PHOTOSENSITIZATION MECHANISMS IN HYPOXIC MEDIA

缺氧介质中的光敏化机制

• 批准号: 2683617
• 负责人: ROBERT W REDMOND
• 金额: $ 19.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-16 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683617
• 关键词: cytotoxicity; drug screening /evaluation; erythrocyte membrane; flash photolysis; free radical oxygen; hypoxia; light scattering; lipid bilayer membrane; liposomes; neoplasm /cancer photoradiation therapy; neoplastic cell; oxygen consumption; photobiology; photochemistry; photosensitizing agents; porphyrins; singlet oxygen; tissue /cell culture; triplet state; ultraviolet radiation

DESCRIPTION: (adapted from the investigator's abstract) This proposal explores the limitations set by the local microenvironment in vivo on conventional photosensitizers which act via generation of toxic singlet oxygen. Hypoxia is thus a limiting factor to PDT. The systematic determination of the oxygen dependence of these photosensitizers will facilitate a better understanding of in vivo photosensitization. The development of alternative oxygen-independent sensitization mechanisms of photodamage which overcome existing limitations in PDT is proposed. The 1st specific aim is to investigate the direct effects of the biological microenvironment of the photosensitizer on its mechanism and efficiency. the effects of (i) high local sensitizer concentration; (ii) direct reaction of photosensitizer intermediates with integral biomolecules and (iii) cellular localization sites, on the photophysics and phototoxicity of photosensitizers will be determined in liposomes, erythrocyte ghosts and malignant cell suspensions. The 2nd specific aim is to construct a general relationship to predict efficacy of singlet oxygen photosensitizers to cause cell damage. Diffuse reflectance laser flash photolysis will measure oxygen concentrations in vivo using oxygen-dependent triplet state kinetics. Measured [O2] will be combined with rate constants for natural decay and oxygen quenching of the triplet state to predict photosensitizer efficiency. This relationship will be tested using photosensitizers with different natural triplet lifetimes, varying [O2] through N2/O2 gas mixtures and correlating observed phototoxicity with the efficiency predicted by the photophysical method. The 3rd specific aim is to develop alternative oxygen-independent photosensitization mechanisms for photosensitized damage in biological media which overcome the limitations of hypoxia. Radical species, rather than singlet oxygen, will be generated through bond cleavage and photosensitization processes in related compounds. A correlation of reaction mechanisms with photoionization normal and hypoxic cellular systems will ascertain the potential of radical-based strategies to effect oxygen-independent photodamage.

描述：（改编自研究者的摘要）该提案 探索体内局部微环境所设置的局限性 通过产生有毒单线态起作用的传统光敏剂 氧。 因此，缺氧是 PDT 的限制因素。 系统化的 确定这些光敏剂的氧依赖性将 有助于更好地了解体内光敏作用。 这 开发替代的不依赖氧的敏化机制 提出了克服 PDT 现有局限性的光损伤研究。 第一个具体目标是调查的直接影响 光敏剂生物微环境对其作用机制及影响 效率。 (i) 高局部敏化剂浓度的影响； (ii) 光敏剂中间体与积分直接反应 光物理学上的生物分子和 (iii) 细胞定位位点 光敏剂的光毒性将在脂质体中测定， 红细胞血影和恶性细胞悬浮液。第二具体 目的是构建一个一般关系来预测功效 单线态氧光敏剂引起细胞损伤。 扩散 反射激光闪光光解将测量氧气浓度 体内使用氧依赖性三重态动力学。 测量[O2] 将与自然衰变和氧气的速率常数相结合 三重态淬灭以预测光敏剂效率。 这种关系将使用不同的光敏剂进行测试 自然三重态寿命，通过 N2/O2 气体混合物改变 [O2] 和 将观察到的光毒性与预测的效率相关联 光物理方法。 第三个具体目标是开发替代方案 光敏化的不依赖氧的光敏机制 克服缺氧局限性的生物介质损伤。 自由基物种，而不是单线态氧，将通过以下方式产生： 相关化合物中的键断裂和光敏化过程。 一个 反应机制与光电离正常和的相关性 缺氧细胞系统将确定基于自由基的潜力 影响不依赖于氧的光损伤的策略。