Hongsheng Li1, Shimin Ye1, Jiawei Zhong1,2, Qingsong Yan1,2, Yuhua Zhong3, Pengju Feng2, Kongzhen Hu4. 1. GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China. 2. Department of Chemistry, Jinan University, Guangzhou, 510632, China. 3. Department of Rehabilitation Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. 4. GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China. kzhu@smu.edu.cn.
Abstract
PURPOSE: Fibroblast activation protein (FAP) has become a promising cancer-related target for diagnosis and therapy. The aim of this study was to develop a bivalent FAP ligand for both diagnostic PET imaging and endoradiotherapy. METHODS: We synthesized a bivalent FAP ligand (ND-bisFAP) and labeled it with 18F or 177Lu. FAP-positive A549-FAP cells were used to study competitive binding to FAP, cellular internalization, and efflux properties in vitro. Micro-PET imaging with [18F]AlF-ND-bisFAPI was conducted in mice bearing A549-FAP or U87MG tumors. Biodistribution and therapeutic efficacy of [177Lu]Lu-ND-bisFAPI were conducted in mice bearing A549-FAP tumors. RESULTS: The FAP binding affinity of ND-bisFAPI is 0.25 ± 0.05 nM, eightfold higher in potency than the monomeric DOTA-FAPI-04 (IC50 = 2.0 ± 0.18 nM). In A549-FAP cells, ND-bisFAPI showed specific uptake, a high internalized fraction, and slow cellular efflux. Compared to the monomeric [18F]AlF-FAPI-42, micro-PET imaging with [18F]AlF-ND-bisFAPI showed higher specific tumor uptake and retention for at least 6 h. Biodistribution studies showed that [177Lu]Lu-ND-bisFAPI had higher tumor uptake than [177Lu]Lu-FAPI-04 at the 24, 72, 120, and 168 h time points (all P < 0.01). [177Lu]Lu-ND-bisFAPI delivered fourfold higher radiation than [177Lu]Lu-FAPI-04 to A549-FAP tumors. For the endoradiotherapy study, 37 MBq of [177Lu]Lu-ND-bisFAPI significantly reduced tumor growth compared to the same dose of [177Lu]Lu-FAPI-04. Half of the dose of [177Lu]Lu-ND-bisFAPI (18.5 MBq) has comparable median survival as 37 MBq of [177Lu]Lu-FAPI-04 (37 vs 36 days). CONCLUSION: The novel bivalent FAP ligand was developed as a theranostic radiopharmaceutical and showed promising properties including higher tumor uptake and retention compared to the established radioligands [18F]AlF-FAPI-42 and [177Lu]Lu-FAPI-04. Preliminary experiments with 18F- or 177Lu-labeled ND-bisFAPI showed promising imaging properties and favorable anti-tumor responses.
PURPOSE: Fibroblast activation protein (FAP) has become a promising cancer-related target for diagnosis and therapy. The aim of this study was to develop a bivalent FAP ligand for both diagnostic PET imaging and endoradiotherapy. METHODS: We synthesized a bivalent FAP ligand (ND-bisFAP) and labeled it with 18F or 177Lu. FAP-positive A549-FAP cells were used to study competitive binding to FAP, cellular internalization, and efflux properties in vitro. Micro-PET imaging with [18F]AlF-ND-bisFAPI was conducted in mice bearing A549-FAP or U87MG tumors. Biodistribution and therapeutic efficacy of [177Lu]Lu-ND-bisFAPI were conducted in mice bearing A549-FAP tumors. RESULTS: The FAP binding affinity of ND-bisFAPI is 0.25 ± 0.05 nM, eightfold higher in potency than the monomeric DOTA-FAPI-04 (IC50 = 2.0 ± 0.18 nM). In A549-FAP cells, ND-bisFAPI showed specific uptake, a high internalized fraction, and slow cellular efflux. Compared to the monomeric [18F]AlF-FAPI-42, micro-PET imaging with [18F]AlF-ND-bisFAPI showed higher specific tumor uptake and retention for at least 6 h. Biodistribution studies showed that [177Lu]Lu-ND-bisFAPI had higher tumor uptake than [177Lu]Lu-FAPI-04 at the 24, 72, 120, and 168 h time points (all P < 0.01). [177Lu]Lu-ND-bisFAPI delivered fourfold higher radiation than [177Lu]Lu-FAPI-04 to A549-FAP tumors. For the endoradiotherapy study, 37 MBq of [177Lu]Lu-ND-bisFAPI significantly reduced tumor growth compared to the same dose of [177Lu]Lu-FAPI-04. Half of the dose of [177Lu]Lu-ND-bisFAPI (18.5 MBq) has comparable median survival as 37 MBq of [177Lu]Lu-FAPI-04 (37 vs 36 days). CONCLUSION: The novel bivalent FAP ligand was developed as a theranostic radiopharmaceutical and showed promising properties including higher tumor uptake and retention compared to the established radioligands [18F]AlF-FAPI-42 and [177Lu]Lu-FAPI-04. Preliminary experiments with 18F- or 177Lu-labeled ND-bisFAPI showed promising imaging properties and favorable anti-tumor responses.
Authors: Di Zhu; Yu Lu; Lin Gui; Wenjing Wang; Xi Hu; Su Chen; Yanming Wang; Yuji Wang Journal: Acta Pharm Sin B Date: 2021-11-12 Impact factor: 14.903
Authors: Song Xue; Rui Guo; Karl Peter Bohn; Jared Matzke; Marco Viscione; Ian Alberts; Hongping Meng; Chenwei Sun; Miao Zhang; Min Zhang; Raphael Sznitman; Georges El Fakhri; Axel Rominger; Biao Li; Kuangyu Shi Journal: Eur J Nucl Med Mol Imaging Date: 2021-12-24 Impact factor: 10.057
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