Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069155-02
Application #
2517682
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1996-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260

  Publications

Wagner, Stephen J; Skripchenko, Andrey; Donnelly, David J et al. (2005) Chalcogenoxanthylium photosensitizers for the photodynamic purging of blood-borne viral and bacterial pathogens. Bioorg Med Chem 13:5927-35
Detty, Michael R; Gibson, Scott L; Hilf, Russell (2004) Comparison of the dark and light-induced toxicity of thio and seleno analogues of the thiopyrylium dye AA1. Bioorg Med Chem 12:2589-96
Detty, Michael R; Prasad, Paras N; Donnelly, David J et al. (2004) Synthesis, properties, and photodynamic properties in vitro of heavy-chalcogen analogues of tetramethylrosamine. Bioorg Med Chem 12:2537-44
Detty, Michael R; Gibson, Scott L; Wagner, Stephen J (2004) Current clinical and preclinical photosensitizers for use in photodynamic therapy. J Med Chem 47:3897-915
Brennan, Nancy K; Donnelly, David J; Detty, Michael R (2003) Selenoxanthones via directed metalations in 2-arylselenobenzamide derivatives. J Org Chem 68:3344-7
You, Youngjae; Gibson, Scott L; Hilf, Russell et al. (2003) Water soluble, core-modified porphyrins. 3. Synthesis, photophysical properties, and in vitro studies of photosensitization, uptake, and localization with carboxylic acid-substituted derivatives. J Med Chem 46:3734-47
Brennan, Nancy K; Hall, Jonathan P; Davies, Sherry R et al. (2002) In vitro photodynamic properties of chalcogenopyrylium analogues of the thiopyrylium antitumor agent AA1. J Med Chem 45:5123-35
Stilts, C E; Nelen, M I; Hilmey, D G et al. (2000) Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy. J Med Chem 43:2403-10
Leonard, K A; Hall, J P; Nelen, M I et al. (2000) A selenopyrylium photosensitizer for photodynamic therapy related in structure to the antitumor agent AA1 with potent in vivo activity and no long-term skin photosensitization. J Med Chem 43:4488-98
Leonard, K A; Nelen, M I; Anderson, L T et al. (1999) 2,4,6-triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer. J Med Chem 42:3942-52

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