Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

促进肿瘤生长和进展的成纤维细胞活化蛋白（FAP）在许多人上皮癌的癌症相关成纤维细胞中过表达。由于FAP在正常器官中的低表达，因此它是治疗诊断学的理想靶标。在这项研究中，我们使用了具有较长半衰期，⁶⁴ Cu（半衰期12.7 h）和²²⁵ Ac（半衰期10 d）的放射性核素来标记人胰腺癌异种移植小鼠中的FAP抑制剂（FAPI）。 。方法：给雄性裸鼠（体重22.5±1.2 g）皮下注射人胰腺癌细胞（PANC-1，n = 12； MIA PaCa-2，n = 8）。静脉注射⁶⁴只后调查了肿瘤异种移植小鼠通过动态和延迟PET扫描（注射后2.5小时）检测Cu-FAPI-04（7.21±0.46 MBq）。使用同一组小鼠（n = 8），在注射⁶⁸ Ga-FAPI-04（3.6±1.4 MBq）1小时后也进行了静态扫描，以进行比较。使用FAP-α抗体进行免疫组织化学染色以确认FAP在肿瘤异种移植物中的表达。对于放射性配体疗法，将²²⁵ Ac-FAPI-04（34 kBq）注射到PANC-1异种移植小鼠中（n = 6）。监测肿瘤大小并将其与对照小鼠的大小进行比较（n = 6）。结果：⁶⁴ Cu-FAPI-04的动态成像显示通过肾脏快速清除，并从肿瘤中缓慢清除。延迟PET成像⁶⁴ Cu-FAPI-04在肿瘤中显示轻度摄取，而在肝脏和肠道中则显示相对较高的摄取。在肿瘤或正常器官积累水平为显著更高⁶⁴的Cu-FAPI-04比⁶⁸ Ga的FAPI-04，除了在心脏和排泄在尿中较高为⁶⁸比Ga的FAPI-04 ⁶⁴铜-FAPI-04。免疫组织化学染色显示异种移植物基质中大量FAP表达。与对照组小鼠相比，注射²²⁵ Ac-FAPI-04注射剂在PANC-1异种移植小鼠中显示出显着的肿瘤生长抑制，而体重没有明显变化。结论：这项概念验证研究显示⁶⁴ Cu-FAPI-04和²²⁵ Ac-FAPI-04可用于治疗法中表达FAP的胰腺癌。针对癌症基质中的FAP的α疗法是有效的，并将有助于开发新的治疗策略。