Biological Responsiveness and Metabolic Performance of Liposome-Encapsulated Hemoglobin (Hemoglobin-Vesicles) in Apolipoprotein E-Deficient Mice after Massive Intravenous Injection

Abstract

The hemoglobin-vesicle (HbV), a vesicle in which a concentrated human hemoglobin solution is encapsulated, was developed as an artificial oxygen carrier. Although HbV has a favorable safety, metabolic, and excretion performance in healthy animals, the effect of a massive amount of HbV, which also contains a large amount of a lipid component including cholesterol, on physiological response and metabolic performance under hyperlipidemic conditions is unclear. The aim of this study was to evaluate whether administration of HbV causes toxicity in apolipoprotein E-deficient mice (hyperlipidemic model mice). Apolipoprotein Edeficient mice were given a single injection of HbV (2000 mg hemoglobin/kg), and physiological responses and metabolic profiles were monitored for 14 d thereafter. All the mice tolerated the massive amount of HbV and survived, and adequate biocompatibility was observed. Serum biochemical parameters indicate that liver and kidney function were not remarkably affected, and morphological changes in the liver and spleen were negligible. Lipid parameters in serum were significantly increased until 3 d after HbV administration, but recovered within 7 d after the administration. In a pharmacokinetic study, HbV was mainly found distributed in the liver and spleen, and disappeared from the body within 14 d. In conclusion, even under conditions of hyperlipidemia, a massive dose of HbV and its components resulted in favorable biological compatibility, metabolic, and excretion profiles. These findings provide further support for the safety of HbV for clinical use.Key words hemoglobin; hemoglobin-vesicle (HbV); liposome; artificial blood; hyperlipidemia It is well known that liposomes (phospholipid vesicles) can be used as a carrier for some drugs, genes, proteins, and that they can enhance the blood circulation and specific targeting of encapsulated materials. Given these characteristics, many liposome type drugs have now been approved for clinical use in antifungal or anticancer therapies.1) In addition to their use in transporting drugs, phospholipid vesicles encapsulating concentrated hemoglobin (Hb), referred to as hemoglobin vesicles (HbV), have also been developed as artificial oxygen carriers. HbV has been shown to possess several superior characteristics to red blood cell (RBC) transfusions including the absence of viral contamination, a long-term storage period at room temperature of over 2 years and no need for cross-matching etc.2) Furthermore, it has been clearly shown that the transport of oxygen by HbV is comparable to RBC in hemorrhagic shock models.2,3) Based on these facts, HbV appears to have potential for use as an alternative to RBCs, and is expected to be of use in other clinical indications that cannot be solved with conventional blood transfusions in clinical settings.It is very important to accumulate data related to the overall safety of HbV because high doses of HbV, in excess of hundreds of times higher than that of other commercially available liposomal formulations of doxorubicin a...

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

“…We previously investigated the pharmacokinetic properties of HbV in Apo E deficient mice (B6.KOR/StmSlc-Apoe shl mice) because of the concern that the disposition of HbV, especially lipid components, may be altered due to their poor metabolic and excretion profiles [113]. Biological parameters which are related to lipid metabolites of HbV such as cholesterol were temporarily increased after an HbV injection in B6.KOR/StmSlc-Apoe shl mice, but completely recovered to basal levels at 7 days after the injection.…”

Pharmaceutical Technology Innovation Strategy Based on the Function of Blood Transport Proteins as DDS Carriers for the Treatment of Intractable Disorders and Cancer

“…According to numerous animal studies, Hb-V potentially exhibits a favorable safety profile, including blood compatibility (no platelet and complement activation) and lack of tissue damage, nephrotoxicity, and hypertension, even if repeatedly administered at high doses. 3) Furthermore, as summarized in Table 1, it exhibited well-defined pharmacokinetic characteristics such as blood retention; distribution, metabolic, and excretion profiles; the influence of accelerated blood clearance phenomenon; and drug-interaction with CYP [6][7][8][9][10][11][12][13][14][15][16][17] . On the basis of accumulated evidence, some basic research has been conducted to investigate the possibility that Hb-V can be applied as an oxygen carrier against various ischemic or hypoxic disorders such as hemorrhagic shock, 18) brain ischemia, 19) and pre-eclampsia.…”

“…Hb-V mainly distributes in the liver and spleen in healthy animals 6,8) and in animal models of hemorrhagic shock, 9) cirrhosis, 11) and hyperlipidemia. 12) Hb-V does not transfer from mother to fetus in pregnant rats.…”

Carbon monoxide-bound hemoglobin vesicles ameliorate multiorgan injuries induced by severe acute pancreatitis in mice by their anti-inflammatory and antioxidant properties

“…This indicates that HbV has the capacity to carry and release CO in vivo. Accumulating evidence has confirmed the safety and usefulness of HbV as an oxygen carrier such as its biological compatibility, 22 the absence of toxicity, 23 no accumulation in the body, 52,53 and ability to transport oxygen. 54,55 These beneficial properties of HbV can be retained, even in the form of CO-HbV.…”