Albumin-Heme

   Entirely synthetic oxygen carriers without using hemoglobin (Hb) have also been developed. In particular, recombinant human serum albumin (rHSA) containing synthetic heme, so called albumin-heme, is the most promising material as a new class of oxygen infusion for clinical use with good solution properties and biocompatibility. Human serum albumin is the most abundant plasma protein (ca 60%) in our blood stream and is a very common simple protein studied widely so far. However, since its crystal structure was revealed by Carter et al. in 1989, albumin has been suddenly focused on again in many research fields. Furthermore, advances in genetic engineering enable production of a mass of rHSA by inserting relevant human genes into the methylotropic yeast Pichia pastoris. A large manufacturing plant with a capability of one million vials production per year has already been constructed, and rHSA will be appearing on the Japanese market within a few years.

   We have recently found that synthetic heme with a covalently linked proximal base is easily incorporated into the rHSA molecule, and the obtained hemoprotein can bind and release oxygen reversibly under physiological conditions similar to Hb (Fig. 4).

Fig. 4 Character and structure of albumin-heme

   The maximal binding number of FeP was determined to be eight, which is twice that of Hb s. The highly-ordered structure, surface charge distribution, and solution properties of the rHSA host are not changed after incorporation of FeP. The oxygen-binding affinity is almost identical to that of the red blood cell, and its value can be regulated by the chemical structure of FeP. The exchange transfusion test with hemorrhagic animals demonstrated that it satisfies the initial clinical requirements for an oxygen-carrying resuscitative fluid.

   The administration of extracellular Hb-based oxygen carriers often elicits an acute increase in blood pressure due to vasoconstriction. This side effect is now recognized to be due to the depletion of nitric oxide (endothelial-derived relaxing factor) by the extravasuated Hbs. On the contrary, the infusion of this rHSA-based oxygen carrier does not induce such a hypertensive action, because of its low permeability through the vascular endothelium. Moreover, small particles of rHSA-FeP show quite good efficacy for oxygenation of a hypoxic region in a solid tumor.

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