Design, Synthesis and Study of New Sensitizers for PDT

描述：(申请人提供)本研究的最终目的是 提供可行的临床试剂，在光动力学中用作增敏剂 癌症的光动力疗法。拟议研究的一个目标是设计， 合成和评价用于光动力疗法的新型增敏剂：1)选择性 保留在肿瘤中，2)不显示长期皮肤光敏，3)有高 细胞毒性事件的量子产率，4)消耗谷胱甘肽水平 以及5)吸收较长波长的光，其中光穿透到 组织是最好的。这些所需的特征可以通过替换氧气来获得 或具有重原子硒或重原子的增感发色团中的硫 碲。两种抗癌药物AA1的硒和碲类似物 罗丹明染料将被制备并评估其光谱， 化学和光物理性质，包括正辛醇水分配 系数，单线态氧产生的量子产额，pH敏感 水解率、与单线态氧的反应性和反应速率 含有谷胱甘肽的氧化染料。具有生物活性的新药 将评估适当的光谱、化学和光物理特性 在体外对几种癌细胞株进行测定：1)对染料的摄取， 2)暗毒性和光毒性；3)光毒性机制。孤立 线粒体悬浮液也将被用于评估 光毒性。在体外研究中表现出希望的增敏剂或 适当修改的新衍生物将在体内使用大鼠进行评估 乳腺肿瘤模型治疗效果、染料药代动力学研究 在正常组织和癌组织中的分布和滞留及其对 细胞内谷胱甘肽水平。用硒吡喃染料KL-Se进行的光动力疗法，这表明 在29毫克(62微克)/公斤没有毒性，并被肿瘤选择性地保留，将 在肿瘤加倍时间增加300%的基础上进行优化 (相对于未经治疗的对照组)在最初的PDT研究中已经观察到 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.