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Yang D, Chen J, He G, Zhou Z, Xu J, Peng Y, Shen X, Jiang X, Pan Q, Zhao L, Fei Y, Luo Y, Yang H. Comparisons of [ 68 Ga]Ga-FAPI-04 PET/CT with X-ray imaging in the assessment of patients with rheumatoid arthritis. Clin Rheumatol 2025; 44:2191-2199. [PMID: 40293620 DOI: 10.1007/s10067-025-07414-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 03/04/2025] [Accepted: 03/20/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVE This study aimed to compare the value of [68 Ga]Ga-FAPI-04 PET/CT with X-ray imaging in assessing disease activity and treatment response in patients with rheumatoid arthritis (RA). METHOD All patients underwent clinical and laboratory assessments, [68 Ga]Ga-FAPI-04 PET/CT, and X-ray imaging, with a 6-month follow-up to assess disease activity and treatment response. Bland-Altman analysis assessed the agreement between PET/CT and X-ray parameters. Correlation analyses were performed between clinical characteristics and imaging parameters. Receiver operating characteristic (ROC) curve analyses were used to predict treatment response. RESULTS We prospectively enrolled 17 patients with RA (14 females and 3 males; median age, 55.0 yr [IQR: 50.0-58.5 yr]). [68 Ga]Ga-FAPI-04 PET/CT showed strong agreement with X-ray in evaluating the number of joints involved. PET/CT imaging-derived parameters, including PET joint count (PJCFAPI), PET articular index (PAIFAPI), total synovitis uptake (TSUFAPI), and metabolic synovitis volume (MSVFAPI) were significantly correlated with C-reactive protein levels. Moreover, PJCFAPI and PAIFAPI were associated with tender or swollen joint count (TJC/SJC), disease activity score with 28-joint counts (DAS28), and Simplified Disease Activity Index (SDAI), respectively. No correlations were observed between the X-ray findings and disease activity parameters. The baseline PAIFAPI > cutoff values could discriminate responders and non-responders at the 6-month follow-up according to the Clinical Disease Activity Index (CDAI) and SDAI response criteria, while X-ray could not predict treatment response. CONCLUSIONS [68 Ga]Ga-FAPI-04 PET/CT was superior to X-ray imaging in evaluating disease activity and predicting treatment response in patients with RA. TRIAL REGISTRATION ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register. CLINICALTRIALS gov/prs/app/action/SelectProtocol?sid=S000A4PN&selectaction=Edit&uid=U0001JRW&ts=2&cx=-×9t7p.
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Affiliation(s)
- Dan Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Jiana Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Guangyuan He
- Department of Nuclear Medicine, The Second People'S Hospital of Changzhou, Changzhou, 213000, Jiangsu, China
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Ziyue Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Jiaqi Xu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Yezi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Xiangyi Shen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- School of Basic Medical Sciences, Tsinghua University, Beijing, 100084, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Xu Jiang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qingqing Pan
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Yunyun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Yaping Luo
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China.
- State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing, 100730, China.
| | - Huaxia Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China.
