The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers

Abstract

Intravenous injection of nanopharmaceuticals can induce severe hypersensitivity reactions (HSRs) resulting in anaphylactoid shock in a small percentage of patients, a phenomenon explicitly reproducible in pigs. However, there is a debate in the literature on whether the pig model of HSRs can be used as a safety test for the prediction of severe adverse reactions in humans. Given the importance of using appropriate animal models for toxicity/safety testing, the choice of the right species and model is a critical decision. In order to facilitate the decision process and to expand the relevant information regarding the pig or no pig dilemma, this review examines an ill-fated clinical development program conducted by Baxter Corporation in the United States 24 years ago, when HemeAssist, an αα (diaspirin) crosslinked hemoglobin-based O 2 carrier (HBOC) was tested in trauma patients. The study showed increased mortality in the treatment group relative to controls and had to be stopped. This disappointing result had far-reaching consequences and contributed to the setback in blood substitute research ever since. Importantly, the increased mortality of trauma patients was predicted in pig experiments conducted by US Army scientists, yet they were considered irrelevant to humans. Here we draw attention to that the underlying cause of hemoglobin-induced aggravation of hemorrhagic shock and severe HSRs have a common pathomechanism: cardiovascular distress due to vasoconstrictive effects of hemoglobin (Hb) and reactogenic nanomedicines, manifested, among others, in pulmonary hypertension. The main difference is that in the case of Hb this effect is due to NO-binding, while nanomedicines can trigger the release of proinflammatory mediators. Because of the higher sensitivity of cloven-hoof animals to this kind of cardiopulmonary

Current perspectives of artificial oxygen carriers as red blood cell substitutes: a review of old to cutting-edge technologies using in vitro and in vivo assessments

“…HBOCs are used as universal oxygen carrier systems that can use in several life-threatening conditions, such as hemorrhagic shock, trauma, stroke, myocardial infarction, and acute blood loss (Bedőcs and Szebeni 2020 ). At first Cell-free Hb was used for oxygen delivery, but it had several problems in carrying oxygen.…”

“…MP4OX has been used to treat sickle cell anemia to reduce the associated pain and duration (Keipert and MP4CO-SCD-105 Study Investigators 2016 ). PEG-Hb and SanFlow (PNPH) are bovine and human Hb products modified with polyethylene glycol conjugated (PEGylated) and polynitroxylated polyethylene glycol conjugated (PEGylated) Hb, respectively (Bedőcs and Szebeni 2020 ). Sanguinate was extracted from bovine Hb and cross-linked with polyethylene glycol-conjugated (PEGylated) carboxyhemoglobin with a molecular weight of 120 kDa.…”

“…HemO 2 Life/Hemarina-M101 (Hemarina) was created from lungworms, Arenicola marina (invertebrate), which is not attached to Hb or other membranes (Ferenz and Steinbicker 2019 ; Bedőcs and Szebeni 2020 ; Varney et al 2021 ). Hb (extracellular) has 40 times more oxygen receptivity than vertebrate Hb (Lupon et al 2021 ).…”

“…Oxyvita Hb has a greater success in controlling severe hemorrhage in a battlefield model than other HBOCs. It has a half-life of 72 h (Bedőcs and Szebeni 2020 ). A summary of chemically altered HBOCs is presented in Table 2 .…”

“…HemAssist reached phase III clinical trial for use during cardiac surgery and trauma/stroke, but was terminated in 1999 due to increased mortality rate (Chen et al 2009 ; Jahr et al 2012 ). Optro reached a phase II trial for elective surgery and showed fewer adverse effects, although it was discontinued in 2014 due to NO scavenging panic (Bedőcs and Szebeni 2020 ). Hemolink was halted in 2003 after a phase II trial and subsequently terminated in 2004.…”