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... Show moreThe 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 nano-conjugates 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(H))](PF6)(2) ([1](PF6)(2)), where bpy = 2,2-bipyridine and 3(H) 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 x 10(3) 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. Show less
The biological application of ruthenium anticancer prodrugs for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) is restricted by the need to use poorly penetrating high-energy... Show moreThe biological application of ruthenium anticancer prodrugs for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) is restricted by the need to use poorly penetrating high-energy photons for their activation, i.e., typically blue or green light. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, may solve this issue, provided that the coupling between the UCNP surface and the Ru prodrug is optimized to produce stable nanoconjugates with efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the two structurally related ruthenium(II) polypyridyl complexes [Ru(bpy)2(5)](PF6)2 ([1](PF6)2) and [Ru(bpy)2(6)](PF6)2 ([2](PF6)2), where bpy = 2,2-bipyridine, 5 is 5,6-bis(dodecyloxy)-2,9-dimethyl-1,10-phenanthroline, and 6 is 5,6-bis(dodecyloxy)-1,10-phenanthroline. [1](PF6)2 is photolabile as a result of the steric strain induced by ligand 5, but the irradiation of [1](PF6)2 in solution leads to the nonselective and slow photosubstitution of one of its three ligands, making it a poor PACT compound. On the other hand, [2](PF6)2 is an efficient and photostable PDT photosensitizer. The water-dispersible, negatively charged nanoconjugate UCNP@lipid/[2] was prepared by the encapsulation of 44 nm diameter NaYF4:Yb3+,Tm3+ UCNPs in a mixture of 1,2-dioleoyl-sn-glycero-3-phosphate and 1,2-dioleoyl-sn-glycero-3-phosphocholine phospholipids, cholesterol, and the amphiphilic complex [2](PF6)2. A nonradiative energy transfer efficiency of 12% between the Tm3+ ions in the UCNP and the Ru2+ acceptor [2]2+ was found using time-resolved emission spectroscopy. Under irradiation with NIR light (969 nm), UCNP@lipid/[2] was found to produce reactive oxygen species (ROS), as judged by the oxidation of the nonspecific ROS probe 2′,7′-dichlorodihydrofluorescein (DCFH2–). Determination of the type of ROS produced was precluded by the negative surface charge of the nanoconjugate, which resulted in the electrostatic repulsion of the more specific but also negatively charged 1O2 probe tetrasodium 9,10-anthracenediyl-bis(methylene)dimalonate (Na4(ADMBMA)). Show less
The biological application of ruthenium anticancer prodrugs for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) is restricted by the need to use poorly penetrating high-energy... Show moreThe biological application of ruthenium anticancer prodrugs for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) is restricted by the need to use poorly penetrating high-energy photons for their activation, i.e., typically blue or green light. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, may solve this issue, provided that the coupling between the UCNP surface and the Ru prodrug is optimized to produce stable nanoconjugates with efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the two structurally related ruthenium(II) polypyridyl complexes [Ru(bpy)2(5)](PF6)2 ([1](PF6)2) and [Ru(bpy)2(6)](PF6)2 ([2](PF6)2), where bpy = 2,2-bipyridine, 5 is 5,6-bis(dodecyloxy)-2,9-dimethyl-1,10-phenanthroline, and 6 is 5,6-bis(dodecyloxy)-1,10-phenanthroline. [1](PF6)2 is photolabile as a result of the steric strain induced by ligand 5, but the irradiation of [1](PF6)2 in solution leads to the nonselective and slow photosubstitution of one of its three ligands, making it a poor PACT compound. On the other hand, [2](PF6)2 is an efficient and photostable PDT photosensitizer. The water-dispersible, negatively charged nanoconjugate UCNP@lipid/[2] was prepared by the encapsulation of 44 nm diameter NaYF4:Yb3+,Tm3+ UCNPs in a mixture of 1,2-dioleoyl-sn-glycero-3-phosphate and 1,2-dioleoyl-sn-glycero-3-phosphocholine phospholipids, cholesterol, and the amphiphilic complex [2](PF6)2. A nonradiative energy transfer efficiency of 12% between the Tm3+ ions in the UCNP and the Ru2+ acceptor [2]2+ was found using time-resolved emission spectroscopy. Under irradiation with NIR light (969 nm), UCNP@lipid/[2] was found to produce reactive oxygen species (ROS), as judged by the oxidation of the nonspecific ROS probe 2′,7′-dichlorodihydrofluorescein (DCFH2–). Determination of the type of ROS produced was precluded by the negative surface charge of the nanoconjugate, which resulted in the electrostatic repulsion of the more specific but also negatively charged 1O2 probe tetrasodium 9,10-anthracenediyl-bis(methylene)dimalonate (Na4(ADMBMA)). Show less
