MP4, a new nonvasoactive polyethylene glycol-hemoglobin conjugate

A new hemoglobin derivative, MP4, for use as a temporary oxygen-carrying plasma expander, has been prepared. The design of the molecule is based on novel criteria for optimized efficacy and safety, which include increased molecular radius, increased viscosity, increased oncotic pressure, and reduced p50. The chemical entity, MalPEG-Hb, is formulated at 4.2 g/dL in lactated Ringer's solution (MP4). It has a p50 of 5-6 mm Hg, oncotic pressure of 49 mm Hg and viscosity of 2.2 cPs. After 50% exchange transfusion with MP4, rats survive a 60% controlled hemorrhage in spite of total hemoglobin of 7.8 g/dL and plasma hemoglobin concentration of 1.6 g/dL. Although its binding affinity for NO is not different from that of purified hemoglobin A, it does not produce hypertension in a number of animal models and does not cause vasoconstriction in hamster microcirculation. Oxygen supply to tissue has been confirmed by direct observation in the hamster skinfold model, in which O2 release in precapillary and capillary vessels was quantified. The data demonstrate that the effectiveness of MP4 results from its ability to conserve O2 in precapillary vessels and release O2 in capillaries, thereby "targeting" O2 to hypoxic tissue. Preservation of functional capillary density and prevention of vasoconstriction further contribute to the effectiveness of this new formulation. MP4 is currently being tested in humans.