MP4, a vasodilatory PEGylated hemoglobin

Abstract

A vasodilatory hemoglobin (Hb)-based O2 carrier (HBOC) has been developed by surface conjugation polyethylene glycol to tetrameric human Hb (MP4, Sangart, San Diego). Because the NO-binding kinetics of MP4 are similar to vasoconstrictiveHBOCs, we propose that the decoupling of NO scavenging from vascular response is a consequence of MP4's high O2 affinity (p50 = 5 mmHg) and unique surface chemistry. The release of ATP from erythrocytes is vasodilatory and the application of a high O2 affinity HBOC minimizes ATP interference with intravascular ATP signaling. 1 A second potential mechanism of action for MP4 involves the surface conjugation of polyethylene glycol (PEG) to tetrameric human Hb. It has been shown that the addition of unconjugated high molecular weight (Mw) PEG to cultured lung endothelial cells causes an immediate and significant reduction in endothelial permeability; an effect opposite to that of endothelial agonists such as cell-free Hb. 2 It appears that some of the benefits of the PEG-endothelium interaction are carried onto molecules such as PEGylated Hb and PEGylated albumin, as demonstrated by favorable hemodynamic responses in vivo. PEGylation of β93 cysteine residues, as in MP4, has also been reported to increase the nitrite reductase activity of Hb and enhance conversion of endogenous nitrite to bioactive NO.3 © 2011 Springer Science+Business Media, LLC.