State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China.
Department of Nuclear Medicine & Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
J Med Chem. 2022 Jun 23;65(12):8245-8257. doi: 10.1021/acs.jmedchem.1c02162. Epub 2022 Jun 5.
The fibroblast activation protein (FAP), overexpressed on cancer-associated fibroblasts (CAFs), has become a valuable target for tumor diagnosis and therapy. However, most FAP-based radioligands show insufficient tumor uptake and retention. In this study, three novel albumin-binding FAP ligands (denoted as FSDDI, FSDDI, and FSDDI) were labeled with Ga and Lu to overcome these limitations. Cell-based studies and molecular docking assays were performed to identify the specificity and protein-binding properties for FAP. Positron emission tomography (PET) scans in human hepatocellular carcinoma patient-derived xenografts (HCC-PDXs) animal models revealed longer blood retention of Ga-FSDDI than Ga-FAPI-04, Ga-FSDDI, and Ga-FSDDI. Remarkably, Ga-FSDDI had prominent tumor-to-nontarget (T/NT) ratios. The prominent tumor retention properties of Lu-FSDDI in single photon emission computed tomography (SPECT) imaging and biodistribution studies were demonstrated. In summary, this study reports a proof-of-concept study of albumin-binding radioligands for FAP-targeted imaging and targeted radionuclide therapy (TRT).
成纤维细胞激活蛋白（FAP）在癌相关成纤维细胞（CAFs）上过度表达，已成为肿瘤诊断和治疗的有价值的靶点。然而，大多数基于 FAP 的放射性配体显示出不足的肿瘤摄取和保留。在这项研究中，三种新型的白蛋白结合 FAP 配体（表示为 FSDDI、FSDDI 和 FSDDI）用 Ga 和 Lu 标记，以克服这些限制。基于细胞的研究和分子对接实验用于鉴定 FAP 的特异性和蛋白结合特性。在人肝细胞癌患者来源异种移植（HCC-PDX）动物模型中的正电子发射断层扫描（PET）扫描显示，Ga-FSDDI 的血液保留时间长于 Ga-FAPI-04、Ga-FSDDI 和 Ga-FSDDI。值得注意的是，Ga-FSDDI 具有显著的肿瘤与非靶（T/NT）比值。单光子发射计算机断层扫描（SPECT）成像和生物分布研究表明，Lu-FSDDI 具有显著的肿瘤保留特性。总之，本研究报告了一种用于 FAP 靶向成像和靶向放射性核素治疗（TRT）的白蛋白结合放射性配体的概念验证研究。
