Converting an Almost Noncytotoxic Ru(II) Complex with Photolabile Ligands into a Highly Efficient PACT Agent

Abstract Ru(II) complexes with weak ligand fields may undergo light‐induced ligand dissociation, and the resulted Ru(II) aqua complexes may bind with biomolecules such as DNA, showing potential as photoactivated chemotherapy (PACT) agents. However, Ru(II) complexes with efficient PACT activity are still rare. Some Ru(II) complexes exhibit efficient photoinduced ligand dissociation but poor cytotoxicity. It is speculated that the low nuclear accumulation levels may account for their low PACT efficacy. In order to confirm this hypothesis, the almost noncytotoxic [Ru(7‐OCH 3 ‐dppz)(4‐OCH 3 ‐py) 4 ](PF 6 ) 2 (Ru1) is loaded on nucleus‐targeted C 5 N 2 nanoparticles (NPs). Compared with the free Ru1, Ru1–C 5 N 2 NPs exhibit significantly increased cellular uptake and nuclear accumulation. Therefore, Ru1–C 5 N 2 NPs show efficient PACT activity toward various cancer cell lines (including cisplatin‐resistant one) with half maximal inhibitory concentration (IC 50 ) values of 0.18 × 10 −6 –0.29 × 10 −6 m and phototoxicity index (IC 50 dark /IC 50 light ) values above 137 under both normoxic and hypoxic conditions. Moreover, Ru1–C 5 N 2 NPs also exhibit efficient PACT activity toward cisplatin‐resistant 3D multicellular tumor spheroids upon two‐photon irradiation (800 nm). The same strategy is also feasible to greatly improve the PACT activity of [Ru(7‐OCH 3 ‐dppz)(py) 4 ] 2+ , which itself only has a medium effect. The results may provide new sights for developing efficient Ru(II) PACT agents.