Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log P_o/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.