DESIGN, SYNTHESIS AND STUDY OF NEW SENSITIZERS FOR PDT

描述：本研究的最终目标是提供可行的 光动力疗法(PDT)中用作增敏剂的临床制剂 用于治疗癌症。光动力疗法是一种相对较新的发展。 一种癌症治疗方法，将光与敏化剂相结合，产生一种 肿瘤细胞中的细胞毒性事件。这是拟议中的一个具体目标 研究设计、合成和评估用于光动力疗法的新型增敏剂，包括： 1)选择性地保留或定位在肿瘤中，2)产生反应性 在PDT过程中消耗谷胱甘肽水平并吸附的中间体 较短波长的光阻止对更深层次的肿瘤细胞的屏蔽 组织，以及3)吸收较长波长的光，其中穿透 组织是最好的。这些所需的功能可以设计成新的 掺入碲原子的PDT增敏剂 感光剂发色团。具体地说，就是碲比林染料， 含碲罗丹明(黄色胺)染料和含碲 将制备苯并(尼罗蓝)染料并对其进行评价 它们的光谱、化学和光物理性质。这些措施包括 吸收光谱、正辛醇/水分配系数、量子产率 对于单线态氧的产生，作为pH的函数的水解率， 与单线态氧的反应性，以及与谷胱甘肽的反应速率。这个 具有适当光谱、化学、生物活性的新药 光物理特性将在人类的体外培养中进行评估 鳞癌细胞和正常上皮细胞的测定：1) 染料的相对上染率，2)染料的暗毒性，3) 染料对正常细胞和转化细胞的光毒性。增敏剂 在体外研究中表现出希望的或适当修改的新的 衍生物将在体内使用小鼠上皮肿瘤模型进行评估 对于治疗效果，染料分布和药物动力学研究 在转化组织和正常组织中的滞留及其对细胞的影响 谷胱甘肽水平。

DESCRIPTION: The ultimate objective of this research is to provide viable clinical agents that are useful as sensitizers in photodynamic therapy (PDT) for the treatment of cancer. PDT is a relatively recent development in cancer therapy in which light is combined with a sensitizer to produce a cytotoxic event in the tumor cell. It is a specific aim of the proposed research to design, synthesize, and evaluate new sensitizers for PDT which: 1) are selectively retained or localized in tumors, 2) produce reactive intermediates that deplete glutathione levels during PDT and that adsorb shorter wavelengths of light preventing shielding of tumor cells deeper in tissue, and 3) absorb longer wavelengths of light where penetration of tissue is optimal. These desirable features can be designed into new sensitizers for PDT by the incorporation of a tellurium atom in the sensitizer chromophore. Specifically, telluropyrylium dyes, tellurium-containing rhodamine (xanthylium) dyes, and tellurium-containing benzophenothiazinium (nile blue) dyes will be prepared and evaluated for their spectral, chemical, and photophysical properties. These include absorption spectra, n-octanol/water partition coefficients, quantum yields for singlet oxygen generation, hydrolysis rates as a function of pH, reactivity with singlet oxygen, and rates of reaction with glutathione. The biological activity of the new drugs with appropriate spectral, chemical, and photophysical properties will be evaluated in vitro in cultures of human squamous carcinoma cells and normal epithelial cells to determine: 1) relative uptake of the dyes, 2) dark toxicity of the dyes, and 3) phototoxicity of the dyes toward normal and transformed cells. Sensitizers that show promise in the in vitro studies or appropriately modified new derivatives will be evaluated in vivo using a murine epithelial tumor model for therapeutic efficacy, pharmacokinetic studies of dye distribution and retention in transformed and normal tissue, and effects on cellular glutathione levels.