Use of tumor-targeted fluorescence dyes to help surgeons identify otherwise undetected tumor nodules, decrease the incidence of cancer-positive margins, and facilitate localization of malignant lymph nodes has demonstrated considerable promise for improving cancer debulking surgery. Unfortunately, the repertoire of available tumor-targeted fluorescent dyes does not permit identification of all cancer types, raising the need to develop additional tumor-specific fluorescent dyes to ensure localization of all malignant lesions during cancer surgeries. By comparing the mRNA levels of the hypoxia-induced plasma membrane protein carbonic anhydrase IX (CA IX) in 13 major human cancers with the same mRNA levels in corresponding normal tissues, we document that CA IX constitutes a nearly universal marker for the design of tumor-targeted fluorescent dyes. Motivated by this expression profile, we synthesize two new CA IX-targeted near-infrared (NIR) fluorescent imaging agents and characterize their physical and biological properties both in vitro and in vivo. We report that conjugation of either acetazolamide or 6-aminosaccharin (i.e., two CA-IX-specific ligands) to the NIR fluorescent dye, S0456, via an extended phenolic spacer creates a brightly fluorescent dye that binds CA IX with high affinity and allows rapid visualization of hypoxic regions of solid tumors at depths >1 cm beneath a tissue surface. Taken together, these data suggest that a CA IX-targeted NIR dye can constitute a useful addition to a cocktail of tumor-targeted NIR dyes designed to image all human cancers.

中文翻译：

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碳酸酐酶IX靶向的近红外染料对缺氧肿瘤的荧光成像

使用靶向肿瘤的荧光染料来帮助外科医生识别其他情况下未发现的肿瘤结节，降低癌症阳性切缘的发生率并促进恶性淋巴结的定位，这已被证明可以改善癌症切除手术的前景。不幸的是，可用的以肿瘤为靶标的荧光染料的目录不能识别所有癌症类型，从而增加了开发其他肿瘤特异性荧光染料以确保癌症手术期间所有恶性病变的定位的需要。通过比较低氧诱导的13种主要人类癌症中缺氧诱导的质膜蛋白碳酸酐酶IX（CA IX）的mRNA水平，相应的正常组织中的mRNA水平相同，我们证明CA IX构成了肿瘤设计的近乎通用的标志物靶向荧光染料。体外和体内。我们报告说，乙酰唑胺或6-氨基糖精（即两个CA-IX特异性配体）通过扩展的酚间隔基与NIR荧光染料S0456的缀合产生了一种明亮的荧光染料，该染料以高亲和力结合了CA IX，并允许快速在组织表面以下> 1 cm深度的实体瘤缺氧区域的可视化。综上所述，这些数据表明，以CA IX为靶标的NIR染料可以构成对旨在对所有人类癌症成像的以肿瘤为靶标的NIR染料混合物的有用补充。