Although targeted- and immuno- therapies are nowadays considered among the most promising tools in fighting cancer, combination protocols including new biologically-smart agents and old cytotoxic drugs (the Pt(II)-based ones, in particular) result to be useful, especially against very aggressive tumors.

Octahedral Pt(IV) derivatives are intensively studied as prodrugs, being deprived of most of the heavy side effects of cisplatin and suitable to be administered orally. These complexes reach tumor cells in their intact form and then are reduced (ideally only) in the hypoxic intracellular milieu to cytotoxic cisplatin, with the simultaneous loss of the two remaining ligands from the axial position (activation by reduction). The well-established Pt(IV) chemistry permits to design dual-action drug candidates that can act as single-molecule combination-therapy, often called combo. Indeed, two adjuvant/synergistic drugs (generally in form of carboxylates) are conjugated to the Pt(IV) core (frequently obtained by cisplatin oxidation) in axial positions. These Pt(IV) derivatives are much more lipophilic than their progenitors (i.e., the hydrophilic cisplatin and the amphiphilic carboxylate anions). Their assembly permits a more efficient cellular uptake (via passive diffusion) than that of the separate components (synergistic cellular accumulation), increasing the intracellular concentration of the two drugs.

Nowadays, dozens of dual- or even multi-action antitumor Pt(IV) prodrugs (mitochondria-targeted complexes, glutathione-S-transferase-targeted complexes, cyclooxygenases inhibitors, histone deacetylase inhibitors, etc.) have been designed, synthesized and tested in vitro and in vivo, and a number of them moved into clinical trials. In this presentation some prototypal Pt(IV) prodrugs will be shown as case studies.