Construction of Hemoglobin-vesicle with long-term in vivo oxygen transporting ability

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The hemoglobin vesicles (HbV) encapsulating hemoglobin (Hb), which binds oxygen reversibly, in the phospholipid vesicle (liposome) function as an artificial oxygen carrier. However, Hb loses an oxygen binding capacity when central iron is oxidized from two valences to three (metHb formation). In this phenomenon, metHb formation (autoxidation) by one electron transfer from the central iron to the bound oxygen and the further metHb formation by the resulting reactive oxygen (peroxide) are taken place in a row. We have found out that a (metHb Hb/L-tyrosine) system eliminates peroxide promptly. In present study, it was confirmed that the hydrogen peroxide elimination system utilizing the peroxidase activity of metHb which uses L-tyrosine as a substrate was effective for suppression of metHb formation. Moreover, we confirmed the remarkable suppression of metHb formation of HbV which included this system in their inner aqueous phase, even if hydrogen peroxide were continuously added to the H … More bV dispersion. When the 20mL/kg of the HbV dispersion was administrated into rats, the half time of metHb formation in this HbV extended till 44 hours in comparison with 14 hours of the conventional HbV. Furthermore, from a novel screening method which measured the reaction rate of ferryl Hb radical with 14 kinds of candidate substances other than Tyr, we found that some derivatives which possesses indore rings such as tryptophane or carboxyl groups showed the suppressive effect higher than Tyr.On the other hand, metHb formation caused from autoxidation does not occur for carbonyl Hb (HbCO). And if we use the phenomenon of the gradual conversion of HbCO into HbO_2 in blood circulation, we can maintain an oxygen carrying capacity by suppressing the metHb formation of HbV containing HbCO. In present study, we measured the change of the metHb formation rate of HbV containing HbCO and clarified that the rate of metHb from the remaining HbO_2 was the same in spite of the differed portion of HbCO. Therefore, it is suggested that gentle metHb formation system can be constructed in accompanied with the elimination of CO from HbCO. As mentioned above, if these dual approaches are paired, it is expected that the metHb formation of HbV can be effectively controlled by in vivo. Less