SBIR-STTR Award

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.

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.