Keio University
Hydrogen sulphide (H2S) is a toxic substance that causes acute and fatal poisoning when exposed to mammals. Many workers in the agricultural, petroleum, and sewage treatment industries are affected by H2S poisoning yearly. The mechanism of H2S toxicity is via inhibition of cytochrome c oxidase located in the complex IV of mitochondria, similar to cyanide poisoning. Since there is no approved and promising treatment for H2S poisoning, sodium nitrite (NaNO2), a cyanide antidote, is empirically used to treat patients suffering from H2S toxicity in clinical situations. NaNO2 oxidises haemoglobin (Hb) in red blood cells, and cyanide subsequently binds to the oxidised Hb (methaemoglobin: metHb) with high affinity. MetHb has been previously reported to inherently bind H2S with high affinity and form sulphide-metHb, suggesting that metHb itself can serve as a detoxifying agent for H2S toxicity. However, naked metHb has poor blood retention properties and induces severe renal toxicity.This study shows that liposome-encapsulated methaemoglobin (metHb-V), nanosized biomimetic red blood cells, exhibit superior H2S detoxifying efficacy with no adverse effects. MetHb-V consists of concentrated metHb in its aqueous core and a lipid membrane resembling the red blood cell membrane, which provides favourable characteristics as an H2S scavenger through high-affinity binding and membrane permeability for H2S. Upon H2S exposure, metHb-V showed cytoprotective effect with preserving sufficient cell viability and mitochondrial function in H9c2 cells. In lethal H2S poisoning mice, metHb-V treatment dramatically improved mortality compared to saline treatment (negative-control) and NaNO2 treatment. MetHb-V also possesses good pharmacokinetic properties with no renal toxicity. In conclusion, our findings show a novel drug development concept of biomimetic red blood cell preparations with promising H2S detoxifying properties for pharmaceutical applications.
Abstract
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