796 nm Activation of a Photocleavable Ruthenium(II) Complex Conjugated to an Upconverting Nanoparticle through Two...

The biological application of photoactivatable ruthenium anticancer prodrugs is limited by the need to use poorly penetrating high-energy visible light for their activation. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, can solve this issue, provided that they form stable, water (H₂O)-dispersible nanoconjugates with the prodrug and that there is efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the ruthenium(II) polypyridyl complex [Ru(bpy)₂(3)](PF₆)₂ ([1](PF₆)₂), where bpy = 2,2-bipyridine and 3 is a photocleavable bis(thioether) ligand modified with two phosphonate moieties. This ligand was coordinated to the ruthenium center through its thioether groups and could be dissociated under blue-light irradiation. Complex [1](PF₆)₂ was bound to the surface of NaYF₄:Yb³⁺,Tm³⁺@NaYF₄:Nd³⁺@NaYF₄ core-shell-shell (CSS-)UCNPs through its bis(phosphonate) group, thereby creating a H₂O-dispersible, thermally stable nanoconjugate (CSS-UCNP@[1]). Conjugation to the nanoparticle surface was found to be most efficient in neutral to slightly basic conditions, resulting in up to 2.4 × 10³ Ru^II ions per UCNP. The incorporation of a neodymium-doped shell layer allowed for the generation of blue light using low-energy, deep-penetrating light (796 nm). This wavelength prevents the undesired heating seen with conventional UCNPs activated at 980 nm. Irradiation of CSS-UCNP@[1] with NIR light led to activation of the ruthenium complex [1](PF₆)₂. Although only one of the two thioether groups was dissociated under irradiation at 50 W·cm^-2, we provide the first demonstration of the photoactivation of a ruthenium thioether complex using 796 nm irradiation of a H₂O-dispersible nanoconjugate.