The overall goal of this project is to advance the technique of phototherapy for bladder cancer. We have made substantial progress during the past funding period in basic studies and in preclinical and clinical development of this treatment using hematoporphyrin derivative (HPD) as the photosensitizer. Phase III clinical trials for HPD-phototherapy are now underway. We now focus our efforts on improving and expanding this treatment by searching for more effective photosensitizers. We intend to approach this search from the direction of high tumor- selectivity for the photosensiti. Our target is a group of oxazine related dyes that have demonstrated, from early and from our preliminary work on a number of systems, to be highly selective in localizing in tumors. We are able to enhance the photoactivity of the oxazines buy modifying their structures; up to 65% absolute singlet oxygen yield has been achieved. In this project, we propose to evaluate and further develop these compounds into effective and selective sensitizers for phototherapy of tumors. An important part of this investigation is in our efforts to correlate molecular structures of chromophores with their physicochemical and photochemical properties, and further with their selective localization and photoactivity in cells and in tumors.
The specific aims of this project are: (1) To select, synthesize and characterize a systematic series of oxazine derivatives chosen to allow us to determine structure-function relationships pertaining to selective-tumor localization, photodynamic activity. (2) To evaluate these oxazine derivatives for their selective tumor localization in animal tumor models and in cultured cells. (3) To evaluate and optimize the effectiveness of the oxazines in mediating photo-cytotoxicity in vitro, photodestruction of single, infiltrating, microscopic and metastatic tumors, as well as their dark toxicity. (4) To investigate molecular mechanisms dictating selective-tumor localization and photoactivity of chromophores by examining relationships between molecular structure, photochemical and photophysical properties, and tumor-selectivity and photoavtivity of chromophores. This project will likely lead to improvement of phototherapy by discovering new, effective and tumor-selective sensitizers. This may expand the utility of this therapy to treat life-threatening infiltrating and metastatic tumors. Our study could provide a better understanding for molecular factors dictating tumor- selective and photoreactivity. This will provide guidances for future development of even better photosensiti and greater utilizations of phototherapy. Finally, we expect that this project will obtain adequate information on these dyes to provide the basis for lunching preclinical and clinical studies.
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