The ultimate objective of this research is to provide viable clinical agents that are useful as sensitizers in photodynamic therapy (PDT) for the treatment of cancer. PDT is a relatively recent development in cancer therapy in which light is combined with a sensitizer to produce a cytotoxic event in the tumor cell. It is a specific aim of the proposed research to design, synthesize, and evaluate new sensitizers for PDT which: 1) are selectively retained or localized in tumors, 2) produce reactive intermediates that deplete glutathione levels during PDT and that adsorb shorter wavelengths of light preventing shielding of tumor cells deeper in tissue, and 3) absorb longer wavelengths of light where penetration of tissue is optimal. These desirable features can be designed into new sensitizers for PDT by the incorporation of a tellurium atom in the sensitizer chromophore. Specifically, telluropyrylium dyes, tellurium-containing rhodamine (xanthylium) dyes, and tellurium-containing benzophenothiazinium (nile blue) dyes will be prepared and evaluated for their spectral, chemical, and photophysical properties. These include absorption spectra, n-octanol/water partition coefficients, quantum yields for singlet oxygen generation, hydrolysis rates as a function of pH, reactivity with singlet oxygen, and rates of reaction with glutathione. The biological activity of the new drugs with appropriate spectral, chemical, and photophysical properties will be evaluated in vitro in cultures of human squamous carcinoma cells and normal epithelial cells to determine: 1) relative uptake of the dyes, 2) dark toxicity of the dyes, and 3) phototoxicity of the dyes toward normal and transformed cells. Sensitizers that show promise in the in vitro studies or appropriately modified new derivatives will be evaluated in vivo using a murine epithelial tumor model for therapeutic efficacy, pharmacokinetic studies of dye distribution and retention in transformed and normal tissue, and effects on cellular glutathione levels.
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