PHOTOPHYSICS OF NILE BLUE PHOTODYNAMIC THERAPY

尼罗河蓝光光动力疗法的光物理学

• 批准号: 2700632
• 负责人: THOMAS Harrison FOSTER
• 金额: $ 14.86万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700632
• 关键词: analog; athymic mouse; cytochromes; dosage; drug design /synthesis /production; drug screening /evaluation; dyes; enzyme mechanism; fluorescence microscopy; hemoglobin; laboratory rat; microelectrodes; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; nonvisual photosensitivity; oxygen consumption; oxygen tension; photochemistry; photosensitizing agents; porphyrins; pulmonary diffusion; respiratory oxygenation; selenium; spectrometry; sulfur

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.

Photofrin敏化的光动力疗法（PDT）的最新批准 在加拿大和荷兰，这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 进一步研究设计，合成和评估新的照片， 致敏剂，其寻求克服某些局限性， 第一代龙蜥 在这些公认的 限制是在光穿透 在组织中是最佳的，相对于肿瘤的特异性较差 和正常组织的吸收和保留， 光敏性 许多候选的“第二代”化合物 已经被提出并研究。 这些拟议研究的重点是 一个家族的阳离子染料，显示出特别的前景作为敏化剂， PDT直接破坏肿瘤细胞。 使用的初步经验 这些化合物，被描述为尼罗蓝衍生物， 有趣和具有挑战性的研究问题， 解决，以优化这些光敏剂的有效性。 此外，这些问题可能具有普遍重要性， 寻找直接靶向肿瘤细胞的最佳PDT方法。 在大量实验和理论工作的基础上， 在过去的几年里，我们的实验室，我们假设， 与光化学耗氧和扩散有关的问题 将是优化使用尼罗河蓝的关键方面， PDT的衍生物。 这些问题对这些人来说尤其重要。 染料，因为它们通过酶和光还原而漂白 在低氧浓度条件下的机制。 小心 注意这些过程的细节可以产生重要的 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 尼罗蓝敏化的PDT诱导的氧消耗的测量 多细胞肿瘤球体和光动力学速率的测定 氧耗量;（2）确定这些阈值剂量 多细胞肿瘤球体系统中的染料;（3）光学切片 尼罗蓝敏化球状体的（共聚焦）荧光显微术 在各种孵育条件下和在辐照期间， 漂白速率和机制;（4）光学反射光谱 尼罗蓝敏化PDT期间的肿瘤氧合，重点是 血红蛋白O2饱和度和细胞色素氧化还原状态;以及（5） 优化尼罗蓝敏化PDT照射方案， 啮齿动物肿瘤系统。