PDT--MECHANISMS AND STRATEGIES FOR OPTIMIZATION

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It is the long term, overall goal of this Program Project to increase the understanding of structure-activity relationships of photosensitizers, both anionic and cationic, used in photodynamic therapy, and the in vitro and in vivo mechanisms of their action. The mechanistic information derived will be used to devise strategies to improve the efficacy of photodynamic/photochemotherapy. This will be achieved through the following Individual Research Projects: 1. New anionic photosensitizers of specific incremental structural changes and long-wavelength absorbing photosensitizers will be synthesized and made available to other projects. The photophysical properties of these sensitizers will be determined and a concept for comparison of sensitizer efficiency will be developed. 2. Structure/activity relationships of novel photosensitizers will be defined with regard to the determinants for tumor cell and vascular photosensitization. Tumor perfusion and photosensitivity of cells in well and poorly perfused tumor regions will be assessed. Local and systemic host response mechanisms to photosensitizer and photodynamic treatment will be studied. 3. New cationic photosensitizers will be synthesized and structure-activity relationships and mechanisms of in vitro and in vivo mechanisms of phototoxicity will be defined. Multiagent treatments and combination treatments will be devised to enhance the efficacy of photochemotherapy. 4. The dynamics of the response to photodynamic therapy of human tumors will be studied, including sensitizer uptake, time frame of vascular response, photobleaching and effects of previous treatments. The Individual Research Projects will be supported by two very important technical core components -- one for drug evaluation and flow cytometry, one for optical aspects of the research and non-invasive monitoring of treatment progress. These are critical to ensure overall progress and productivity. Biomathematics and administrative core components complete this multi-disciplinary Program Project.