Photophysics of Photodynamic Therapy

描述(申请人提供)：光动力疗法(PDT)治疗癌症和其他各种疾病继续获得临床认可。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。该实验室的研究旨在定量定义治疗诱导的光化学耗氧量对治疗结果的影响。这项工作的一个至关重要的方面是，以一种可以转化为临床相关测量的方式，更准确地定义致敏药物的光降解、光动力学诱导的氧气消耗、光动力剂量的详细沉积和生物反应之间的关系。这反过来需要改进的方法来执行和分析肿瘤的荧光光谱结果，并对肿瘤的氧合进行非侵入性评估。为此，本申请提出了以下三个具体目标：(1)扩大光动力疗法中氧问题的实验研究和理论分析；(2)建立增敏剂荧光光谱报告体内肿瘤生物学反应的能力，并从空间分辨荧光测量中探索同时光谱评估血氧、NADH和增敏剂漂白/光产物动力学的可行性；以及(3)确定诱导特定基因的光动力疗法阈值剂量以及诱导低氧诱导因子-10c表达所需的光动力疗法诱导低氧诱导因子-10c的特定严重程度和持续时间。实现这些目标的实验方法包括氧敏感微电极的使用、激光扫描光学切片荧光显微镜和显微荧光光谱、体内荧光光谱和漫反射吸收光谱。

DESCRIPTION (provided by applicant): Photodynamic therapy (PDT) of cancer and of various 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. Research in this laboratory has been directed at defining quantitatively the consequences of therapy-induced, photochemical oxygen consumption for therapeutic outcome. A critically important aspect of this effort is to define more precisely and in a manner that can be translated into clinically relevant measurements the relationship between the photodegradation of the sensitizing drug, the PDT-induced consumption of oxygen, the detailed deposition of photodynamic dose and the biological response. This in turn requires improved methods for performing and analyzing results from fluorescence spectroscopy in tumors and for the noninvasive assessment of tumor oxygenation. Toward these general ends, the application poses the following three specific aims: (1) to expand the experimental investigation and theoretical analysis of the oxygen problem in PDT; (2) to establish the ability of sensitizer fluorescence spectroscopy to report biological response of tumors in vivo and to investigate the feasibility of simultaneous spectroscopic assessment of blood oxygen, NADH and sensitizer bleaching/photoproduct kinetics from spatially resolved measurements of fluorescence; and (3) to determine the PDT threshold dose for induction of specific genes and the specific severity and duration of PDT-induced hypoxia required to induce the expression of hypoxia-inducible factor-10c. The experimental methods that will be used to accomplish these aims include the use of O2-sensitive microelectrodes, laser scanning optical sectioning fluorescence microscopy and microspectrofluorimetry, fluorescence spectroscopy in vivo and diffuse reflectance absorption spectroscopy.