Polyurethane-polyurea hybrid nanocapsules as efficient delivery systems of anticancer Ir(III) metallodrugs

Abstract

Cyclometalated Ir(III) complexes hold great promise as an alternative to platinum metallodrugs for the therapy and diagnosis of cancer. However, their low aqueous solubility and poor cell membrane permeability are obstacles for in vivo applications. Here we have encapsulated for the first time, using polyurethane-polyurea hybrid nanocapsules (NCs), two phosphorescent tris-cyclometalated Ir(III) complexes incorporating deprotonated 2-arylbenzimidazole ligands, Ir1 and Ir2. Ir(III)-Loaded nanocapsules (NC-Ir1 and NC-Ir2) showed a roughly round shape and controlled particle size distribution around 18 nm. The photophysical properties of aqueous solutions of NCs were similar to those of the free complexes in CH2Cl2, which accounts for the hydrophobic and protective environment generated by the nanoparticles around the cargo. Nanoencapsulation had also a positive effect on the cellular uptake of the metallodrugs and NCs were found to be highly cytotoxic towards several cancer cell lines, whereas Ir(III) complexes alone were found to be inactive. A strong tumor growth inhibition effect was also found in 3D tumorsphere cancer models owing to the high penetration capacity of small NCs. Finally, the mode of cell death of the NCs was found to be related to oncosis, and the mitochondrial dysfunction and generation of extensive oxidative stress appeared to be also involved in the mechanism of action of these novel nanomedicines.