BACKGROUND: The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical trials of many materials have reported adverse side effects that may come from the scavenging of the vasodilator nitric oxide (NO). A compensating reaction, reduction of endogenous nitrite by hemoglobin (Hb) and its derivatives, generates NO. Polyethylene glycol (PEG) conjugation of Hb enhances the rate of the reaction. STUDY DESIGN AND METHODS: Hemoglobin bis-tetramers (BT) and their PEGylated derivative (BT-PEG) bind oxygen with a degree of cooperativity and also have significantly enhanced nitrite reductase activity compared to the native protein. Circulatory evaluation will test if the properties of BT and BT-PEG are reflected in their effects in vivo. BT and BT-PEG were evaluated as infusions into healthy wild-type (WT) and diabetic (db/db) mouse models. The effects were compared to infusions of murine Hb. RESULTS: The materials were found not to cause significant increases in systemic blood pressure in either WT mice or db/db mice. The latter are highly sensitive to NO scavenging. Further hemodynamic measurements in WT mice indicate that while a slight increase in systemic vascular resistance (SVR) was observed after infusion of BT, the extent is not significant. No change in SVR from baseline was observed after infusion of BT-PEG. CONCLUSION: The enlarged Hb derivatives do not evoke unfavorable circulatory responses that have been noted to result from infusion of Hb derivatives. These results suggest that a compromise between the P(50) , n(50) , and nitrite reductase activity of a Hb derivative can serve as the basis for producing HBOCs that can be tested for vasoactivity.
BACKGROUND: The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical trials of many materials have reported adverse side effects that may come from the scavenging of the vasodilator nitric oxide (NO). A compensating reaction, reduction of endogenous nitrite by hemoglobin (Hb) and its derivatives, generates NO. Polyethylene glycol (PEG) conjugation of Hb enhances the rate of the reaction. STUDY DESIGN AND METHODS: Hemoglobin bis-tetramers (BT) and their PEGylated derivative (BT-PEG) bind oxygen with a degree of cooperativity and also have significantly enhanced nitrite reductase activity compared to the native protein. Circulatory evaluation will test if the properties of BT and BT-PEG are reflected in their effects in vivo. BT and BT-PEG were evaluated as infusions into healthy wild-type (WT) and diabetic (db/db) mouse models. The effects were compared to infusions of murine Hb. RESULTS: The materials were found not to cause significant increases in systemic blood pressure in either WT mice or db/db mice. The latter are highly sensitive to NO scavenging. Further hemodynamic measurements in WT mice indicate that while a slight increase in systemic vascular resistance (SVR) was observed after infusion of BT, the extent is not significant. No change in SVR from baseline was observed after infusion of BT-PEG. CONCLUSION: The enlarged Hb derivatives do not evoke unfavorable circulatory responses that have been noted to result from infusion of Hb derivatives. These results suggest that a compromise between the P(50) , n(50) , and nitrite reductase activity of a Hb derivative can serve as the basis for producing HBOCs that can be tested for vasoactivity.
Authors: Benjamin W Fischer-Valuck; Lauren Henke; Olga Green; Rojano Kashani; Sahaja Acharya; Jeffrey D Bradley; Clifford G Robinson; Maria Thomas; Imran Zoberi; Wade Thorstad; Hiram Gay; Jiayi Huang; Michael Roach; Vivian Rodriguez; Lakshmi Santanam; Harold Li; Hua Li; Jessika Contreras; Thomas Mazur; Dennis Hallahan; Jeffrey R Olsen; Parag Parikh; Sasa Mutic; Jeff Michalski Journal: Adv Radiat Oncol Date: 2017-06-01