Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
J Nucl Med. 2023 Sep;64(9):1449-1455. doi: 10.2967/jnumed.123.265599. Epub 2023 Jun 15.
Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) have shown promise as cancer diagnostic agents; however, the relatively short tumor retention of FAPIs may limit their application in radioligand therapy. In this paper, we report the design, synthesis, and evaluation of a FAPI tetramer. The aim of the study was to evaluate the tumor-targeting characteristics of radiolabeled FAPI multimers in vitro and in vivo, thereby providing information for the design of FAP-targeted radiopharmaceuticals based on the polyvalency principle. FAPI tetramers were synthesized on the basis of FAPI-46 and radiolabeled with Ga, Cu, and Lu. In vitro FAP-binding characteristics were identified using a competitive cell-binding experiment. To evaluate their pharmacokinetics, small-animal PET, SPECT, and ex vivo biodistribution analyses were performed on HT-1080-FAP and U87MG tumor-bearing mice. In addition, the 2 tumor xenografts received radioligand therapy with Lu-DOTA-4P(FAPI), and the antitumor efficacy of the Lu-FAPI tetramer was evaluated and compared with that of the Lu-FAPI dimer and monomer. Ga-DOTA-4P(FAPI) and Lu-DOTA-4P(FAPI) were highly stable in phosphate-buffered saline and fetal bovine serum. The FAPI tetramer exhibited high FAP-binding affinity and specificity both in vitro and in vivo. Ga-, Cu-, and Lu-labeled FAPI tetramers exhibited higher tumor uptake, longer tumor retention, and slower clearance than FAPI dimers and FAPI-46 in HT-1080-FAP tumors. The uptake (percentage injected dose per gram) of Lu-DOTA-4P(FAPI), Lu-DOTA-2P(FAPI), and Lu-FAPI-46 in HT-1080-FAP tumors at 24 h was 21.4 ± 1.7, 17.1 ± 3.9, and 3.4 ± 0.7, respectively. Moreover, Ga-DOTA-4P(FAPI) uptake in U87MG tumors was approximately 2-fold the uptake of Ga-DOTA-2P(FAPI) (SUV, 0.72 ± 0.02 vs. 0.42 ± 0.03, < 0.001) and more than 4-fold the uptake of Ga-FAPI-46 (0.16 ± 0.01, < 0.001). In the radioligand therapy study, remarkable tumor suppression was observed with the Lu-FAPI tetramer in both HT-1080-FAP and U87MG tumor-bearing mice. The satisfactory FAP-binding affinity and specificity, as well as the favorable in vivo pharmacokinetics of the FAPI tetramer, make it a promising radiopharmaceutical for theranostic applications. Improved tumor uptake and prolonged retention of the Lu-FAPI tetramer resulted in excellent characteristics for FAPI imaging and radioligand therapy.
放射性标记的成纤维细胞激活蛋白（FAP）抑制剂（FAPIs）已显示出作为癌症诊断剂的潜力；然而，FAPIs 在肿瘤中的相对较短的保留时间可能限制了它们在放射性配体治疗中的应用。本文报道了 FAPI 四聚体的设计、合成和评估。研究的目的是评估放射性标记的 FAPI 多聚体在体外和体内的肿瘤靶向特性，从而为基于多价原理设计 FAP 靶向放射性药物提供信息。 FAPI 四聚体是在 FAPI-46 的基础上合成的，并与 Ga、Cu 和 Lu 进行放射性标记。通过竞争性细胞结合实验鉴定了体外 FAP 结合特性。为了评估它们的药代动力学，在 HT-1080-FAP 和 U87MG 荷瘤小鼠上进行了小动物 PET、SPECT 和离体生物分布分析。此外，这 2 个肿瘤异种移植接受了 Lu-DOTA-4P（FAPI）的放射性配体治疗，并评估和比较了 Lu-FAPI 四聚体、Lu-FAPI 二聚体和 Lu-FAPI-46 的抗肿瘤疗效。 Ga-DOTA-4P（FAPI）和 Lu-DOTA-4P（FAPI）在磷酸盐缓冲盐水和胎牛血清中均高度稳定。FAPI 四聚体在体外和体内均表现出高的 FAP 结合亲和力和特异性。 Ga、Cu 和 Lu 标记的 FAPI 四聚体在 HT-1080-FAP 肿瘤中的肿瘤摄取更高、保留时间更长、清除速度更慢，与 FAPI 二聚体和 FAPI-46 相比。Lu-DOTA-4P（FAPI）、Lu-DOTA-2P（FAPI）和 Lu-FAPI-46 在 HT-1080-FAP 肿瘤中 24 h 的摄取（每克注射剂量的百分比）分别为 21.4±1.7、17.1±3.9 和 3.4±0.7。此外，Ga-DOTA-4P（FAPI）在 U87MG 肿瘤中的摄取约为 Ga-DOTA-2P（FAPI）摄取的 2 倍（SUV，0.72±0.02 比 0.42±0.03，<0.001），是 Ga-FAPI-46 摄取的 4 倍以上（0.16±0.01，<0.001）。在放射性配体治疗研究中，Lu-FAPI 四聚体在 HT-1080-FAP 和 U87MG 荷瘤小鼠中均观察到显著的肿瘤抑制作用。 FAPI 四聚体具有令人满意的 FAP 结合亲和力和特异性，以及有利的体内药代动力学特性，使其成为一种有前途的治疗应用放射性药物。Lu-FAPI 四聚体的肿瘤摄取增加和保留时间延长导致了 FAPI 成像和放射性配体治疗的优异特性。
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