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
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Yang F, Lu C, Pan Q, Zhang R, Yang M, Wang Q, Li M, Zeng X, Luo Y, Leng X. 68Ga-FAPI and 18F-NaF PET/CT in psoriatic arthritis: a comparative study. Rheumatology (Oxford) 2025; 64:2575-2582. [PMID: 39576694 PMCID: PMC12048064 DOI: 10.1093/rheumatology/keae577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 09/21/2024] [Accepted: 10/08/2024] [Indexed: 05/04/2025] Open
Abstract
OBJECTIVES As fibroblast-like synoviocyte activation and bone formation are associated with PsA, PET using the tracers of 68Ga-fibroblast activation protein inhibitor (FAPI) and 18F-sodium fluoride (NaF) may sensitively detect the disease. In this prospective study, we aimed to evaluate the performance of 68Ga-FAPI PET/CT in PsA and to compare it with 18F-NaF PET/CT. METHODS Sixteen participants (female 7/16, age 42.31 ± 10.66 years) with PsA were prospectively enrolled and underwent dual-tracer PET/CT, clinical assessment and ultrasonography. PET/CT images were scored for PET-positive lesions at the peripheral joints, entheses, and axial joints. RESULTS The positivity rate of 68Ga-FAPI in peripheral joints was higher than that in entheses and axial joints (21.84% vs 12.15% vs 0%), whereas high positivity rates of 18F-NaF in peripheral joints, entheses, and axial joints were observed (85.23%, 78.13% and 75%, respectively). The DAS 28 was higher in the PET-positive than in the PET-negative group with 68Ga-FAPI (5.25 ± 1.84 vs 2.55 ± 0.94, P = 0.037), but not with 18F-NaF. In addition, the PET joint count at 68Ga-FAPI PET/CT was positively correlated with the tender joint count (r = 0.604, P = 0.017), swollen joint count (r = 0.773, P = 0.001), DAS28-CRP (r = 0.556, P = 0.032), Psoriatic Arthritis Disease Activity Score (PASDAS) (r = 0.540, P = 0.038) and PsASon13 (r = 0.701, P = 0.005), while no correlation was observed in 18F-NaF PET/CT. CONCLUSION The positivity rates of 68Ga-FAPI- and 18F-NaF PET/CT were different in patients with PsA in peripheral joints, entheses, and axial joints. The extent of joint involvement as shown in 68Ga-FAPI PET/CT correlated with clinical and US variables as well as with disease activity. TRIAL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT05686876.
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Affiliation(s)
- Fan Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
- Department of Rheumatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Chaofan Lu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Qingqing Pan
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
| | - Rui Zhang
- Department of Ultrasonography, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Yang
- Department of Ultrasonography, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Yaping Luo
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing, China
| | - Xiaomei Leng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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Outzen L, Ludolfs D, Irl M, Kossatz S, Maison W. Isopeptidic Desferrioxamine Analogues: The Role of Hydroxamate Spacing for Chelation of Zr 4. ChemMedChem 2025; 20:e202400890. [PMID: 39655362 PMCID: PMC11911295 DOI: 10.1002/cmdc.202400890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/09/2024] [Accepted: 12/09/2024] [Indexed: 12/24/2024]
Abstract
[89Zr]Zr4+ is a radionuclide of increasing clinical relevance for PET (positron emission tomography). However, an ideal chelator for stable Zr-chelation remains to be discovered. This study describes the solid-phase synthesis of octadentate Zr-chelators based on an isopeptidic (ip) scaffold derived from the natural siderophore desferrioxamine (DFOB). Several analogues with different spacers separating the chelating hydroxamates have been prepared and converted to [89Zr]Zr-complexes. The stability of these complexes was evaluated in human serum and in competition to excess of competing chelators. The assays revealed a beneficial effect of long hydroxamate spacing (9 atoms). Shorter spacing led to a decrease in complex stability. The most stable [89Zr]Zr-ipDFO complex had a high stability in challenging competition experiments with a large excess of EDTA for 72 h as determined by radio TLC and LC/MS. The straightforward synthesis, high complex stability and a modular character make ipDFO derivatives promising chelators for applications in targeted PET.
