Hemoglobin Encapsulated Poly(Ethylene Glycol) Surface Conjugated Vesicles Attenuate Vasoactivity of Cell-Free Hemoglobin

Abstract

Widespread clinical use of acellular hemoglobin (Hb)-based O2 carriers (HBOCs) has been hampered by their ability to elicit both vasoconstriction and systemic hypertension. This is primarily due to the ability of acellular Hb to extravasate through the blood vessel wall and scavenge endothelial-derived nitric oxide (NO). Encapsulation of Hb inside the aqueous core of liposomes retards the rates of NO dioxygenation and O2 release, which should reduce or eliminate the vasoactivity of Hb. Our aim is to determine the extent of systemic and microvascular vasoactive responses (hypertension, vasoconstriction and hypoperfusion) after infusion of vesicle encapsulated Hbs, in which the encapsulated Hb is in either the deoxygenated or carbon monoxide (CO) state (HbV and COHbV, respectively). To investigate this hypothesis, we used the hamster window chamber model subjected to two successive hypervolemic infusions of HbV and COHbV solutions (each infusion represents 10% of the animal’s calculated blood volume) at Hb concentrations of either 7 or 10 g/dL. The hypervolemic infusion model used in this study has all the regulatory mechanisms responsible for predicting the vasoconstrictive responses of HBOCs. The results of this study demonstrate the absence of vasoconstrictive and hypertensive responses upon single and multiple infusions of HbV and COHbV solutions. The HbV and COHbV solutions increased the plasma O2 carrying capacity. However, COHbV delivered low therapeutic levels of CO without inducing any microcirculatory disturbances. Significance: Vesicles containing Hb can be used as a new therapeutic agent in transfusion medicine to treat anemia and revert hypoperfusion.

Nanovesicular liposome-encapsulated hemoglobin (LEH) prevents multi-organ injuries in a rat model of hemorrhagic shock

“…LEH also belongs to this lineage which could overcome several of the drawbacks associated with the oxygen carriers presenting naked hemoglobin in polymerized or PEGylated form. Compared to these acellular hemoglobin-based products, encapsulated hemoglobin can provide longer circulation persistence without any vasoactivity and renal toxicity (Awasthi et al, 2006; Cabrales et al, 2012). Moreover, LEH can also carry hemoglobin stabilizers and allosteric modifiers of oxygen affinity, which can be co-encapsulated, to enhance the functional efficacy of the product (Kettisen et al, 2015).…”

Tissue engineering red blood cells: a therapeutic

“…PEG can also stabilize the particles in the aqueous medium of blood and prolong the systemic circulation of the micelles (Li et al, 2011). The use of PEG in this type of micelle is described in the literature (Shi et al, 2009), as is its use in HBOC lipid vesicles to improve the circulation time (Cabrales et al, 2012;Centis and Vermette, 2008;Chang, 2012).…”