Photodynamic therapy consumes oxygen at rates much higher than other cancer therapies. The production of singlet oxygen in high yields is thought to be the phototoxic mechanism responsible for tumor necrosis through both vascular occlusion and direct cellular damage. Optimum treatment requires an understanding of the tumor pathobiology, the sensitizer location and photochemical kinetics in order to predict the best treatment plan. This proposal plans to directly measure the temporal oxygen tension before, during and after therapy, in both the RIF-1 murine tumor and the metastatic MatLyLu rat prostate tumor. This study will examine the effects of (1) different dose rates and dose schedules of oscillating light on and off (on the time scale of seconds), as well as (2) the optimum time for PDT fractionation (on the time scale of days) upon the measured pO2 of the tumor, and correlate these measurements to the tumor treatment outcomes. Three clinically relevant photosensitizers will be examined in this study: (1) benzoporphyrin derivative (BPD), (2) 5-delta-aminolevulinic acid induced protoporpyrin-IX (ALA), and (3) 5-ethylamino-9-diethylaminobenzo[a] phenothiazinium chloride (EtNBS), which have varying degrees of vascular versus direct cellular effects on the tumor necrosis, and hence have very different oxygen supply needs during and after the therapy. Two complementary methods for non-invasive p02 measurement will be used. First, electron paramagnetic resonance oximetry will monitor the local oxygen pO2 in tissue before, during and after treatment, giving a good localized picture of the oxygen dynamics. The second method is transient diffuse reflectance spectroscopy of the photosensitizer molecule, which is a direct probe of the pO2 at the site of the photosensitizer. These p02 measurements will be combined with measurement of photosensitizer concentration in tissue, tissue optical properties, and tumor perfusion measurements to allow a comprehensive analysis of the process. In these studies, a systematic progression from (1) cell slurry, to (2) subcutaneous tumor to (3) metastatic prostate tumor will be used to evaluate the effects on treatment outcome. Finally, an improved model of dosimetry for PDT will identify the relative roles of oxygen supply, tumor capillary density, tumor perfusion, photosensitizer uptake, tissue optical properties, site of localization and light fluence rate for optimal PDT treatment outcomes.
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