Methemoglobin as a redox-responsive nanocarrier to trigger the in situ anticancer ability of artemisinin

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. A hemoglobin complex that uses tumor tissue to switch on a free radical–generating drug has potent in vivo activity, reports a team in China. Extracted from a herbal medicine used since antiquity, artemisinin is an effective anti-malaria medicine that splits molecules apart into cell-damaging radicals in the presence of ferrous iron (Fe2+). Jian Ji and colleagues from Zhejiang University have now made artemisinin perform the same trick in live mice bearing skin cancer tumors. They encapsulated artemisinin inside fully oxidized hemoglobin proteins featuring ferric (Fe3+) ions. The team then targeted glutathione, a compound that grows to elevated levels in many tumors, as a trigger that could reduce Fe3+ to Fe2+ in the biocarrier and activate the drug. In animal studies, the new complex arrested tumor growth considerably compared to control groups. Learning from the antimalarial mechanism of artemisinin in nature, we explored the methemoglobin as a smart nanocarrier of artemisinin. While the methemoglobin reacts very slow with artemisinin, the upregulated reducing capacity of tumor tissue can work as an excellent biogenic trigger to reduce ferric iron in methemoglobin to ferrous state, hence turn on the free radical generation ability and cytotoxicity of artemisinin in situ. The bioinspired nanocarrier may pave a new way to achieve targeted toxicity to cancer cells with extremely low side effects.