# PEGylated megahemoglobin for use as a red blood cell substitute

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $695,646

## Abstract

Project Abstract
 In the United States (U.S.), demand for red blood cells (RBCs) for use in transfusion medicine is steadily
growing and will exceed the supply with a projected shortage of 4 million units of RBCs by the year 2030. In
addition, frequent seasonal blood shortages, decreasing donation rates, risks of disease transmission, the
RBC storage lesion and other side-effects threaten the existing supply of RBCs. Therefore, a viable short-term
alternative to donated human RBCs must be developed which is safe, available in large quantities at low cost,
and free of the risks of disease transmission and immune suppression, as well as address concerns over
religious objections to receiving transfused blood. RBC substitutes should be used to treat conditions in which
the use of banked blood is unreasonable or for which there is no therapy. Despite decades of research and
clinical trials, mammalian hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are still plagued by severe
side-effects, such as vasoconstriction at the microcirculatory level, systemic hypertension, myocardial
infarction and increased mortality rates.
 It has been hypothesized that the side-effects associated with previous generations of HBOCs were caused
by HBOC extravasation through the blood vessel wall into the tissue space, which led to scavenging of nitric
oxide (NO). NO is also known as endothelium-derived relaxing factor (EDRF), and the endothelium (inner
lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, resulting in vasodilation and
increased blood flow. Previous generations of HBOCs were also easily oxidized in vivo, creating a significant
amount of oxidative stress and tissue damage. All of these problems are a direct consequence of removing Hb
from the protective environment of the RBC.
 We propose that many of these side-effects may be prevented or reduced by using naturally occurring
acellular Earthworm Hb (erythrocruorin, LtEc), which has evolved to exist outside of RBCs. Unlike other Hbs
(64 kDa), LtEc is naturally large (3.6 MDa) and should not extravasate through the pores lining the blood
vessel wall. This feature should prevent/limit its vasoactivity and the extent of systemic hypertension. LtEc is
also extremely stable and resistant to oxidation. Therefore, it should elicit limited oxidative stress and tissue
toxicity compared to acellular HBOCs synthesized from mammalian Hbs. In addition, LtEc appears to have a
much slower or non-existent NO scavenging rate compared to mammalian Hbs, which is the hypothesized root
cause of vasoconstriction and hypertension observed in previous generations of acellular HBOCs.
Interestingly, the O2 transport characteristics of LtEc are similar to human RBCs, which suggests it will
effectively transport O2 to tissues and organs in vivo. Polyethylene glycol (PEG) conjugation to the surface of
purified LtEc camouflages the molecule against recognition by the immune system and increases LtEc
circula...

## Key facts

- **NIH application ID:** 9975883
- **Project number:** 5R01HL138116-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Pedro Cabrales
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $695,646
- **Award type:** 5
- **Project period:** 2017-08-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975883

## Citation

> US National Institutes of Health, RePORTER application 9975883, PEGylated megahemoglobin for use as a red blood cell substitute (5R01HL138116-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975883. Licensed CC0.

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