Design, Synthesis and Study of New Sensitizers for PDT

描述：（由申请人提供）本研究的最终目的是 为了提供在光动力学中用作敏化剂的可行的临床试剂， 光动力疗法（PDT）拟议研究的一个目的是设计， 合成并评价新PDT敏化剂，其：1）选择性地 保留在肿瘤中，2）没有长期的皮肤光敏性，3）具有高的 细胞毒性事件的量子产率，4）在细胞毒性期间消耗谷胱甘肽水平， PDT，以及5）吸收较长波长的光，其中光穿透进入 组织是最佳的。这些理想的特征可以通过替换氧来获得 或具有重原子硒的敏化剂发色团中的硫， 碲。抗癌剂AA 1的硒和碲类似物 并且制备罗丹明染料并评估其光谱， 化学和物理性质，其中包括正辛醇水分配 系数，单线态氧产生的量子产率，pH敏感 水解速率，与单线态氧的反应性，以及 谷胱甘肽氧化染料。新药的生物活性与 将对适当的光谱、化学和物理特性进行评估 在体外对抗几种癌细胞系以测定：1）染料的摄取， 2)黑暗和光毒性; 3）光毒性机制。分离 线粒体悬浮液也将用于评估 光毒性在体外研究中显示出前景的致敏剂，或 适当修饰的新衍生物将使用大鼠在体内进行评价 乳腺肿瘤模型的治疗效果，染料的药代动力学研究 在正常和癌组织中的分布和保留，以及对 细胞谷胱甘肽水平PDT与硒代吡喃染料KL-Se，其显示 在29 mg（62 umol）/ kg时无毒性，并被肿瘤选择性保留， 优化以改善肿瘤倍增时间增加300%， （相对于未处理的对照）已经在初始PDT研究中观察到 KL-Se。

DESCRIPTION: (provided by applicant) The ultimate objective of this research is to provide viable clinical agents useful as sensitizers in the photodynamic therapy (PDT) of cancer. One aim of the proposed research is to design, synthesize, and evaluate new sensitizers for PDT that: 1) are selectively retained in tumors, 2) display no long-term skin photosensitivity, 3) have high quantum yields for the cytotoxic event, 4) deplete glutathione levels during PDT, and 5) absorb longer wavelengths of light where light penetration into tissue is optimal. These desirable features can be obtained by replacing oxygen or sulfur in the sensitizer chromophore with the heavy atoms selenium or tellurium. Selenium and tellurium analogues of both the anticarcinoma agent AA1 and the rhodamine dyes will be prepared and evaluated for their spectral, chemical, and photophysical properties, which include n-octanol water partition coefficients, quantum yields for singlet oxygen generation, pH-sensitive hydrolysis rates, reactivity with singlet oxygen, and rates of reaction of oxidized dyes with glutathione. The biological activity of the new drugs with appropriate spectral, chemical, and photophysical properties will be evaluated in vitro against several cancer cell lines to determine: 1) uptake of the dyes, 2) dark and phototoxicities, and 3) mechanisms of phototoxicity. Isolated mitochondrial suspensions will also be used to evaluate mechanisms of phototoxicity. Sensitizers that show promise in the in vitro studies or appropriately modified new derivatives will be evaluated in vivo using a rat mammary tumor model for therapeutic efficacy, pharmacokinetic studies of dye distribution and retention in normal and cancer tissues, and effects on cellular glutathione levels. PDT with the selenopyrylium dye KL-Se, which shows no toxicity at 29 mg (62 umol)/ kg and is selectively retained by tumors, will be optimized to improve upon the 300 percent increase in tumor doubling time (relative to untreated controls) already observed in initial PDT studies with KL-Se.