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).
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.
| Winslow, Robert M (2005) Targeted O2 delivery by low-p50 hemoglobin: a new basis for hemoglobin-based oxygen carriers. Artif Cells Blood Substit Immobil Biotechnol 33:1-12 |
| Drobin, Dan; Kjellstrom, B Thomas; Malm, Elisabeth et al. (2004) Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4). J Appl Physiol 96:1843-53 |
| Winslow, Robert M (2004) MP4, a new nonvasoactive polyethylene glycol-hemoglobin conjugate. Artif Organs 28:800-6 |
| Winslow, Robert M; Lohman, Jeff; Malavalli, Ashok et al. (2004) Comparison of PEG-modified albumin and hemoglobin in extreme hemodilution in the rat. J Appl Physiol 97:1527-34 |
| Winslow, R M (2003) Current status of blood substitute research: towards a new paradigm. J Intern Med 253:508-17 |
| Vandegriff, Kim D; Malavalli, Ashok; Wooldridge, Jerod et al. (2003) MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion 43:509-16 |
