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.
Photoactivable chemotherapy (PACT) using metallic complexes provides spatiotemporal selectivity over drug activation for targeted anticancer therapy. However, the poor absorption in near-infrared (NIR) light region of most metallic complexes renders tissue penetration challenging. Herein, an NIR light triggered dinuclear photoactivable Ru(II) complex ( Ru2 ) is presented and the antitumor mechanism is comprehensively investigated. The introduction of a donor–acceptor–donor (D–A–D) linker greatly enhances the intramolecular charge transition, resulting in a high molar extinction coefficient in the NIR region with an extended triplet excited state lifetime. Most importantly, when activated by 700 nm NIR light, Ru2 exhibits unique slow photodissociation kinetics that facilitates synergistic photosensitization and photocatalytic activity to destroy diverse intracellular biomolecules. In vitro and in vivo experiments show that when activated by 700 nm NIR light, Ru2 exhibits nanomolar photocytotoxicity toward 4T1 cancer cells via the induction of calcium overload and endoplasmic reticulum (ER) stress. These findings provide a robust foundation for the development of NIR-activated Ru(II) PACT complexes for phototherapeutic application.
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