Modulation of the polyethylene glycol-hemoglobin structure to increase the efficiency of plasma expansion and O2carrying capacity

SUMMARY Polyethylene glycol (PEG) surface decoration of hemoglobin (Hb) is being developed as a design strategy for generating an oxygen carrier with optimal plasma expansion characteristics and maintenance of microvascular function. HexaPEGylated Hb using six copies of 5 kDa PEG provides excellent tissue perfusion when used to correct blood volume losses at a plasma concentration of 2 g Hb/dL (as compared with unPEGylated Hbs used at 6–9 g Hb/dL). Efficacy attained with limited concentration of Hb allows effective use of available Hb obtained from outdated blood. However, the high oxygen affinity of PEG-Hb in combination with its low plasma concentration limits the effective oxygen delivery capacity, impacting tissue oxygenation. This problem can be remedied either by lowering oxygen affinity of PEG-Hb or by increasing its concentration in the circulation. PEGylation of low oxygen affinity intramolecularly cross-linked Hbs, for example αα-fumaryl-Hb, lowers oxygen affinity and modulating the pattern of PEGylation (size and number of PEG-chains to lower the colloidal osmotic pressure of PEG-Hb) reduces the tendency to dilute the PEG-Hb concentration in circulation because of fluid shifts into the intravascular volume. Novel chemistry platforms for PEGylation set the stage for next generation lower oxygen affinity PEGylated Hbs that optimizes oxygen delivery and tissue perfusion.