Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position

We
report herein the design, synthesis, and biological investigation
of a series of novel Pt­(IV) prodrugs with non-steroidal anti-inflammatory
drugs naproxen, diclofenac, and flurbiprofen, as well as these with
stearic acid in the axial position. Six Pt­(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity
compared to cisplatin as well as an ability to overcome tumor cell
line resistance to cisplatin. By tuning the drug lipophilicity via
variation of the axial ligands, the most potent Pt­(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of
up to 153-fold that of cisplatin and nanomolar cytotoxicity both in
2D and 3D cell cultures. Pt2+ species were detected at
different depths of MCF-7 spheroids after incubation with Pt­(IV) prodrugs
using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in
vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after
Pt­(IV) prodrug injection was proved electrochemically as well. The
drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.