Unlike first-generation red cell substitutes that exploit only oxygen delivery as a therapeutic target. This project focuses on creating a product capable of both oxygen delivery and anti-oxidant activity mimicking red cell enzymes. Without antioxidant enzyme activities like superoxide dismutase (SOD) and catalase. hemoglobin-based products cannot prevent the generation of oxidants, e.g. free radicals, from autooxidation. Hemoglobin can also break down more readily in vivo to release toxic heme and iron in the presence of oxidants resulting from ischemia/reperfusion, a common condition in stroke and trauma. The goal of this project is to develop polymeric conjugated polynitroxyl hemoglobin (PolyPNH) as a second- generation blood substitute with catalase-mimetic and SOD-mimetic antioxidant enzyme activities and physiological oxygen affinity. This is accomplished by covalently attaching multiple nitroxides which serve as catalase- and SOD-mimics on hemoglobin. In this Phase I project we propose to (1) prepare and characterize PolyPNH and (2) test its efficacy in terms of hemodynamics, oxygen consumption, and base deficit in a severe rat hemorrhagic shock model by comparing with shed blood.
This project will, if successful, lead toward preclinical testing of a second generation blood substitute capable both of delivering oxygen and inhibiting the array of ischemia/reperfusion injuries. Commercialization would focus on shock/trauma resuscitation and other indications requiring oxygen delivery and protection against reperfusion injury such as CABG surgery.
