NOVEL PEG-HEMOGLOBIN MODIFICATION FOR BLOOD REPLACEMENT

用于血液替代的新型聚乙二醇血红蛋白修饰

• 批准号: 6390382
• 负责人: KIM VANDEGRIFF
• 金额: $ 46.4万
• 依托单位: SANGART, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-05 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390382
• 关键词: blood /plasma substitute; blood pressure; blood transfusion; chemical synthesis; drug design /synthesis /production; hamsters; hemoglobin; laboratory rat; maleimides; microcirculation; osmotic pressure; oxygen transport; polyethylene glycols; thermodynamics; viscosity

The goal of this Phase II proposal is to produce and test a new pegylated hemoglobin solution formulated under Phase I(HL 62818-01) with the long-term goal to commercialize this solution for blood replacement therapies based on oxygen transport and blood expansion properties. Critical physicochemical properties of hemoglobin solutions have been defined that work effectively at blood replacement. This is due to the absence of a vasoconstrictive response, a side-effect that is the rule rather than the exception for commercial hemoglobin-based oxygen carriers now in clinical trials. Key properties for an effective solution are: l) high viscosity, 2) high colloid osmotic pressure, and 3) high oxygen affinity. Phase I research formulated a specific hemoglobin solution using new, maleimide pegylation chemistry. This Phase II application proposes to produce pilot-scale batches of this protein (Specific Aim 1), and to test for in vitro diffusive oxygen transport using an artificial capillary system (Specific Aim 2), evaluation of blood pressure responses, cardiac output, and prevention of tissue hypoxia in a rat model (Specific Aim 3), and evaluation of effects on the microcirculation, including functional capillary density, vessel diameters, direct measurements of intravascular and tissue oxygenation, and NO levels in a hamster model (Specific Aim 4). PROPOSED COMMERCIAL APPLICATIONS: The method to modify hemoglobin with polyethylene glycol has significant potential to be developed into a commercial product for use as a blood replacement fluid. Such a product can be used in emergencies, wartime, or anytime blood is not available. Moreover, this product has the potential to be inexpensive and universally compatible with recipients.

该第二阶段提案的目标是生产和测试根据第一阶段（HL 62818-01）配制的新型聚乙二醇化血红蛋白溶液，长期目标是将该解决方案商业化，用于基于氧气输送和血液扩张特性的血液替代疗法。血红蛋白溶液的关键物理化学特性已被定义，可以有效地进行血液替代。这是由于缺乏血管收缩反应，对于目前处于临床试验中的商业血红蛋白氧载体来说，这种副作用是常见现象，而不是例外。有效解决方案的关键特性是：l) 高粘度，2) 高胶体渗透压，以及 3) 高氧亲和力。第一阶段研究使用新的马来酰亚胺聚乙二醇化化学制剂配制了特定的血红蛋白溶液。该 II 期申请计划生产该蛋白质的中试批次（具体目标 1），并使用人工毛细血管系统测试体外扩散氧运输（具体目标 2），评估大鼠模型中的血压反应、心输出量和预防组织缺氧（具体目标 3），以及评估对微循环的影响，包括功能性毛细血管密度、血管直径、直接测量 仓鼠模型中的血管内和组织氧合以及一氧化氮水平（具体目标 4）。拟议的商业应用：用聚乙二醇修饰血红蛋白的方法具有开发成用作血液替代液的商业产品的巨大潜力。这种产品可以在紧急情况、战时或无法获得血液的任何时候使用。此外，该产品具有价格低廉且与接受者普遍兼容的潜力。