Oral Anticancer Heterobimetallic Pt<sup>IV</sup>−Au<sup>I</sup>Complexes Show High In Vivo Activity and Low Toxicity
Tomer Babu, Hiba Ghareeb, Uttara Basu, Hemma Schueffl, Sarah Theiner, Petra Heffeter, Gunda Koellensperger, Norman Metanis, Valentina Gandin, Ingo Ott, Claudia Schmidt, Dan Gibson
Abstract
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.