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Affiliation(s)
- Lasse Outzen
- Department of ChemistryUniversity of HamburgBundesstrasse 4520146HamburgGermany
| | - Darius Ludolfs
- Department of ChemistryUniversity of HamburgBundesstrasse 4520146HamburgGermany
| | - Maximilian Irl
- Department of Nuclear MedicineSchool of MedicineTUM University Hospital and Central Institute for Translational Cancer Research (TranslaTUM)Technical University MunichIsmaninger Straße 2281675MunichGermany
| | - Susanne Kossatz
- Department of Nuclear MedicineSchool of MedicineTUM University Hospital and Central Institute for Translational Cancer Research (TranslaTUM)Technical University MunichIsmaninger Straße 2281675MunichGermany
| | - Wolfgang Maison
- Department of ChemistryUniversity of HamburgBundesstrasse 4520146HamburgGermany
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Ruan D, Wu S, Lin X, Zhao L, Cai J, Xu W, Pang Y, Xie Q, Qu X, Chen H. Current status of FAP-directed cancer theranostics: a bibliometric analysis. BIOPHYSICS REPORTS 2024; 10:388-402. [PMID: 39758423 PMCID: PMC11693499 DOI: 10.52601/bpr.2024.240022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 07/22/2024] [Indexed: 01/07/2025] Open
Abstract
Fibroblast activation protein (FAP) is a key molecule in the field of oncology, with significant impacts on tumor diagnosis and treatment. Importantly, it has paved the way for the development of radiotracers for quinoline-based FAP inhibitors (FAPIs), which are currently among the most promising radiotracers for PET imaging in cancer. We performed a bibliometric analysis of scientific publications related to FAP and FAPI-based radiotracers, which included the quantification and visualization of current research trends and prospects based on various bibliometric indicators. In our survey of FAP-related studies in the Web of Science Core Collection databases, R and VOSviewer were used for visualization and bibliometric analyses based on country, institute, author, journal, and keywords. We also examined the methodology, radionuclide type, imaging instruments, and major diseases associated with studies on FAPI-based radiotracers. The results revealed 2,664 FAP-related publications from 1992 to the present. Germany, the USA, and China dominated paper publications, multinational collaborations, and societal impacts on FAP research. Southwest Medical University was the most productive institute, while Haberkorn Uwe authored the most cited papers and the highest H-index. The European Journal of Nuclear Medicine and Molecular Imaging and the Journal of Nuclear Medicine were the most influential periodicals. Keywords "FAP", "68Ga-FAPI", and "PET/CT" emerged as the most significant in this field. This study may help elucidate current research trends, hotspots, and directions for future research.
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Affiliation(s)
- Dan Ruan
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
- National Institute for Data Science in Health and Medicine, Department of Electronic Science, Intelligent Medical Imaging R & D Center, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361102, Fujian, China
| | - Simin Wu
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Xuehua Lin
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Liang Zhao
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Jiayu Cai
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Weizhi Xu
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Yizhen Pang
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Qiang Xie
- Department of Cardiology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
| | - Xiaobo Qu
- National Institute for Data Science in Health and Medicine, Department of Electronic Science, Intelligent Medical Imaging R & D Center, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361102, Fujian, China
| | - Haojun Chen
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Development and Translation of Radiopharmaceuticals, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian, China
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, Fujian, China
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Suzuki H, Matsukawa M, Madokoro R, Terasaka Y, Kannaka K, Uehara T. Reduction of the hepatic radioactivity levels of [ 111In]In-DOTA-labeled antibodies via cleavage of a linkage metabolized in lysosomes. Nucl Med Biol 2024; 132-133:108910. [PMID: 38636351 DOI: 10.1016/j.nucmedbio.2024.108910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/15/2024] [Accepted: 04/04/2024] [Indexed: 04/20/2024]
Abstract
