Model-based evaluation of the microhemodynamic effects of PEGylated HBOC molecules in the rat brain cortex: a laser speckle imaging study

Abstract

Hemoglobin-based oxygen carriers (HBOCs) were developed with the aim of substituting transfusions in emergency events. However, they exhibit adverse events, such as nitric oxide (NO) scavenging, vasoactivity, enhanced platelet aggregation, presently hampering their clinical application. The impact of two prototypical PEGylated HBOCs, Euro-PEG-Hb and PEG-HbO2, endowed by different oxygen affinities and hydrodynamic volumes, was assessed on the cerebrocortical parenchymal microhemodynamics, and extravasation through the blood-brain-barrier (BBB) by laser speckle contrast imaging (LSCI) method and near-infrared (NIR) imaging, respectively. By evaluating voxel-wise cerebrocortical red blood cell velocity, non-invasively for its mean kernel-wise value ( v ¯ RBC ), and model-derived kernel-wise predictions for microregional tissue hematocrit, THt, and fractional change in hematocrit-corrected vascular resistance, R’, as measures of potential adverse effects (enhanced platelet aggregation and vasoactivity, respectively) we found i) no significant difference between tested HBOCs in the systemic and microregional parameters, and in the relative spatial dispersion of THt, and R’ as additional measures of HBOC-related adverse effects, and ii) no extravasation through BBB by Euro-PEG-Hb. We conclude that Euro-PEG-Hb does not exhibit adverse effects in the brain microcirculation that could be directly attributed to NO scavenging.

Research Progress in Oxygen Carrier Design and Application

“…Based on this, attempts have been made to use reagents such as 2-iminothiolane to introduce thiols at the terminal amino residues and surface lysines to achieve MAL-PEG conjugation at noncysteine residues. A series of products based on this PEGylation approach have been successfully developed for preclinical animal studies, such as Hemospan (discontinued), Euro-PEG-Hb, and Sanguinate. , …”

“…Based on this, attempts have been made to use reagents such as 2-iminothiolane to introduce thiols at the terminal amino residues and surface lysines to achieve MAL-PEG conjugation at noncysteine residues. A series of products based on this PEGylation approach have been successfully developed for preclinical animal studies, such as Hemospan (discontinued 24 ), Euro-PEG-Hb, 25 and Sanguinate. 26,27 However, this approach presents two great challenges: (1) Different protein sites react with different efficiencies, and the degree of PEGylation at these residues varies, resulting in very high heterogeneity of the final product; (2) The introduced thiol-reactive sites are often at the α/β dimer interface, resulting in a higher oxygen affinity compared to native Hb, which in turn limits oxygen release.…”

The artificial oxygen carrier erythrocruorin—characteristics and potential significance in medicine

“…. As a consequence, clinical trials have been halted in 2011 [30] and none of the listed polyHbs have been approved for general use by the U.S. Food and Drug Administration (FDA) or European Medicines Agency [15,[31][32][33][34][35][36].…”