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.

与第一代红细胞替代品不同，仅利用氧气递送作为治疗靶标。该项目着重于创建能够模仿红细胞酶的氧气和抗氧化活性的产品。没有抗氧化剂活性，例如超氧化物歧化酶（SOD）和过氧化氢酶。基于血红蛋白的产品无法阻止产生氧化剂，例如自由基，来自自动氧化。血红蛋白还可以在体内更容易分解，以在缺血/再灌注引起的氧化剂的情况下释放有毒血红素和铁，这是中风和创伤的常见状况。该项目的目的是开发聚合物共轭多硝基血红蛋白（PolypNH）作为第二代血液替代品，具有过氧化氢酶模拟和模拟抗氧化剂的酶活性和生理氧亲和力。这是通过共价连接多种硝化氧化物来实现的，这些硝酸是血红蛋白上的过氧化氢酶和SOD仿真。在这个阶段I项目中，我们建议（1）准备和表征息肉，（2）通过与淋巴结的血液进行比较，在严重的大鼠出血性休克模型中测试其在血液动力学，消耗和基本缺陷方面的功效。拟议的商业应用：如果成功的话，该项目将导致第二代血液替代品的临床前测试，能够递送氧气并抑制一系列缺血/再灌注损伤。商业化将集中于休克/创伤复苏和其他需要氧气递送和防止再灌注损伤（例如CABG手术）的适应症。