Photophysics of Photodynamic Therapy

描述（由申请人提供）：癌症和其他疾病的光动力疗法（PDT）继续获得临床认可。三种光敏药物（Photofrin、Visudyne和Levulan）在美国的批准，以及世界各地几种有前景的新药正在进行的临床评估，为正在进行的实验室研究提供了背景，旨在进一步了解和优化这种疗法。在过去的几年中，该领域对光敏药物、光和氧之间复杂和动态的相互作用有了更深入的了解，这些相互作用共同决定了PDT的剂量学。十多年来，该实验室的研究已经证明并强调了氧气和光敏剂在肿瘤中的微观梯度的存在和后果，探索了几种形式的光谱学和成像作为监测光动力剂量沉积和评估PDT生物反应的手段，最近，利用荧光报告器对PDT诱导的基因表达进行了体内成像。上一个筹资周期的进展创造了若干机会，可以在这些问题和密切相关的问题上取得进一步重大进展。为此，本申请提出以下三个具体目标：(1)进一步扩大光敏剂浓度、氧可用性和剂量沉积等微观异质性的实验研究和理论分析；(2)利用分子成像策略来确定肿瘤对PDT反应的异质性，并开发控制免疫反应募集机制的成像手段；(3)测量人肾细胞癌和正常肾脏的光学特性，探索进一步建立深部肿瘤图像引导间质PDT的方法。实验方法将用于实现这些目标，包括激光扫描光学切片荧光显微镜和显微荧光法，全鼠荧光成像和光谱在体内，漫反射光谱。与公众健康相关：光动力疗法已被批准用于治疗几种癌症和癌前病变。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。本赠款中提出的研究解决了这两个目标。

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.