Ru-Based Photocaged Kinase Inhibitors Operative under Deep-Red Light Irradiation

Abstract

Light-activated control over drug activity offers a powerful strategy to improve therapeutic selectivity, yet most photoresponsive systems rely on ultraviolet or short-wavelength visible light with limited tissue penetration. Here we report two ruthenium(II) polypyridyl complexes bearing extended donor−π–acceptor ligands and a photocaged kinase inhibitor, imatinib, that enable efficient drug release under deep-red light (660 nm) irradiation. Systematic photophysical and photochemical studies demonstrate that π-conjugation engineering red-shifts metal-to-ligand charge-transfer absorption while preserving clean photoinduced release of coordinated imatinib from the ruthenium center. In BCR–ABL–positive leukemia cells, these complexes exhibit minimal dark toxicity but pronounced light-dependent cytotoxicity, accompanied by apoptosis and suppression of oncogenic BCR–ABL phosphorylation. Effective activity in 3D tumor spheroids was also observed, confirming efficient penetration and photoactivation in a physiologically relevant model. Together, these results establish a molecular design strategy for developing deep-red-light-activated Ru(II) photocages and highlight their potential for spatiotemporally controlled kinase inhibition in cancer therapy.