Photophysics of Photodynamic Therapy

描述(由申请人提供)：光动力疗法(PDT)治疗癌症和其他疾病继续获得临床接受。三种光敏药物Photofrin、Visudyne和Levulan在美国的批准，以及世界各地正在进行的几种有希望的新药的临床评估，为正在进行的实验室研究提供了背景，这些研究旨在进一步了解和优化这种疗法。在过去的几年里，该领域对光敏药物、光和氧之间复杂而动态的相互作用有了更深的理解，这些相互作用共同定义了PDT的剂量学。十多年来，该实验室的研究证实了氧和光敏剂在肿瘤中微观梯度的存在并强调了其后果，探索了几种形式的光学光谱和成像作为监测光动力剂量沉积和评估PDT生物响应的手段，最近，使用荧光记者对PDT诱导的基因表达进行了体内成像。在上一个供资周期取得的进展为在这些密切相关的问题上取得进一步重大进展创造了许多机会。为此，本申请提出了以下三个具体目标：(1)进一步扩大光敏剂浓度、氧气可获得性和剂量沉积微观异质性的实验研究和理论分析；(2)开发分子成像策略以确定肿瘤对PDT反应的异质性，并开发控制免疫反应招募的成像手段；(3)测量人肾细胞癌和正常肾脏的光学特性，并探索进一步建立图像引导的、针对深层肿瘤的间质PDT的方法。实现这些目标的实验方法包括激光扫描光学切片荧光显微镜和显微荧光分光光度法、全鼠体内荧光成像和光谱分析以及漫反射光谱分析。与公共健康相关：光动力疗法被批准用于治疗几种癌症和癌前疾病。随着我们更全面地了解限制其有效性的因素，并将研究结果从实验室转化为临床，它的潜力将得到更充分的实现。这笔赠款中提议的研究涉及这两个目标。

DESCRIPTION (provided by applicant): Photodynamic therapy (PDT) of cancer and of other conditions continues to gain clinical acceptance. The approvals of three photosensitizing drugs, Photofrin, Visudyne, and Levulan, in the United States and the ongoing clinical evaluation of several promising new agents throughout the world provide the context for ongoing laboratory studies that are designed to understand further and to optimize this therapy. During the past several years, the field has gained a deeper appreciation of the complex and dynamic interactions among the photosensitizing drug, light, and oxygen that together define the dosimetry of PDT. For more than a decade, research in this laboratory has demonstrated the existence and emphasized the consequences of microscopic gradients of oxygen and of photosensitizer in tumors, explored several forms of optical spectroscopy and imaging as means of monitoring photodynamic dose deposition and evaluating biological response to PDT, and more recently, undertaken the use of fluorescent reporters to image PDT-induced gene expression in vivo. Progress during the previous funding cycle has created a number of opportunities to make further significant progress on these and closely related problems. Toward these general ends, the application poses the following three specific aims: (1) to further expand the experimental investigation and theoretical analysis of microscopic heterogeneities in photosensitizer concentration, oxygen availability, and dose deposition; (2) to exploit molecular imaging strategies to determine heterogeneities in tumor response to PDT and to develop means of imaging the mechanisms governing the recruitment of immune responses; and (3) to measure optical properties of human renal cell carcinoma and of normal kidney and to explore means of further establishing image-guided, interstitial PDT for deep tumors. The experimental methods that will be used to accomplish these aims include laser scanning optical sectioning fluorescence microscopy and microspectrofluorimetry, whole mouse fluorescence imaging and spectroscopy in vivo, and diffuse reflectance spectroscopy. Relevance to public health: Photodynamic therapy is approved for the treatment of several cancers and pre-cancerous conditions. Its potential will be more fully realized as we understand more completely the factors that limit its effectiveness and translate findings from the laboratory to the clinic. Studies proposed in this grant address both of these objectives.