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使用 [Lu]FAPI-46 对比 [Ac]FAPI-46 的成纤维细胞激活蛋白靶向治疗在胰腺癌模型中的应用。

Fibroblast activation protein targeted therapy using [Lu]FAPI-46 compared with [Ac]FAPI-46 in a pancreatic cancer model.

机构信息

Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Institute for Radiation Sciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

出版信息

Eur J Nucl Med Mol Imaging. 2022 Feb;49(3):871-880. doi: 10.1007/s00259-021-05554-2. Epub 2021 Sep 18.

DOI:10.1007/s00259-021-05554-2
PMID:34537893
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8803706/
Abstract

PURPOSE

Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used Cu and Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (Lu)-labelled FAPI-46 and alpha-emitter (Ac)-labelled FAPI-46 in pancreatic cancer models.

METHODS

PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [Lu]FAPI-46 and [Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [Lu]FAPI-46 and [Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [Ac]FAPI-46. Tumour sizes and body weights were followed.

RESULTS

[F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [Lu]FAPI-46 and [Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [Lu]FAPI-46 and [Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [Lu]FAPI-46 were relatively slow but lasted longer than those of [Ac]FAPI-46.

CONCLUSION

This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

摘要

目的

成纤维细胞激活蛋白（FAP）在上皮癌相关成纤维细胞中高表达，可作为治疗诊断的靶点。我们之前的研究使用 Cu 和 Ac 标记的 FAP 抑制剂（FAPI-04）对表达 FAP 的胰腺癌细胞移植瘤进行成像和治疗。然而，FAPI 的最佳治疗放射性核素仍需进一步研究。在本研究中，我们评估了 β 发射器（Lu）标记的 FAPI-46 和 α 发射器（Ac）标记的 FAPI-46 在胰腺癌细胞模型中的治疗效果。

方法

在 PANC-1 异种移植瘤小鼠（n=9）注射[F]FAPI-74（12.4±1.7 MBq）1 小时后进行 PET 扫描，用于伴随成像。在异种移植模型中评估[Lu]FAPI-46 和[Ac]FAPI-46 的生物分布（总 n=12）。为了确定治疗效果，将[Lu]FAPI-46 和[Ac]FAPI-46 以不同剂量注入 PANC-1 异种移植瘤小鼠：3 MBq（n=6）、10 MBq（n=6）、30 MBq（n=6）、对照（n=4）用于[Lu]FAPI-46，和 3 kBq（n=3）、10 kBq（n=2）、30 kBq（n=6）、对照（n=7）用于[Ac]FAPI-46。监测肿瘤大小和体重。

结果

[F]FAPI-74 在注射后 1 小时内通过肾脏快速清除，并在肿瘤和肠道中高度积聚。[Lu]FAPI-46 和[Ac]FAPI-46 也在 3 小时内通过肾脏快速清除，并在肿瘤中相对高度积聚。[Lu]FAPI-46 和[Ac]FAPI-46 均具有抑制肿瘤生长的作用，且体重轻度下降。[Lu]FAPI-46 的治疗效果相对较慢，但持续时间长于[Ac]FAPI-46。

结论

本研究提示 FAPI 配体放射性核素治疗在表达 FAP 的胰腺癌细胞中的应用可能。需要进一步评估寻找半衰期更短、与直接靶向肿瘤细胞的治疗方法相结合的最佳放射性核素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/37c8aeb877fc/259_2021_5554_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/62f7b5019c62/259_2021_5554_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/06e8e9acfc6f/259_2021_5554_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/1188ecc7d8a6/259_2021_5554_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/d58c00725a4e/259_2021_5554_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/1ded9def1183/259_2021_5554_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/37c8aeb877fc/259_2021_5554_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/62f7b5019c62/259_2021_5554_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/06e8e9acfc6f/259_2021_5554_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/1188ecc7d8a6/259_2021_5554_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/d58c00725a4e/259_2021_5554_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/1ded9def1183/259_2021_5554_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5842/8803706/37c8aeb877fc/259_2021_5554_Fig6_HTML.jpg

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