FAPI and Tumor Microenvironments
Development of radiolabeled tetramer that targeting fibroblast activation protein and theranostic research in tumor xenografts
Zhao Liang, Chen Jianhao, Pang Yizhen, Fang Jianyang, Guo Zhide, Wu Hua, Sun Long, Lin Qin, Chen Haojun
Published 2023-06-25
Cite as Chin J Nucl Med Mol Imaging, 2023, 43(6): 343-348. DOI: 10.3760/cma.j.cn321828-20230221-00042
Abstract
ObjectiveTo develop a tetramer probe targeting fibroblast activation protein (FAP), named 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-4P(FAP inhibitor (FAPI))4, evaluate its biodistribution and PET image in FAP-positive-tumor bearing nude mice, and explore its feasibility as a novel radio-regent for treatment of FAP-positive tumor.
MethodsFAP tetramer probe was constructed on the FAPI-46 motif with four mini-polyethylene glycol (PEG)(PEG3) spacers between the four FAPI motifs, denoted as 4P(FAPI)4. DOTA was used as the chelator for radiolabeling with 68Ga and 177Lu. The FAP binding characteristics were test by in vitro cell competitive binding experiment. Small-animal PET, in vivo biodistribution, and radionuclide targeting therapy were performed in HT-1080-FAP tumor bearing nude mice (n=39). Independent-sample t test was performed to analyze tumor uptake data, and two-factor repeated measures analysis of variance was utilized to compare tumor volume data in radioactive isotope therapy.
ResultsCell experiment showed that FAPI-tetramer and FAPI-monomer had similar half maximal inhibitory concentration values (3.29 and 2.15 nmol/L). 68Ga/177Lu radiolabeled FAPI-tetramer had better tumor uptake and retention than FAPI-monomer in small-animal PET and in vivo biodistribution experiment, with the tumor uptake for 177Lu-DOTA-4P(FAPI)4 and 177Lu-FAPI-46 at 48 h of (18.72±1.32) vs (2.72±1.20) percentage activity of injection dose per gram of tissue (%ID/g) (t=15.55, P<0.001). 177Lu-DOTA-4P(FAPI)4 group showed best anti-tumor efficacy compared with 177Lu-FAPI-46 and control group in radionuclide targeting therapy. On the 2nd day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the control group (mean difference 67.19 mm3, P=0.049); on the 14th day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the monomer treatment group (mean difference 414.33 mm3, P=0.005).
ConclusionFAPI-tetramer can improve tumor uptake and retention ability compared with FAPI-46, and 177Lu-DOTA-4P(FAPI)4 can be a promising radio-agent for FAP-positive tumor therapy.
Key words:
Quinoline; Gallium radioisotopes; Lutetium; Fibrosarcoma; Mice, nude
Contributor Information
Zhao Liang
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Chen Jianhao
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Pang Yizhen
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Fang Jianyang
Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
Guo Zhide
Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
Wu Hua
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Sun Long
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Lin Qin
Department of Radiation Oncology, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Chen Haojun
Department of Nuclear Medicine &
Minnan PET Center, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
