Bis[Pyrrolyl Ru(II)] Triads: a New Class of Photosensitizers for Metal-Organic Photodynamic Therapy

Abstract

A new family of ten dinuclear Ru(II) complexes based on the bis[pyrrolyl Ru(II)] triad scaffold, where two Ru(bpy)2 centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and in vitro photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(II)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (e) ≥104 at 600–620 nm and longer. Phosphorescence quantum yields (Fp) were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields (FD) ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC50 values in the range of 10– 100 μM and phototherapeutic indices (PIs) as large as 5,400 and 260 with broadband visible (28 J cm-2, 7.8 mW cm-2) and 625-nm red (100 J cm-2, 42 mW cm-2) light, respectively. The bis[pyrrolyl Ru(II)] triad with a pyrenyl linker (5h) was especially potent, with an EC50 value of 1 nM and PI >27,000 with visible light and subnanomolar activity with 625-nm light (100 J cm-2, 28 mW cm- 2). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxcicity in this more resistant model (EC50=60 nM and PI>1,200 with 625-nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC50 values and PIs >300 against S. mutans and S. aureus were obtained with visible light. This activity was attenuated with 625-nm red light, but PIs were still near 50. The ligand-localized 3ππ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.