ATP-Adenosine-Glutathione Cross-Linked Hemoglobin as Clinically Useful Oxygen Carrier

Abstract

To attenuate hemoglobin's (Hb) intrinsic toxicity, Texas Tech University scientists developed a novel concept of "pharmacologic cross-linking" to formulate an effective oxygen carrier, HemoTech, which consists of purified bovine Hb cross-linked intramolecularly with ATP and intermolecularly with adenosine, and conjugated with reduced glutathione (GSH). In this composition, while ATP prevents Hb dimerization, adenosine permits the formation of homogeneous polymers. ATP also serves as a regulator of blood vessel tone via activation of the P2Y receptor, whereas adenosine counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine A2 and A3 receptors. GSH introduces electronegative charge onto the Hb surface that blocks Hb's transglomerular and transendothelial passage. Besides, GSH shields heme from nitric oxide and reactive oxygen species, thus enhancing vasodilation and lowering Hb prooxidative potential. HemoTech underwent favorable initial pre-clinical testing and proof of medical concept, and is under commercial development by HemoBioTech Inc. HemoTech has entered the regulatory process in the US. Several mandated requirements have already been met, including viral/transmissible spongiform encephalopathy (TSE) clearance validation studies and various pre-clinical pharmacological, pharmacokinetic, toxicological, genotoxicity and efficacy tests. These studies provided further evidence that "pharmacologic cross-linking" of the Hb molecule with ATP, adenosine and GSH, is useful for designing a viable Hb-based oxygen carrier.

Genotoxicity of Different Nanocarriers: Possible Modifications for the Delivery of Nucleic Acids

“…Nanotoxicology studies mechanisms of cytotoxicity of nanomaterials while nanogenotoxicology is focused on analyzing the potential of engineered nanomaterials on damaging DNA. While cytotoxicity of nanocarriers is relatively widely analyzed for different nanomaterials, genotoxicity of nanocarriers were investigated only in limited number of recent publications [3][4][5][7][8][9][10][11][12][13][14][15]. Meanwhile, genotoxicity of drug carriers should be avoided especially for prolonged chronic treatment.…”

Blood Substitutes

“…The chemical modification with ATP, adenosine, and GSH does not interfere with Hb O 2 transport capacity, and provides the Hb molecule with properties that counteract the intrinsic toxic effects of Hb, namely vasoconstriction, oxidative stress, and inflammation. 70 In this HBOC, the ATP stabilizes the Hb tetramer and prevents its dimerization, and adenosine allows the creation of Hb oligomers, 70 in addition ATP and adenosine counteract the vasoconstrictive and proinflammatory properties of acellular Hb, and prevents platelet aggregation. 70 Lastly, GSH shields heme from reactive O 2 species (ROS), and introduces a electronegative charge onto the surface of Hb reducing renal excretion, extravasation, and phagocytociss.…”

“…70 In this HBOC, the ATP stabilizes the Hb tetramer and prevents its dimerization, and adenosine allows the creation of Hb oligomers, 70 in addition ATP and adenosine counteract the vasoconstrictive and proinflammatory properties of acellular Hb, and prevents platelet aggregation. 70 Lastly, GSH shields heme from reactive O 2 species (ROS), and introduces a electronegative charge onto the surface of Hb reducing renal excretion, extravasation, and phagocytociss. 70 Studies by Simoni et al investigated the potential of ATP-ADO-GSH-Hb as an erythropoiesis stimulating agent.…”

Genotoxicity of Different Nanocarriers: Possible Modifications for the Delivery of Nucleic Acids

“…Nanotoxicology studies mechanisms of cytotoxicity of nanomaterials while nanogenotoxicology is focused on analyzing the potential of engineered nanomaterials on damaging DNA. While cytotoxicity of nanocarriers is relatively widely analyzed for different nanomaterials, genotoxicity of nanocarriers were investigated only in limited number of recent publications [3–5, 7–15]. Meanwhile, genotoxicity of drug carriers should be avoided especially for prolonged chronic treatment.…”