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

Abstract Au I ‐carbene and Pt IV −Au I ‐carbene prodrugs display low to sub‐μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt‐derived Pt IV (phenylbutyrate) complex to a Au I ‐phenylimidazolylidene complex 2 , yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug Pt IV (phenylbutyrate)‐Au I ‐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.