Bioconjugation of the gold drug auranofin to human ferritin yields a potent cytotoxin

Ferritin may serve as a nanocarrier for the selective delivery of anticancer metallodrugs. Here, we have prepared and characterized a well-defined conjugate between the gold drug auranofin and apoferritin containing similar to 14 gold atoms per nanocage (HuHf@AF hereafter). Site directed mutagenesis combined with ESI MS and ICP-OES experiments revealed that gold binding occurs exclusively at cysteines 90 and 102. HuHf@AF was found to manifest potent cytotoxic properties against A2780 cancer cells and to overcome cisplatin resistance. Interestingly, we observed that HuHf@AF induced alterations in the NMR-detectable metabolome very similar to those caused by AF implying a roughly identical mode of action. Accordingly, we also show that HuHf@AF like AF metalates efficiently the C-terminal dodecapeptide of thioredoxin reductase bearing the thiol-selenol active site (this enzyme being the main intracellular target of AF). Some features of the cellular uptake of HuHf@AF and of subsequent gold release are analyzed. On these grounds, HuHf@AF is proposed as an innovative anticancer agent, with a pharmacological profile similar to free AF, where the reactivity of the gold center, its delivery and its side effects are tightly controlled by the ferritin nanocage.

Automated summary

Ferritin can serve as a nanocarrier for targeted delivery of anticancer metallodrugs. In this study, a conjugate between the gold drug auranofin and apoferritin was prepared and characterized. The conjugate showed potent cytotoxic properties against cancer cells and overcame cisplatin resistance. The mode of action and cellular uptake of the conjugate were found to be similar to auranofin. The study proposes the conjugate as an innovative anticancer agent with controlled reactivity, delivery, and side effects.