The photodynamic therapy or neoplastic disease currently involves the use of a product derived from hematoporphyrin and termed hematoporphyrin derivative (HPD). The degree of tumor localization following systemic HPD administration is sufficient to permit identification of neoplastic loci by fluorescence imaging, and to catalyze selective tumor eradication if a sufficient light flux is provided. The major limitations of photodynamic therapy (PDT) are (1) a persistent photosensitization of the skin, (2) the requirement for irradiation at 630 nm, a wavelength difficult to achieve by current technology, (3) limited depth of tissue penetration by 630 nm light. This study is designed to explore new photosensitizing dyes with substantial absorbance at wavelengths greater than 650 nm. A ideal sensitizer will be at least as active as HPD, with a more limited half-life in the circulation, and no dark toxicity. Absorbance at wavelengths greater than 750 nm would permit the use of diode lasers, for dye activation. While rational considerations will govern drug design, the applicant will allow for the possibility that unknown factors may play a role in structure- activity relationships. An initial screen will rule by dyes with host toxicity, low PDT efficiency or inadequate tumor localization. Work will then be directed toward delineating modes of actin and determinants of dye localization and distribution. As the relative effectiveness of new dyes becomes known; the applicant can identify properties that predict for superior tumor-localizing and photosensitizing behavior. Experimental techniques will involve characterization of dye hydrophobicity, transport, affinity for plasma protein and lipoproteins, properties of dye-binding sites, and the nature of dye-mediated photo-damage. Effectiveness of repair systems will be evaluated. Additional biologic studies will determine patterns and pharmacokinetics of dye distribution in the mouse, along with the potential for synergistic antitumor toxicity from concurrent hyperthermia. Exploration of these phenomena should facilitate the design of new dyes for PDT.
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