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

• Lipophilicity, cellular accumulation and growth inhibition of Pt(IV) prodrugs have been studied.
• Unlike cisplatin, Pt(IV) complexes are not substrates for influx/efflux copper transporters.
• Passive diffusion appears to be the internalization mechanism operating for Pt(IV) complexes.
• The most lipophilic compound shows the highest Pt accumulation and cell growth inhibition.
• DNA platination is persistent over time indicating efficient storing and poor detoxification.

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 Po/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.

Lipophilicity, cellular accumulation and interaction with copper transport proteins indicate that passive diffusion is the cellular internalization mechanism operating for Pt(IV) prodrugs, whereas persistence of DNA platination over time indicates efficient storing and poor detoxification for the most lipophilic Pt(IV) compounds.Figure optionsDownload as PowerPoint slide