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Oral Anticancer Heterobimetallic PtIV−AuI Complexes Show High In Vivo Activity and Low Toxicity

Oral anticancer heterobimetallic PtIV−AuI N-heterocyclic carbene complexes with a dual mechanism of action show high potency with low toxicity in vivo. The conjugation of two metals results in an enhanced inhibitory effect towards thioredoxin reductase and facilitates the co-transport of the prodrug into the tumor before activation.


AuI-carbene and PtIV−AuI-carbene prodrugs display low to sub-μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt-derived PtIV(phenylbutyrate) complex to a AuI-phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug PtIV(phenylbutyrate)-AuI-carbene (7) and the 1 : 1 : 1 co-administration of cisPt: phenylbutyrate:2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2, 20 % for cisPt and >30 % for the co-administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser-ablation (LA)-ICP-TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there.

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