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Biologics are emerging as the most important class of drugs and are used to treat a large variety of pathologies. Most of biologics are proteins administered in large amounts, either by intramuscular injection or by intravenous infusion. Asparaginase is a large tetrameric protein assembly, currently used against acute lymphoblastic leukemia. Here, a gadolinium(III)-DOTA derivative has been conjugated to asparaginase, and its relaxation properties have been investigated to assess its efficiency as a possible theranostic agent. The field-dependent 1H longitudinal relaxation measurements of water solutions of gadolinium(III)-labeled asparaginase indicate a very large increase in the relaxivity of this paramagnetic protein complex with respect to small gadolinium chelates, opening up the possibility of its use as an MRI contrast agent.

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 (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.