Name: Peter Wipf, Professor

Department: Chemistry

Country/Region

USA