PHOTOSENSTIZATION MECHANISMS IN HYPOXIC MEDIA

缺氧介质中的光敏化机制

基本信息

批准号：
2850457
负责人：
ROBERT W REDMOND
金额：
$ 18.81万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-04-16 至 2004-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2850457
关键词：
cytotoxicity flash photolysis free radical oxygen hypoxia laboratory mouse lipid bilayer membrane lysosomes mitochondria neoplasm /cancer photoradiation therapy oxygen consumption photobiology photochemistry photolysis photosensitizing agents protein localization singlet oxygen tissue /cell culture ultraviolet radiation

项目摘要

Photosensitization processes are used in a variety of medical applications to effect a therapeutic response in abnormal tissue. Photodynamic Therapy (PDT) is a developing approach for the treatment of cancer and other diseases which relies on the combination of light and drug (photosensitizer, PS) to produce reactive species, such as singlet oxygen (1O2), which are toxic to the target tissue. PDT in its current form is dependent on reactions of the PS with oxygen for its efficacy. Thus, hypoxia is currently a limitation to effective PDT. An understanding of subtle microenvironment effects on PS photophysics and photochemistry and development of strategies to reduce PDT- induced hypoxia or provide oxygen-independent phytotoxicity will aid in overcoming these limitations. The first specific aim addresses the influence of the biological microenvironment on the mechanism by which the PS can induce phototoxicity in cells, with specific focus on the role of the subcellular localization site of the PS. The influence of local PS concentration (which arises from confinement in small intracellular volumes) and oxygen concentration on photosensitization mechanism will be addressed. The relative susceptibility of the cell to damage at plasma membrane, mitochondria and lysosomes caused by both singlet oxygen and radicals will be determined, in addition to a quantitative comparison of phytotoxic potential of singlet oxygen and radicals. The second specific aim is the application of a non-invasive, spectroscopic, oxygen-sensing technique to monitor therapeutically- induced hypoxia in real time. The technique, based on oxygen dependence of the PS excited state lifetime, will be applied to investigate the effects of fluence rate on induction of hypoxia and to guide on-line, feedback control of light dosimetry. Onset of irreversible hypoxia, caused by vascular occlusion, will be investigated as a practical end- point for PDT treatment. The culmination of these studies will be a dynamic approach to PDT dosimetry which is unaffected by tumor to tumor variations between patients and capable of ensuring optimal therapeutic outcomes in the shortest possible treatment duration. The final specific aim is the development of a novel strategy for oxygen- independent photosensitization via radical generation on irradiation with low intensity red light, as used currently in PDT. The applicability of photoinduced intramolecular radical generators (PIRGs) to overcome hypoxia by producing reactive radicals under mild irradiation conditions will be determined. The ability of a PIRG to modulate between oxygen-dependent and independent photosensitization mechanisms in direct response to oxygen levels will be investigated.

光敏化过程用于多种医疗领域在异常组织中产生治疗反应的应用。光动力疗法（PDT）是一种正在发展的治疗方法癌症和其他疾病的治疗依赖于光的结合和药物（光敏剂，PS）产生活性物质，例如单线态氧 (1O2)，对靶组织有毒。 PDT 在其目前的形式取决于 PS 与氧气的反应功效。因此，缺氧目前是有效PDT的限制。了解微环境对 PS 光物理学的微妙影响和光化学以及减少PDT-的策略的开发诱导缺氧或提供不依赖于氧气的植物毒性将有助于克服这些限制。第一个具体目标解决了生物因素的影响微环境对PS诱导机制的影响细胞中的光毒性，特别关注光毒性的作用 PS 的亚细胞定位位点。当地PS的影响浓度（由于限制在小的细胞内体积）和氧气浓度对光敏机制的影响得到解决。细胞对损伤的相对敏感性质膜、线粒体和溶酶体均由单线态引起除了定量之外，还将测定氧和自由基单线态氧和自由基的植物毒性潜力的比较。第二个具体目标是应用非侵入性、光谱、氧传感技术来监测治疗- 实时诱导缺氧。该技术基于氧依赖性 PS激发态寿命，将用于研究注量率对缺氧诱导的影响并在线指导，光剂量测定的反馈控制。发生不可逆转的缺氧，由血管闭塞引起的，将作为实际终点进行研究 PDT 治疗的要点。这些研究的高潮将是不受肿瘤间影响的动态 PDT 剂量测定方法患者之间存在差异，能够确保最佳治疗在尽可能短的治疗时间内获得结果。决赛具体目标是开发一种新的氧气策略通过照射时产生自由基实现独立光敏化使用低强度红光，如目前 PDT 中使用的那样。这光诱导分子内自由基发生器（PIRG）的适用性通过在温和条件下产生活性自由基来克服缺氧照射条件将被确定。 PIRG 的能力在氧依赖性和非依赖性光敏之间进行调节将研究对氧气水平直接反应的机制。