Effects of Photodynamic Therapy on Tumor Oxygenation

光动力疗法对肿瘤氧合的影响

• 批准号: 6333042
• 负责人: CAMERON J KOCH
• 金额: $ 30.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6333042
• 关键词: apoptosis; drug administration rate /duration; fibrosarcoma; flow cytometry; fluorescence microscopy; hypoxia; immunocytochemistry; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; nonhuman therapy evaluation; oxygen transport; photosensitizing agents; vascular endothelium

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.

描述：该项目的目标是量化氧气和 肿瘤中的光敏剂分布，描述光动力的影响 对这些分布的治疗（PDT），并测量对肿瘤的后果 回复。 PDT的照明光已经耗尽肿瘤氧 被确定为潜在的治疗限制。研究这种氧的方法 耗竭包括组织PO的光学针头探针测量（2） 血液氧浓度的光谱测定。肿瘤平均 氧浓度的测量表明PDT可以产生严重的肿瘤 缺氧，但是这些方法缺乏空间分辨率来检测 氧分布。我们假设肿瘤对PDT的反应将是 取决于氧相对于损伤靶标的空间分布 （例如，血管内皮）和光敏剂生物分布。描述 PDT期间的氧气和敏化剂分布可能提出 治疗失败并促进开发更有效的治疗方案。 氟化的2-硝基咪唑低氧标记，包括药物 EF3和EF5是在我们的实验室内开发的。低氧标记是 研究PDT对肿瘤氧合的区域影响的独特手段。 EF3将用于量化通过 细胞悬浮液的冷冻切片和流式细胞术的免疫组织化学。 将缺氧标记结合的模式和强度与 光敏剂分布（由其固有荧光决定），肿瘤 血管性（由抗体标记），肿瘤灌注（由注射标记 荧光染料）和凋亡（通过商业试剂盒检测）。梯度在 肿瘤氧合可能是距血液距离的函数 船只将进行量化。氧气维持的后果或 将检查血管的耗竭在PDT相关方面检查 血管损伤，包括坏死和凋亡的发展。这 操纵通风率和药物剂量以控制局部氧气耗竭 并将检查改善肿瘤反应。调查将进行 使用三个临床相关的光敏剂，即光蛋白，foscan和Lutex。