NOVEL PEG-HEMOGLOBIN MODIFICATION FOR BLOOD REPLACEMENT

该II期提案的目标是生产和测试一种新的聚乙二醇化血红蛋白溶液（HL 62818-01），其长期目标是将该解决方案商业化，用于基于氧运输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性质已经被定义为在血液替代中有效工作。这是由于没有血管收缩反应，这是一种副作用，而不是目前临床试验中基于血红蛋白的商业氧载体的例外。有效溶液的关键特性是：1)高粘度，2)高胶体渗透压，3)高氧亲和力。第一阶段的研究使用新的马来酰亚胺聚乙二醇化化学配方了一种特殊的血红蛋白溶液。该II期申请拟生产该蛋白的中试批量（Specific Aim 1），并使用人工毛细血管系统测试体外弥漫性氧运输（Specific Aim 2），评估血压反应、心输出量，并在大鼠模型中预防组织缺氧（Specific Aim 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、血管内和组织氧合的直接测量。和NO水平在仓鼠模型（特异性Aim 4）。建议的商业应用：用聚乙二醇修饰血红蛋白的方法有很大的潜力被开发成商业产品，用作血液替代液。这种产品可以在紧急情况下使用，战时，或任何时候血液不可用。此外，该产品具有价格低廉和普遍兼容的潜力。

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.