Bilinska Adrianna, Ballal Sanjana, Bal Chandrasekhar, Läppchen Tilman, Pilatis Eirinaios, Menéndez Elena, Moon Euy Sung, Martin Marcel, Rösch Frank, Rominger Axel, Gourni Eleni
Department of Nuclear Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India.
Eur J Nucl Med Mol Imaging. 2025 Feb 26. doi: 10.1007/s00259-025-07141-1.
This study explores the use of fibroblast activation protein inhibitors (FAPI) targeting radiopharmaceuticals as a new approach for pan-cancer treatment, focusing on key factors affecting their effectiveness. We hypothesized that adjusting the administered radiotracer dose one could enhance the tumor-to-background ratios.
In a dose-escalation study with PC3 xenografts, all radiotracers were administered at doses between 10 and 1500 pmol, followed by biodistribution and PET/CT imaging. Their selectivity towards FAP, PREP, and DDP4, along with their stability in vivo, was assessed by biodistribution and metabolite analysis, respectively. Organ FAP expression was quantified using qPCR, and circulating FAP (sFAP) levels were measured in mouse and human blood samples via ELISA. Proof-of-principle human studies were also conducted.
Increasing the dose from 10 to 600 pmol significantly reduced blood uptake and enhanced tumor uptake, optimizing their in vivo performance. All radiotracers showed peak efficacy at 350-600 pmol, with altered pharmacokinetics beyond 600 pmol. Biodistribution studies validated the in vivo selectivity of all radiotracers towards FAP, even in the presence of PREP and DPP4 inhibitors, while they demonstrated remarkable stability in vivo. FAP expression was confirmed in various organs, with sFAP quantified in both healthy mice and humans. Human studies with [Ga]Ga-DOTA.SA.FAPI revealed reduced off-target uptake (e.g., pancreas, salivary glands, heart), aligning with the preclinical findings.
The study highlights the crucial need for precise FAPI-radiotracer dosing, optimizing PET imaging, reducing radiation exposure, and enhancing treatment by accounting for FAP biology and sFAP's influence on pharmacokinetics.
本研究探索使用靶向放射性药物的成纤维细胞活化蛋白抑制剂（FAPI）作为一种新的泛癌治疗方法，重点关注影响其有效性的关键因素。我们假设通过调整放射性示踪剂的给药剂量，可以提高肿瘤与背景的比值。
在一项针对PC3异种移植瘤的剂量递增研究中，所有放射性示踪剂的给药剂量在10至1500皮摩尔之间，随后进行生物分布和PET/CT成像。分别通过生物分布和代谢物分析评估它们对FAP、PREP和DDP4的选择性以及它们在体内的稳定性。使用qPCR对器官FAP表达进行定量，并通过ELISA在小鼠和人类血液样本中测量循环FAP（sFAP）水平。还进行了原理验证性人体研究。
将剂量从10皮摩尔增加到600皮摩尔可显著降低血液摄取并提高肿瘤摄取，优化其体内性能。所有放射性示踪剂在350 - 600皮摩尔时显示出峰值疗效，超过600皮摩尔时药代动力学发生改变。生物分布研究验证了所有放射性示踪剂在体内对FAP的选择性，即使在存在PREP和DDP4抑制剂的情况下也是如此，同时它们在体内表现出显著的稳定性。在各种器官中证实了FAP表达，在健康小鼠和人类中均对sFAP进行了定量。对[Ga]Ga - DOTA.SA.FAPI的人体研究显示非靶向摄取减少（例如胰腺、唾液腺、心脏），与临床前研究结果一致。
该研究强调了精确的FAPI - 放射性示踪剂给药的关键需求，优化PET成像，减少辐射暴露，并通过考虑FAP生物学和sFAP对药代动力学的影响来加强治疗。
