Biophysical Analysis and Preclinical Pharmacokinetics-Pharmacodynamics of Tangential Flow Filtration Fractionated Polymerized Human Hemoglobin as a Red Blood Cell Substitute.
Alisyn GreenfieldDerek R LambXiangming GuKiruphagaran ThangarajuSaini SetuaAhmad YahyaAmid VahediMohd Asim KhanQihong WangPaul W BuehlerAndre F PalmerPublished in: Biomacromolecules (2023)
Red blood cell (RBC) substitutes tested in late-phase clinical trials contained low-molecular-weight hemoglobin species (<500 kDa), resulting in vasoconstriction, hypertension, and oxidative tissue injury; therefore, contributing to poor clinical outcomes. This work aims to improve the safety profile of the RBC substitute, polymerized human hemoglobin (PolyhHb), via in vitro and in vivo screening of PolyhHb fractionated into four molecular weight brackets (50-300 kDa [PolyhHb-B1]; 100-500 kDa [PolyhHb-B2]; 500-750 kDa [PolyhHb-B3]; and 750 kDa to 0.2 μm [PolyhHb-B4]) using a two-stage tangential flow filtration purification process. Analysis showed that PolyhHb's oxygen affinity, and haptoglobin binding kinetics decreased with increasing bracket size. A 25% blood-for-PolyhHb exchange transfusion guinea pig model suggests that hypertension and tissue extravasation decreased with increasing bracket size. PolyhHb-B3 demonstrated extended circulatory pharmacokinetics, no renal tissue distribution, no aberrant blood pressure, or cardiac conduction effects, and may therefore be appropriate material for further evaluation.
Keyphrases
- red blood cell
- blood pressure
- heat shock protein
- endothelial cells
- clinical trial
- induced pluripotent stem cells
- hypertensive patients
- heart rate
- pluripotent stem cells
- stem cells
- metabolic syndrome
- type diabetes
- cardiac surgery
- heart failure
- randomized controlled trial
- mesenchymal stem cells
- extracorporeal membrane oxygenation
- skeletal muscle
- dna binding
- cell therapy
- study protocol
- atrial fibrillation
- adipose tissue
- bone marrow