PHOTOPHYSICS OF PHOTODYNAMIC THERAPY

光敏光动力疗法(PDT)的最新进展 在加拿大和荷兰是历史上的重大事件 这种相对较新的癌症疗法。这些发展将鼓励 在新照片的设计、合成和评估方面进一步研究- 致敏剂，寻求克服某些限制 第一代预防药物。在这些公认的因素中 限制是在光穿透的波长处的弱吸收 在组织中是最佳的，相对于肿瘤来说相对较差的特异性 和正常的组织摄取和滞留，以及延长皮肤 感光性。一些候选的“第二代”化合物 已经被提出并进行了研究。这些拟议研究的重点是 一类阳离子染料，作为增感物质具有特殊的前景 直接破坏肿瘤细胞进行光动力疗法。使用的初步经验 在这些化合物中，被描述为尼罗蓝衍生物的化合物增加了 有趣和具有挑战性的研究问题对 解决方案，以优化这些光敏剂的效果。 此外，这些问题可能在以下方面具有普遍重要性 寻找直接靶向肿瘤细胞的最佳PDT方法。 在此基础上开展了一系列实验和理论工作 在过去的几年里，我们在实验室里假设 与光化学耗氧和扩散有关的问题 将是优化尼罗蓝使用的关键方面 PDT的衍生品。这些问题对这些人来说尤其重要 通过酶和光还原来漂白的染料 低氧条件下的作用机理。小心 对这些过程的细节的关注可以产生重要的 改善治疗效果的机会。为此， 应用提出了五个具体目标：(1)直接微电极 尼罗河蓝敏化细胞光动力耗氧量的测定 多细胞肿瘤球体及其光动力学速率的测定 氧气消耗量；(2)这些物质的阈值剂量的测定 多细胞肿瘤球体系统中的染料；(3)光学切片 尼罗蓝敏化球体的(共焦)荧光显微镜 在各种孵化条件下和辐照过程中测定 漂白速率和机理；(4)光反射光谱 尼罗蓝增敏光动力疗法中的肿瘤氧合作用 血红蛋白氧饱和度和细胞色素氧化还原状态；以及(5) 尼罗蓝增敏PDT照射方案的三次优化 啮齿动物肿瘤系统。

The recent approvals of Photofrin-sensitized photodynamic therapy (PDT) in Canada and the Netherlands are significant events in the history of this relatively new cancer therapy. These developments will encourage further research in the design, synthesis, and evaluation of new photo- sensitizing agents, which seek to overcome certain limitations of the first generation prophyrins. Among these generally recognized limitations are weak absorption at wavelengths where optical penetration in tissue is optimal, relatively poor specificity with respect to tumor and normal tissue uptake and retention, and prolonged skin photosensitivity. A number of candidate 'second generation' compounds have been proposed and studied. The focus of these proposed studies is a family of cationic dyes that show particular promise as sensitizers of direct tumor cell destruction for PDT. Initial experience with the use of these compounds, described as Nile Blue derivatives, raises interesting and challenging research problems that are critical to resolve in order to optimize the effectiveness of these photosensitizers. Furthermore, these questions are likely to be of general importance in the search for optimum PDT methods of targeting tumor cells directly. On the basis of a body of experimental and theoretical work carries out in our laboratory over the past several years, we hypothesize that problems associated with photochemical oxygen consumption and diffusion will be critical aspects of optimizing the use of the Nile Blue derivatives for PDT. These issues are particularly important for these dyes in that they are bleached through enzymatic and photoreduction mechanisms under conditions of low oxygen concentration. Careful attention to the details of these processes can create significant opportunities for improved therapeutic efficacy. Towards this end, the application poses fives specific aims: (1) direct microelectrode measurements of PDT-induced oxygen consumption in Nile blue-sensitized multicell tumor spheroids and determination of photodynamic rates of oxygen consumption; (2) determination of the threshold dose for these dyes in the multicell tumor spheroid system; (3) optical sectioning (confocal) fluorescence microscopy of Nile blue-sensitized spheroids under various incubation conditions and during irradiation to determine bleaching rates and mechanisms; (4 optical reflectance spectroscopy of tumor oxygenation during Nile blue-sensitized PDT with emphasis on hemoglobin O2 saturation and cytochrome redox status; and (5) optimization of Nile blue-sensitized PDT irradiation protocols in three rodent tumor systems.