Abstract：
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.
摘要：
由于癌症相关成纤维细胞的表达上调，成纤维细胞活化蛋白（FAP）已成为实体瘤成像和治疗的有吸引力的生物标志物。虽然许多FAP配体已经被开发用于放射性药物治疗（RPT），大多数人患有肿瘤摄取不足，肿瘤停留时间不足，或者在健康组织中的脱靶积累，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，设计了具有新型配体（FAP8-PEG3-IP-DOTA）的新型FAP靶向RPT。[111In]In或[177Lu]Lu-FAP8-PEG3-IP-DOTA的摄取和保留以KB为单位进行评估，通过放射成像或离体生物分布分析的HT29、MDA-MB-231和4T1鼠肿瘤模型。还通过监测肿瘤生长来研究放射治疗效力和总体毒性。体重,和荷瘤小鼠的组织损伤。结果：FAP8-PEG3-IP-DOTA表现出高亲和力（半最大抑制浓度，1.6nM）和相对于其最接近的同系物对FAP的良好选择性，丙氨酰基寡肽酶(半最大抑制浓度，~14.0nM)和二肽基肽酶-IV(半最大抑制浓度，~860nM)。SPECT/CT扫描在2种不同的实体瘤模型中显示出高保留和在健康组织中的最小摄取。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都超过5倍。活体动物研究表明，在所有4个测试模型中，肿瘤生长抑制65%-93%，具有最小或没有全身毒性的证据。结论：我们得出结论，[177Lu]Lu-FAP8-PEG3-IP-DOTA是FAPα靶向放射性核素治疗实体瘤的有希望且安全的RPT候选物。
