Chalcogenapyrylium dyes as dual-action sensitizers for photodynamic therapy.

Cytochrome c oxidase activity in isolated tumor mitochondria was inhibited by exposure to 570-800 nm of light after addition of cationic dye 1. The alteration in enzyme activity is a consequence of the formation of the highly reactive oxygen species, singlet oxygen, a photochemical product resulting from the irradiation (770 nm of light) of dye 1 in the presence of oxygen. The oxidation of dye 1 by singlet oxygen produces dye 2. Irradiation of mitochondrial suspensions treated with 10(-5) M solutions of dye 2 with 489 +/- 5 nm of light also caused inhibition of cytochrome c oxidase activity, but the addition of scavengers of singlet oxygen, hydrogen peroxide, superoxide, and hydroxyl radical did not prevent the observed inhibition. Similarly, lowering the atmospheric oxygen concentration to 3% had no effect on mitochondrial inhibition. In solution, photoreduction of dye 2 occurred at an increased rate in the presence of 0.01 M tryptophan. ESR studies of dye 2 with 5,5 dimethyl-1-pyrroline-N-oxide (DMPO) (0.1 M) and added tryptophan (0.01 M) suggested the photoproduction of hydroxyl radicals as a possible mechanism for its photodynamic action. We interpret the data as indicating the possibility that after the photooxidative transformation of dye 1 to dye 2, a second mechanism becomes operative for further photodynamic inhibition of enzyme activity. The in vivo or in vitro conversion of dye 1 to dye 2 would allow dye 1 to function as a novel, dual-action photosensitizer.