In vitro demonstration of the heavy-atom effect for photodynamic therapy
In vitro demonstration of the heavy-atom effect for photodynamic therapy
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DOI：
10.1021/ja047649e
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发表时间：
2004-09-01
影响因子：
15
通讯作者：
O'Shea, DF
中科院分区：
文献类型：
--
作者：
Gorman, A;Killoran, J;O'Shea, DF
光动力疗法 (PDT) 是一种新兴的治疗方式，适用于一系列癌症和非癌症疾病。这引发了对新型 PDT 药物的积极追求，这些药物可以针对成功的临床药物所需的独特光物理特性进行优化。我们现在描述一类全新的 PDT 试剂，BF2 螯合的 3,5-二芳基-1H-吡咯-2-基-3,5-二芳基吡咯-2-基-亚胺（四芳基氮杂二吡咯亚甲基）。已开发出优化的合成程序，以促进一系列特定取代衍生物的生成，以证明如何实现对关键治疗参数（例如最大吸光度波长和单线态氧生成）的控制。光敏剂吸收最大值可在人体治疗窗口内变化，范围为 650 至 700 边缘，高消光系数范围为 75 000 至 85 000 M-1 cm(-1)。利用重原子效应来调节光敏剂单线态氧的产生水平。一系列带有或不带有溴原子取代基的光敏剂产生了一系列具有不同单线态氧生成曲线的化合物。 X射线结构证据表明，溴原子的取代并未导致光敏剂的平面变形。每种光敏剂与两种标准品的单线态氧产生水平的比较证明了对单线态氧产生的调节作用，具体取决于光敏剂的取代基模式。 HeLa 宫颈癌细胞中 18a 的共焦激光扫描显微镜成像证明光敏剂仅定位于细胞质。 HeLa 宫颈癌和 MRC5-SV40 转化的成纤维细胞癌细胞系的体外光诱导毒性测定证实，重原子效应在活细胞系统中是可行的，并且可用于调节测定功效。光敏剂18b和19b的功效的直接比较表明，光敏剂18b和19b的功效在两种细胞系中都增加了1000倍以上，光敏剂18b和19b的分子结构仅因存在两个溴原子而不同。在我们的检测系统中，所有光敏剂都具有非常低至不可确定的暗毒性。
Photodynamic therapy (PDT) is an emerging treatment modality for a range of disease classes, both cancerous and noncancerous. This has brought about an active pursuit of new PDT agents that can be optimized for the unique set of photophysical characteristics that are required for a successful clinical agent. We now describe a totally new class of PDT agent, the BF2-chelated 3,5-diaryl-1H-pyrrol-2-yl-3,5-diarylpyrrol-2-yl-ideneamines (tetraarylazadipyrromethenes). Optimized synthetic procedures have been developed to facilitate the generation of an array of specifically substituted derivatives to demonstrate how control of key therapeutic parameters such as wavelength of maximum absorbance and singlet-oxygen generation can be achieved. Photosensitizer absorption maxima can be varied within the body's therapeutic window between 650 and 700 rim, with high extinction coefficients ranging from 75 000 to 85 000 M-1 cm(-1). Photosensitizer singlet-oxygen generation level was modulated by the exploitation of the heavy atom effect. An array of photosensitizers with and without bromine atom substituents gave rise to a series of compounds with varying singlet-oxygen generation profiles. X-ray structural evidence indicates that the substitution of the bromine atoms has not caused a planarity distortion of the photosensitizer. Comparative singlet-oxygen production levels of each photosensitizer versus two standards demonstrated a modulating effect on singlet-oxygen generation depending upon substituent patterns about the photosensitizer. Confocal laser scanning microscopy imaging of 18a in HeLa cervical carcinoma cells proved that the photosensitizer was exclusively localized to the cellular cytoplasm. In vitro light-induced toxicity assays in HeLa cervical carcinoma and MRC5-SV40 transformed fibroblast cancer cell lines confirmed that the heavy-atom effect is viable in a live cellular system and that it can be exploited to modulate assay efficacy. Direct comparison of the efficacy of the photosensitizers 18b and 19b, which only differ in molecular structure by the presence of two bromine atoms, illustrated an increase in efficacy of more than a 1000-fold in both cell lines. All photosensitizers have very low to nondeterminable dark toxicity in our assay system.