POLYNITROXYL HEMOGLOBIN AS A BLOOD SUBSTITUTE

聚硝酰血红蛋白作为血液替代品

• 批准号: 6211999
• 负责人: Carleton Hsia
• 金额: $ 10万
• 依托单位: SYNZYME TECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6211999
• 关键词: antioxidants; biomaterial development /preparation; biotechnology; blood /plasma substitute; dogs; heme; hemodynamics; hemoglobin; laboratory rat; nitric oxide; oxygen consumption; polyethylene glycols; swine

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.

不像第一代红细胞替代品只利用氧气输送作为治疗目标。这个项目的重点是创造一种既能输送氧气又能模拟红细胞酶抗氧化活性的产品。无超氧化物歧化酶（SOD）、过氧化氢酶等抗氧化酶活性。基于血红蛋白的产品不能阻止氧化剂的产生，例如自由基，从自氧化。由于缺血/再灌注（中风和创伤的常见情况），血红蛋白在体内也更容易分解，释放出有毒的血红素和铁。本项目的目标是开发聚合物共轭多硝基血红蛋白（polyypnh）作为第二代血液替代品，具有模拟过氧化氢酶和模拟sod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作为过氧化氢酶和sod模拟物共价附着在血红蛋白上来实现的。在本一期项目中，我们拟(1)制备PolyPNH并对其进行表征；(2)在重症大鼠失血性休克模型中，通过与流出血对比，测试其在血流动力学、耗氧量和碱基亏缺方面的功效。建议的商业应用：该项目如果成功，将进行第二代血液替代品的临床前测试，该血液替代品既能输送氧气，又能抑制一系列缺血/再灌注损伤。商业化将集中在休克/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，如冠状动脉搭桥手术。