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 在光动力疗法（PDT）中用作敏化剂的临床试剂 用于治疗癌症。 PDT是一个相对较新的发展， 一种癌症治疗，其中光与敏化剂组合以产生 肿瘤细胞中的细胞毒性事件。 这是一个具体的目标， 研究设计、合成和评估用于PDT的新敏化剂，其： 1)选择性地保留或定位在肿瘤中，2）产生反应性 PDT过程中消耗谷胱甘肽水平的中间体， 更短波长的光，防止屏蔽肿瘤细胞更深， 组织，和3）吸收较长波长的光，其中穿透 组织是最佳的。 这些期望的特征可以被设计成新的 通过将碲原子掺入到光敏剂中， 敏化剂发色团。 具体地，碲吡喃染料， 含碲的罗丹明（黄原胶）染料，和含碲的 将制备苯并吩噻嗪鎓（尼罗蓝）染料并评价其 它们的光谱、化学和物理性质。 这些包括 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，水解速率作为pH的函数， 与单线态氧的反应性和与谷胱甘肽的反应速率。 的 新药的生物活性与适当的光谱，化学， 和生物物理性质将在体外评估的培养人 鳞状细胞癌细胞和正常上皮细胞，以确定：1） 染料的相对吸收，2）染料的暗毒性，和3） 染料对正常和转化细胞的光毒性。 敏化剂 在体外研究中显示出希望， 将使用鼠上皮肿瘤模型在体内评价衍生物 对于治疗功效，染料分布的药代动力学研究， 在转化组织和正常组织中的保留，以及对细胞的影响 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.