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

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.

Shoot the Arrow at the Target: Innovative Stimulus-Responsive Smart Nanocarriers for Cancer Therapy

“…The intracellular GSH concentration is about 0.5-10 mM, which is more than 100 times the extracellular concentration (2-20 μM) [19,51]. In addition to the reducing substance GSH, tumor cells contain small amounts of divalent iron ions (Fe 2+ ), cysteine (Cys), thioredoxin reductase and lysosomal thiol reductase [52]. Therefore, this difference in the content of reduced substances inside and outside tumor cells (especially GSH) provides new possibilities for designing reduction-responsive nanodrug carriers to achieve reduction-responsive drug release inside the tumor cells.…”

Recent Progresses in Cancer Nanotherapeutics Design Using Artemisinins as Free Radical Precursors

“…Elevated oxidative stress was observed specifically at the tumor site and enhanced tumor eradication was achieved by their nanosystem (Yu et al, 2020). Methemoglobin (MHb) is the most common iron-containing protein, which has also been utilized in ARTs' delivery and controlled activation through the similar mechanisms to transferring (Li et al, 2017). The iron ion in both transferrin and MHb exists mainly as Fe 3+ , it will convert to Fe 2+ under reductive intracellular microenvironment, thus mediating ARTs' activation (Liu et al, 2015).…”