Because of upregulated expression on cancer-associated fibroblasts, fibroblast activation protein (FAP) has emerged as an attractive biomarker for the imaging and therapy of solid tumors. Although many FAP ligands have already been developed for radiopharmaceutical therapies (RPTs), most suffer from inadequate tumor uptake, insufficient tumor residence times, or off-target accumulation in healthy tissues, suggesting a need for further improvements. Methods: A new FAP-targeted RPT with a novel ligand (FAP8-PEG₃-IP-DOTA) was designed by combining the desirable features of several previous ligand-targeted RPTs. Uptake and retention of [¹¹¹In]In or [¹⁷⁷Lu]Lu-FAP8-PEG₃-IP-DOTA were assessed in KB, HT29, MDA-MB-231, and 4T1 murine tumor models by radioimaging or ex vivo biodistribution analyses. Radiotherapeutic potencies and gross toxicities were also investigated by monitoring tumor growth, body weight, and tissue damage in tumor-bearing mice. Results: FAP8-PEG₃-IP-DOTA exhibited high affinity (half-maximal inhibitory concentration, 1.6 nM) and good selectivity for FAP relative to its closest homologs, prolyl oligopeptidase (half-maximal inhibitory concentration, ∼14.0 nM) and dipeptidyl peptidase-IV (half-maximal inhibitory concentration, ∼860 nM). SPECT/CT scans exhibited high retention in 2 different solid tumor models and minimal uptake in healthy tissues. Quantitative biodistribution analyses revealed tumor–to–healthy-tissue ratios of more than 5 times for all major organs, and live animal studies demonstrated 65%–93% suppression of tumor growth in all 4 models tested, with minimal or no evidence of systemic toxicity. Conclusion: We conclude that [¹⁷⁷Lu]Lu-FAP8-PEG₃-IP-DOTA constitutes a promising and safe RPT candidate for FAPα-targeted radionuclide therapy of solid tumors.

由于癌症相关成纤维细胞的表达上调，成纤维细胞激活蛋白（FAP）已成为实体瘤成像和治疗中有吸引力的生物标志物。尽管许多 FAP 配体已经被开发用于放射性药物疗法（RPT），但大多数都存在肿瘤摄取不足、肿瘤停留时间不足或在健康组织中脱靶积累的问题，这表明需要进一步改进。方法：通过结合先前几种配体靶向 RPT 的理想特征，设计了一种具有新型配体 (FAP8-PEG ₃ -IP-DOTA) 的新型 FAP 靶向 RPT。通过放射成像或离体生物分布分析在KB、HT29、MDA-MB-231和4T1鼠肿瘤模型中评估[ ¹¹¹ In]In或[ ¹⁷⁷ Lu]Lu-FAP8-PEG ₃ -IP-DOTA的摄取和保留。还通过监测荷瘤小鼠的肿瘤生长、体重和组织损伤来研究放射治疗效力和总毒性。结果： FAP8-PEG ₃ -IP-DOTA 相对于其最接近的同源物脯氨酰寡肽酶（半最大抑制浓度，~14.0 nM）和二肽基肽酶，对 FAP 表现出高亲和力（半最大抑制浓度，1.6 nM）和良好的选择性-IV（半最大抑制浓度，~860 nM）。 SPECT/CT 扫描在 2 种不同的实体瘤模型中表现出高保留率，而在健康组织中表现出极低的吸收。定量生物分布分析显示，所有主要器官的肿瘤与健康组织的比率均超过 5 倍，活体动物研究表明，在所有 4 个测试模型中，肿瘤生长受到 65%–93% 的抑制，全身毒性的证据极少或没有证据。 结论：我们得出结论，[ ¹⁷⁷ Lu]Lu-FAP8-PEG ₃ -IP-DOTA 构成了 FAPα 靶向放射性核素治疗实体瘤的有前景且安全的 RPT 候选者。