NOVEL PEG HEMOGLOBIN MODIFICATION FOR BLOOD REPLACEMENT

第一阶段的目标是设计一种新型的血红蛋白分子，作为氧载体安全有效地工作。长期目标是根据氧气输送和血容量扩张的功效优化这些血液替代疗法解决方案。化学品必须具有商业化的成本效益。在第一阶段，我们描述了一种新的化学方法，用于将合成的聚乙二醇聚合物（PEG）特异性地、可控地附着在血红蛋白分子的表面。血红蛋白溶液的关键物理化学性质已被定义，可有效用于血液替代。这主要是由于对这些溶液没有血管收缩反应，这是目前临床试验中商业血红蛋白氧载体的规则而不是例外的副作用。关键的物理化学性质是：I）高粘度，2）高胶体渗透压，和3）高氧亲和力。实现这一目标的战略已经确立。第一阶段研究将把PEG表面附着的数量与PEG链的长度相关联，以优化这些特性。II期设计用于在体外测试这些制剂的扩散氧转运和在体内测试这些制剂的组织氧合维持。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品的商业产品的显著潜力。这种产品可以在紧急情况下使用，战争时期，或任何时候血液无法获得。此外，该产品具有价格低廉和与接受者普遍相容的潜力。

The goal of Phase I is to design a new class of hemoglobin molecules that work safely and effectively as oxygen carriers. The long-term goal is to optimize these solutions for blood replacement therapies based on efficacy of oxygen transport and expansion of blood volume. The chemistry must be cost-effective for commercialization. In Phase I, we describe a new chemistry for specific, controlled attachment of synthetic polyethylene glycol polymers (PEG) to the surface of the hemoglobin molecule. Critical physicochemical properties of hemoglobin solutions have been defined that work effectively at blood replacement. This is due primarily to the absence of a vasoconstrictive response to these solutions, a side-effect that is the rule rather than the exception in commercial hemoglobin-based oxygen carriers that are in clinical trials today. The key physicochemical properties are: I) high viscosity, 2) high colloid osmotic pressure, and 3) high oxygen affinity. The strategy to achieve this objective is already well- established . Phase I research will correlate number of PEG surface attachments versus length of PEG chains to optimize these properties. Phase II is designed to test these formulations in vitro for diffusive oxygen transport and in vivo for maintenance of tissue oxygenation. 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. Such a product can be used in emergencies, war time, or any time blood is not available. Moreover, this product has the potential to be inexpensive and universally compatible with recipients.