Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.
J Nucl Med. 2011 Nov;52(11):1778-85. doi: 10.2967/jnumed.111.092833. Epub 2011 Oct 11.
Fluorescence imaging is currently attracting much interest as a method for intraoperative tumor detection, but most current tracers lack tumor specificity. Therefore, this technique can be further improved by tumor-specific detection. With tumor-targeted antibodies bound to a radioactive label, tumor-specific SPECT or PET is feasible in the clinical setting. The aim of the present study was to apply antibody-based tumor detection to intraoperative optical imaging, using preclinical in vivo mouse models.
Anti-vascular endothelial growth factor (VEGF) antibody bevacizumab and anti-human epidermal growth factor receptor (HER) 2 antibody trastuzumab were labeled with the near-infrared (NIR) fluorescence dye IRDye 800CW. Tumor uptake of the fluorescent tracers and their (89)Zr-labeled radioactive counterparts for PET was determined in human xenograft-bearing athymic mice during 1 wk after tracer injection, followed by ex vivo biodistribution and pathologic examination. Intraoperative imaging of fluorescent VEGF- or HER2-positive tumor lesions was performed in subcutaneous tumors and in intraperitoneal dissemination tumor models.
Tumor-to-background ratios, with fluorescent imaging, were 1.93 ± 0.40 for bevacizumab and 2.92 ± 0.29 for trastuzumab on day 6 after tracer injection. Real-time intraoperative imaging detected tumor lesions at even the submillimeter level in intraperitoneal dissemination tumor models. These results were supported by standard histology, immunohistochemistry, and fluorescence microscopy analyses.
NIR fluorescence-labeled antibodies targeting VEGF or HER2 can be used for highly specific and sensitive detection of tumor lesions in vivo. These preclinical findings encourage future clinical studies with NIR fluorescence-labeled tumor-specific antibodies for intraoperative-guided surgery in cancer patients.
荧光成像是目前作为一种术中肿瘤检测方法引起了广泛关注，但大多数目前的示踪剂缺乏肿瘤特异性。因此，通过肿瘤特异性检测可以进一步改善这种技术。通过与放射性标记物结合的肿瘤靶向抗体，肿瘤特异性 SPECT 或 PET 在临床环境中是可行的。本研究的目的是将基于抗体的肿瘤检测应用于术中光学成像，使用临床前体内小鼠模型。
抗血管内皮生长因子（VEGF）抗体贝伐单抗和抗人表皮生长因子受体（HER）2 抗体曲妥珠单抗用近红外（NIR）荧光染料 IRDye 800CW 标记。在注射示踪剂后 1 周内，在荷人异种移植物的无胸腺小鼠中测定荧光示踪剂及其用于 PET 的（89）Zr 标记放射性对应物的肿瘤摄取情况，随后进行离体生物分布和病理检查。在皮下肿瘤和腹腔播散肿瘤模型中进行荧光 VEGF 或 HER2 阳性肿瘤病变的术中成像。
在示踪剂注射后第 6 天，荧光成像的肿瘤与背景比值分别为贝伐单抗的 1.93±0.40 和曲妥珠单抗的 2.92±0.29。实时术中成像甚至可以在腹腔播散肿瘤模型中检测到亚毫米级别的肿瘤病变。这些结果得到了标准组织学、免疫组织化学和荧光显微镜分析的支持。
靶向 VEGF 或 HER2 的近红外荧光标记抗体可用于体内肿瘤病变的高度特异性和敏感检测。这些临床前发现鼓励未来在癌症患者中进行近红外荧光标记的肿瘤特异性抗体用于术中引导手术的临床研究。
