Effects of Photodynamic Therapy on Tumor Oxygenation

光动力疗法对肿瘤氧合的影响

• 批准号: 6633686
• 负责人: Theresa M Busch
• 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/6633686
• 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 肿瘤中光敏剂的分布，描述光动力的影响 对这些分布进行治疗（PDT），并测量对肿瘤的影响 回复。 PDT 照明光消耗肿瘤氧已被证实 被确定为潜在的治疗限制。研究这种氧气的方法 消耗包括极谱针探针测量组织 PO(2) 以及血氧浓度的光谱测定。肿瘤平均 氧浓度测量表明 PDT 可以产生严重的肿瘤 缺氧，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 PDT 的反应是 由氧气相对于损伤目标的空间分布决定 （例如血管内皮）和光敏剂生物分布。描述 PDT 期间氧气和敏化剂的分布可以提示以下原因： 治疗失败并促进制定更有效的治疗方案。 氟化系列2-硝基咪唑缺氧标记物，包括药物 EF3 和 EF5 是在我们的实验室内开发的。缺氧标志物是 研究 PDT 对肿瘤氧合区域影响的独特方法。 EF3 将用于通过以下方式量化小鼠肿瘤的氧合 冰冻切片的免疫组织化学和细胞悬液的流式细胞术。 缺氧标记物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 血管分布（用抗体标记）、肿瘤灌注（用注射液标记） 荧光染料）和细胞凋亡（通过商业试剂盒检测）。梯度在 肿瘤氧合，可能作为距血液距离的函数而存在 船舶，将被量化。维持氧气的后果或 血管的耗竭将根据 PDT 相关进行检查 血管损伤，包括坏死和细胞凋亡的发展。这 控制注量率和药物剂量以控制局部氧消耗 并检查肿瘤反应的改善情况。将进行调查 使用三种临床相关光敏剂：Photofrin、Foscan 和 Lutex。