Effects of Photodynamic Therapy on Tumor Oxygenation

描述：该项目的目标是量化氧气和 光敏剂在肿瘤中的分布，描述了光动力学的影响 治疗(PDT)对这些分布的影响，并衡量其对肿瘤的影响 回应。用于光动力疗法的照明光耗尽了肿瘤的氧气 被确认为潜在的治疗限制。研究这种氧的方法 耗竭包括极谱针头测量组织PO(2) 以及血氧浓度的光谱测定。平均肿瘤数 氧浓度测量表明，光动力疗法可产生严重的肿瘤。 低氧，但这些方法缺乏空间分辨率来检测梯度 氧气分布。我们假设肿瘤对光动力疗法的反应将是 由氧相对于损伤目标的空间分布确定 (如血管内皮细胞)和光敏剂的生物分布。该描述 光动力疗法中氧气和敏化剂分布的变化可能会提示原因 治疗失败并有助于制定更有效的治疗方案。 包括药物在内的氟化系列2-硝基咪唑低氧标志物 EF3和EF5是在我们的实验室内开发出来的。低氧标志物是一种 研究光动力疗法对肿瘤氧合的区域性影响的独特手段。 EF3将用于量化小鼠肿瘤的氧合作用 冰冻切片免疫组织化学和细胞悬液流式细胞术。 低氧标记结合的模式和强度将与 光敏剂分布(由其固有荧光决定)、肿瘤 血管(用抗体标记)、肿瘤灌注量(用注射标记 荧光染料)和细胞凋亡(通过商业试剂盒检测)。渐变 肿瘤氧合，可能作为与血液的距离的函数而存在 船只，将被量化。氧气维持的后果或 血管的耗竭将通过与光动力疗法相关的 血管损伤，包括发展为坏死和细胞凋亡。这个 控制局部氧耗的注量率和用药剂量的控制 并改善肿瘤反应将被检查。将进行调查 使用三种临床上相关的光敏剂，Photofrin，Foscan和Lutex。

DESCRIPTION: The goals of this project are to quantify oxygen and photosensitizer distributions in tumors, describe the effects of photodynamic therapy (PDT) on these distributions, and measure the consequences on tumor response. Depletion of tumor oxygen by the illuminating light for PDT has been identified as potentially therapy-limiting. Methods of studying this oxygen depletion have included polarographic needle probe measurement of tissue PO(2) and spectroscopic determination of blood oxygen concentration. Tumor-averaged measurements of oxygen concentration indicate that PDT can create severe tumor hypoxia, but these methods lack the spatial resolution to detect gradients in oxygen distribution. We hypothesize that tumor responses to PDT will be determined by the spatial distribution of oxygen relative to targets of damage (e.g. the vascular endothelium) and photosensitizer biodistribution. The description of oxygen and sensitizer distributions during PDT could suggest reasons for treatment failure and facilitate the development of more effective treatment protocols. A fluorinated series of 2-nitroimidazole hypoxic markers, including the drugs EF3 and EF5, has been developed within our laboratories. Hypoxic markers are a unique means to investigate the regional effects of PDT on tumor oxygenation. EF3 will be used to quantify the oxygenation of murine tumors through immunohistochemistry of frozen sections and flow cytometry of cell suspensions. Patterns and intensities of hypoxic marker binding will be compared to those of photosensitizer distribution (determined by their inherent fluorescence), tumor vascularity (labeled by antibodies), tumor perfusion (labeled by injected fluorescent dyes), and apoptosis (detected by commercial kits). Gradients in tumor oxygenation, which may exist as a function of distance from the blood vessels, will be quantified. The consequences of oxygen maintenance or depletion at the blood vessels will be examined in terms of PDT-associated vascular damage, including the development of necrosis and apoptosis. The manipulation of fluence rate and drug dose to control local oxygen depletion and improve tumor response will be examined. Investigations will be carried out using three clinically relevant photosensitizers, Photofrin, Foscan and Lutex.