Bioconjugation of the gold drug auranofin to human ferritin yields a potent cytotoxin
Lucrezia Cosottini, Lara Massai, Veronica Ghini, Stefano Zineddu, Andrea Geri, Michele Mannelli, Silvia Ciambellotti, Mirko Severi, Tania Gamberi, Luigi Messori, Paola Turano
Abstract
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 ∼14 gold atoms per nanocage ([email protected] hereafter). Site directed mutagenesis combined with ESI MS and ICP-OES experiments revealed that gold binding occurs exclusively at cysteines 90 and 102. [email protected] was found to manifest potent cytotoxic properties against A2780 cancer cells and to overcome cisplatin resistance. Interestingly, we observed that [email protected] 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 [email protected] 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 [email protected] and of subsequent gold release are analyzed. On these grounds, [email protected] 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.