The ultimate objective of this research is to provide viable clinical agents useful as sensitizers in the photodynamic therapy (PDT) of cancer.
One aim of the proposed research is to design, synthesize, and evaluate new sensitizers for PDT that: 1) are selectively retained in tumors, 2) display no long-term skin photosensitivity, 3) have high quantum yields for the cytotoxic event, 4) deplete glutathione levels during PDT, and 5) absorb longer wavelengths of light where light penetration into tissue is optimal. These desirable features can be obtained by replacing oxygen or sulfur in the sensitizer chromophore with the heavy atoms selenium or tellurium. Selenium and tellurium analogues of both the anticarcinoma agent AA1 and the rhodamine dyes will be prepared and evaluated for their spectral, chemical, and photophysical properties, which include n-octanol water partition coefficients, quantum yields for singlet oxygen generation, pH-sensitive hydrolysis rates, reactivity with singlet oxygen, and rates of reaction of oxidized dyes with glutathione. The biological activity of the new drugs with appropriate spectral, chemical, and photophysical properties will be evaluated in vitro against several cancer cell lines to determine: 1) uptake of the dyes, 2) dark and phototoxicities, and 3) mechanisms of phototoxicity. Isolated mitochondrial suspensions will also be used to evaluate mechanisms of phototoxicity. Sensitizers that show promise in the in vitro studies or appropriately modified new derivatives will be evaluated in vivo using a rat mammary tumor model for therapeutic efficacy, pharmacokinetic studies of dye distribution and retention in normal and cancer tissues, and effects on cellular glutathione levels. PDT with the selenopyrylium dye KL-Se, which shows no toxicity at 29 mg (62 umol)/ kg and is selectively retained by tumors, will be optimized to improve upon the 300 percent increase in tumor doubling time (relative to untreated controls) already observed in initial PDT studies with KL-Se.
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