针对FAP的新型双模态PET/荧光探针用于精确肿瘤边缘勾画的临床前和临床初步评估。
Preclinical and pilot clinical evaluation of novel dual-modality pet/fluorescence probes targeting FAP for accurate tumor margin delineation.
作者信息
Zhao Liang, Pang Yizhen, Xu Daqiang, Chen Jianhao, Yu Shan, Ruan Dan, Yu Lingyu, Wu Zhenyu, Su Guoqiang, Wu Hua, Ai Lin, Sun Long, Fan Di, Chen Haojun
机构信息
Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China.
出版信息
Eur J Nucl Med Mol Imaging. 2025 Aug 23. doi: 10.1007/s00259-025-07512-8.
PURPOSE
Accurate delineation of tumor margins and maximal safe resection are critical for successful curative oncologic surgery. However, fibroblast activation protein (FAP)-targeted probes suitable for fluorescence imaging remain limited. Here, we developed novel FAP-targeted fluorescent probes to accurately delineate tumor margins and enable rapid intraoperative identification of tumor boundaries in resected specimens.
METHODS
DOTA chelator for radiolabelling with gallium-68 was incorporated into dual-modality FAP-targeted probes synthesised by conjugating FAP-2286 and 3BP-3940 with the near-infrared (NIR) fluorophore IRDye800CW. These probes were evaluated both in vitro and in vivo using HEK293T-FAP cells stably expressing FAP and xenograft mouse models. Positron emission tomography (PET) and (NIR-II) fluorescence imaging assessed the specificity and ability of probes to delineate tumor margins. For clinical validation, resected lung tissue was incubated ex vivo with the probes. Tumor regions and margins were identified using fluorescence imaging and subsequently validated by haematoxylin and eosin (H&E) staining and FAP immunohistochemistry.
RESULTS
Both IRDye800CW-FAP-2286 and IRDye800CW-3BP-3940 exhibited high affinity for FAP-positive cells in vitro. PET imaging revealed high tumor specificity for both probes in vivo. In vivo and ex vivo NIR-II fluorescence imaging enabled accurate visualisation of tumor margins, with IRDye800CW-3BP-3940 exhibiting superior performance compared with IRDye800CW-FAP-2286. In the clinical specimen, IRDye800CW-3BP-3940 successfully delineated tumor regions with strong concordance to histopathological findings.
CONCLUSION
We developed and validated a novel dual-modality molecular probe, IRDye800CW-3BP-3940, which integrated PET and NIR fluorescence imaging capabilities. This probe enabled highly specific detection of FAP-positive tumors and precise delineation of tumor margins in resected specimens.
目的
准确描绘肿瘤边界和最大安全切除范围对于成功的根治性肿瘤手术至关重要。然而，适用于荧光成像的成纤维细胞活化蛋白（FAP）靶向探针仍然有限。在此，我们开发了新型FAP靶向荧光探针，以准确描绘肿瘤边界，并在切除标本中实现术中快速识别肿瘤边界。
方法
将用于与镓-68进行放射性标记的DOTA螯合剂纳入通过将FAP-2286和3BP-3940与近红外（NIR）荧光团IRDye800CW偶联而合成的双模态FAP靶向探针中。使用稳定表达FAP的HEK293T-FAP细胞和异种移植小鼠模型对这些探针进行体外和体内评估。正电子发射断层扫描（PET）和（NIR-II）荧光成像评估了探针描绘肿瘤边界的特异性和能力。为了进行临床验证，将切除的肺组织与探针进行离体孵育。使用荧光成像识别肿瘤区域和边界，随后通过苏木精和伊红（H&E）染色以及FAP免疫组织化学进行验证。
结果
IRDye800CW-FAP-2286和IRDye800CW-3BP-3940在体外对FAP阳性细胞均表现出高亲和力。PET成像显示两种探针在体内均具有高肿瘤特异性。体内和离体NIR-II荧光成像能够准确可视化肿瘤边界，与IRDye800CW-FAP-2286相比，IRDye800CW-3BP-3940表现出更优异的性能。在临床标本中，IRDye800CW-3BP-3940成功描绘了肿瘤区域，与组织病理学结果高度一致。
结论
我们开发并验证了一种新型双模态分子探针IRDye800CW-3BP-3940，其整合了PET和NIR荧光成像功能。该探针能够高度特异性地检测FAP阳性肿瘤，并精确描绘切除标本中的肿瘤边界。
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