Abstract
Triplet-triplet annihilation upconversion (TTA-UC) is a promising photophysical tool to shift the activation wavelength of photopharmacological compounds to the red or near-infrared wavelength domain, in which light penetrates human tissue optimally. However, TTA-UC is sensitive to dioxygen, which quenches the triplet states needed for upconversion. Here, we demonstrate not only that the sensitivity of TTA-UC liposomes to dioxygen can be circumvented by adding antioxidants, but also that this strategy is compatible with the activation of ruthenium-based chemotherapeutic compounds. First, red-to-blue upconverting liposomes were functionalized with a blue-light sensitive, membrane-anchored ruthenium polypyridyl complex, and put in solution in presence of a cocktail of antioxidants composed of ascorbic acid and glutathione. Upon red light irradiation with a medical grade 630 nm PDT laser, enough blue light was produced by TTA-UC liposomes under air to efficiently trigger full activation of the Ru-based prodrug. Then, the blue light generated by TTA-UC liposomes under red light irradiation (630 nm, 0.57 W/cm2) through different thicknesses of pork or chicken meat was measured, showing that TTA-UC still occurred even beyond 10 mm of biological tissue. Overall, the rate of activation of the ruthenium compound in TTA-UC liposomes using either blue or red light (1.6 W/cm2) through 7 mm of pork fillet were found comparable, but the blue light caused significant tissue damage, whereas red light did not. Finally, full activation of the ruthenium prodrug in TTA-UC liposomes was obtained under red light irradiation through 7 mm of pork fillet, thereby underlining the in vivo applicability of the activation-by-upconversion strategy.
Highlights
Among the wide variety of photopharmacological compounds known to date, light-activatable ruthenium polypyridyl complexes have received considerable attention as they represent a promising family of anticancer prodrugs
Where applicable, before addition of phosphate buffered saline (PBS) to the lipid film, the buffer was supplemented with a known concentration of L-ascorbic acid (L-Asc) and/or glutathione (GSH) as antioxidants, and neutralized to pH 7.0–7.6 with NaOH
To approach the practical conditions of a phototherapeutic operation, it was first determined that upconverted blue light can still be generated by triplet annihilation upconversion (TTA-UC) through more than 10 mm of chicken or pig meat
Summary
Among the wide variety of photopharmacological compounds known to date, light-activatable ruthenium polypyridyl complexes have received considerable attention as they represent a promising family of anticancer prodrugs. It is possible to anchor ruthenium complex to nanoparticles or liposomes, which allows for targeting the compound to tumors by making use of their leaky vasculature via the enhanced permeability and retention (EPR) effect [6,7]. 21, 1460 (PDT) type 2, which functions by generating highly reactive oxygen. Using light-activatable Ru-complexes may be suitable for hypoxic tumor tissues photodynamic therapy (PDT) type 2, which functions by generating highly reactive oxygen species for which
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