Tuning the Organelle Specificity and Cytotoxicity of Iridium(III) Photosensitizers for Enhanced Phototheranostic Applications

Three new molecular hybrids composed of a cyclometalated iridium(III) polypyridine core and a POSS unit [Ir(pqe)₂(N^X)](PF₆)_n (N^X = bpy-POSS, n = 1 (1); pic-POSS, n = 0 (2); picpy-POSS, n = 1 (3)) and their POSS-free counterparts (N^X = bpy, n = 1 (1a); pic, n = 0 (2a); picpy, n = 1 (3a)) were synthesized and characterized. Upon photoexcitation, these complexes exhibited long-lived orange-red to deep red emission. The complexes displayed not only significant photoinduced ¹O₂ generation but also efficient generation of O₂·^–. Modification of the ancillary N^X ligand enables the complexes to be taken up by the cells via different internalization mechanisms and to target different cellular organelles. Additionally, the POSS complexes were found to be significantly less cytotoxic than their POSS-free counterparts in the dark. However, all the complexes showed substantially high cytotoxic activity upon photoirradiation. The bpy complexes 1 and 1a demonstrated notable photocytotoxicity under hypoxic conditions. Cell death mechanism studies indicated that complex 1 predominantly induced apoptotic cell death upon photoirradiation, while the cells incubated with the complex 1a underwent a mixed apoptotic and paraptotic pathway.