Photodynamic therapy (PDT) of neoplastic disease is a new modality currently undergoing intensive study. The major limitations of PDT are persistent skin photosensization, along with the need for irradiation at 630 nm, a wavelength difficult to achieve by laser technology. This study is designed to examine new photosensitizing dyes based on the dimeric structure which contributes to the tumor-localization by HPD, the current clinical sensitizer, but with alterations designed to promote absorbance at wavelengths greater than 750 nm. These agents will be prepared and chemically characterized by Dr. C.K. Chang. Evaluation of toxicity and of sites of photodynamic action will be carried out by Dr. Henderson. A delineation between direct tumor kill vs. indirect toxicity via vascular damage will be made. Determinants of PDT effectiveness will be determined in vivo and in vitro. We will characterize dye aggregation, hydrophobicity, affinity for different plasma macro- molecules, environmental properties of dye-binding sites and the nature of photodamage. The distribution of sensitizers among plasma protein and lipoproteins will be examined by density-gradient ultracentrifugation, with fluorescence, absorbance and (where feasible) radioactivity used to quantitate dye concentration. As the relative effectiveness of new dyes becomes established, we should be able to identify properties of these agents that predict for superior localizing and photosensitizing behavior. Exploration of these structure-activity relationships is expected to facilitate the design of new dyes for photodynamic therapy. An understanding of the determinants of selective localization and photosensitization will represent a useful contribution to our knowledge of tumor cell biology.
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