Abstract
Learning from the antimalarial mechanism of artemisinin (ART) in nature, we explored methemoglobin (MHb) as a smart nanocarrier of ART, in which anticancer abilities can be turned on in situ through the upregulated reducing capacity of tumor tissue. Ultra violet–visible, electron paramagnetic resonance spectrometry and in vitro cell assessment proved that a reducing agent such as glutathione can work as an excellent biogenic trigger to reduce ferric iron in MHb to the ferrous state, activating the ability of ART to generate free radicals and resulting in cytotoxicity and apoptosis. In vivo investigations showed that the MHb–ART complex had encouraging anticancer outcomes. The bioinspired nanocarrier may pave a new way to achieve targeted toxicity to cancer cells with extremely low side effects.
Highlights
Since malarial parasites use hemoglobin as a major food source, it presents a high intracellular level of Fe2+ that can serve as a trigger to activate the antimalarial ability of ART.[6,7]
The potential generation of free radicals from ART has been considered as a promising way to treat cancers,[9,10,11] and iron is often co-delivered with ART to enhance the free radical generation.[12,13]
On the basis of the natural mechanism underlying the antimalarial ability of ART, we developed the potential of MHb as a redoxresponsive nanocarrier that could be applied to other lethal disease treatments such as for cancer
Summary
Artemisinin (ART) was acknowledged with the 2015 Nobel Prize in Medicine due to its great contribution to saving millions of lives from malaria.[1,2,3] The remarkable therapeutic effect of ART was found to arise from its endoperoxide structure, which can generate cytotoxic free radicals in the presence of ferrous iron (Fe2+).[4,5] Since malarial parasites use hemoglobin as a major food source, it presents a high intracellular level of Fe2+ that can serve as a trigger to activate the antimalarial ability of ART.[6,7] The in situ trigger mechanism provides the basis of its incredibly accurate toxicity to malarial parasites with extremely low side effects.[8]. Using bio-inspiration from the antimalarial mechanism of ART in nature, here we explored methemoglobin (MHb)—an oxidized form of hemoglobin with iron in the ferric state (Fe3+) rather than in the ferrous state (Fe2+)—as a smart nanocarrier for hydrophobic ART. While MHb reacts very slowly with ART,[14,15] the upregulated reducing capacity[16,17,18,19] of the tumor tissue can work as an excellent biogenic trigger to reduce ferric iron in MHb to the ferrous state, activating its ability to generate free radicals and resulting in the cytotoxicity of ART in situ (Scheme 1)
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