POLYNITROXYL HEMOGLOBIN AS A BLOOD SUBSTITUTE

与仅利用氧气输送作为治疗靶点的第一代红细胞替代品不同。该项目专注于创造一种能够提供氧气和模拟红细胞酶的抗氧化活性的产品。没有抗氧化酶活性，如超氧化物歧化酶和过氧化氢酶。以血红蛋白为基础的产品不能防止氧化剂的产生，例如自由基的自氧化。在缺血/再灌流引起的氧化剂存在的情况下，血红蛋白在体内也更容易分解，释放出有毒的血红素和铁，这是中风和创伤中的常见情况。本项目的目标是开发聚合物共轭多氮氧血红蛋白(PolyPNH)作为第二代血液替代品，具有模拟过氧化氢酶和模拟超氧化物歧化酶的抗氧化酶活性和生理氧亲和力。这是通过将多个氮氧化物共价连接到血红蛋白上实现的，这些氮氧化物是过氧化氢酶和超氧化物歧化酶的模拟物。在这个第一阶段的项目中，我们建议(1)制备和表征PolyPNH，并(2)通过与失血性休克模型的比较，从血流动力学、氧耗和碱缺乏方面测试PolyPNH的有效性。拟议的商业应用：如果该项目成功，将导致第二代血液替代品的临床前测试，该替代品既能输送氧气，又能抑制一系列缺血/再灌注损伤。商业化将侧重于休克/创伤复苏和其他需要氧气输送和防止再灌注损伤的适应症，如CABG手术。

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. PROPOSED COMMERCIAL APPLICATIONS: 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.