Pt(IV) Prodrugs Bearing Sunitinib-Derived Ligands Display Exceptional Anticancer Activity against Renal Cell Carcinoma When Compared to Conventional Platinum Chemotherapy

The use of anticancer platinum chemotherapeutics is associated with severe disadvantages, including cytotoxicity to healthy cells. Sunitinib is an FDA-approved tyrosine kinase inhibitor that selectively targets renal cell carcinoma due to the overexpression of its receptors, such as vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Here, three Pt(IV) prodrugs, based on cisplatin, oxaliplatin, and carboplatin, bearing sunitinib-derived axial ligands have been developed to overcome healthy cell toxicity. This study highlights the first Pt(IV) complexes targeting renal carcinoma tumors overexpressing VEGFR. <i>In vitro</i> cytotoxicity and 3D spheroid assays demonstrated the superior activity of the cisplatin-based prodrug over conventional cisplatin chemotherapy. The cisplatin-based prodrug was tested <i>in vivo</i> against renal carcinoma xenografts, revealing high efficacy superior to the cisplatin control. These Pt(IV)-sunitinib conjugates have excellent potential for the treatment of renal cell carcinoma, as they display significantly enhanced tumor reduction and lower systemic toxicity when compared to cisplatin chemotherapy.