INTRODUCTION Radiolabeled antibodies are promising tools for cancer diagnosis using nuclear medicine. A DOTA-chelating system is useful for preparing immuno-positron emission tomography and immuno-single-photon emission computed tomography probes with various radiometals. Radiolabeled antibodies are generally metabolized in the reticuloendothelial system, producing radiometabolites after proteolysis in hepatic lysosomes. Because of the bulkiness and extremely high hydrophilicity of DOTA, radiometabolites containing a radiometal-DOTA complex typically exhibit high and persistent localization in hepatic lysosomes. Radioactivity in the liver impairs the accurate diagnosis of cancer surrounding the liver and liver metastasis, and a high tumor/liver ratio is desirable. In this study, we reduced the hepatic radioactivity of radiometal-labeled antibodies containing a DOTA-chelating system. A cleavable linkage was inserted to liberate the radiometabolite, which exhibited a short residence time in hepatocytes. METHODS Using indium-111 (111In)-labeled antibodies, we prepared 111In-labeled galactosyl-neoglycoalbumins (NGAs) because they are useful for evaluating the residence time of radiometabolites in the liver. An 111In-labeled NGA with a cleavable linkage ([111In]In-DO3AiBu-Bn-FGK-NGA) was administered to normal mice, and biodistribution studies and metabolic analyses of urinary and fecal samples were performed with comparison to an 111In-labeled NGA prepared by a conventional method ([111In]In-DOTA-Bn-SCN-NGA). Then, 111In-labeled antibodies ([111In]In-DO3AiBu-Bn-FGK-IgG and [111In]In-DOTA-Bn-SCN-IgG) were prepared using a procedure similar to that for 111In-labeled NGAs. In vitro plasma stability and biodistribution were investigated for both 111In-labeled antibodies in U87MG tumor-bearing mice. RESULTS Through the liberation of radiometabolites including [111In]In-DO3AiBu-Bn-F, [111In]In-DO3AiBu-Bn-FGK-NGA was cleared more rapidly from the liver than [111In]In-DOTA-Bn-SCN-NGA (4.07 ± 1.54%ID VS 71.68 ± 3.03%ID at 6 h postinjection). [111In]In-DO3AiBu-Bn-FGK-IgG exhibited lower tumor accumulation (8.83 ± 1.48%ID/g) but a significantly higher tumor/liver ratio (2.21 ± 0.53) than [111In]In-DOTA-Bn-SCN-IgG (11.65 ± 2.17%ID/g in the tumor and a tumor/liver ratio of 0.85 ± 0.18) at 72 h after injection. CONCLUSION A molecular design that reduces the high and persistent hepatic radioactivity of radiolabeled antibodies by liberating radiometabolites with a short hepatic residence time in lysosomes would be applicable for radiometal-labeled antibodies using a DOTA-chelating system.
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Affiliation(s)
- Hiroyuki Suzuki
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
| | - Masato Matsukawa
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Rikako Madokoro
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Yui Terasaka
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Kento Kannaka
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Tomoya Uehara
- Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
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Abdalla AME, Miao Y, Ahmed AIM, Meng N, Ouyang C. CAR-T cell therapeutic avenue for fighting cardiac fibrosis: Roadblocks and perspectives. Cell Biochem Funct 2024; 42:e3955. [PMID: 38379220 DOI: 10.1002/cbf.3955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/06/2024] [Accepted: 02/09/2024] [Indexed: 02/22/2024]
Abstract
Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR-T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR-T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR-T cell therapy, and considers future outlooks for research development.
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Affiliation(s)
- Ahmed M E Abdalla
- School of Biological Sciences and Technology, University of Jinan, Jinan, China
- Department of Biochemistry, College of Applied Science, University of Bahri, Khartoum, Sudan
| | - Yu Miao
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Ahmed I M Ahmed
- Department of Biochemistry, College of Applied Science, University of Bahri, Khartoum, Sudan
| | - Ning Meng
- School of Biological Sciences and Technology, University of Jinan, Jinan, China
| | - Chenxi Ouyang
- Department of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Noversa de Sousa R, Tascilar K, Corte G, Atzinger A, Minopoulou I, Ohrndorf S, Waldner M, Schmidkonz C, Kuwert T, Knieling F, Kleyer A, Ramming A, Schett G, Simon D, Fagni F. Metabolic and molecular imaging in inflammatory arthritis. RMD Open 2024; 10:e003880. [PMID: 38341194 PMCID: PMC10862311 DOI: 10.1136/rmdopen-2023-003880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called 'metabolic imaging' tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively.Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation.Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
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Affiliation(s)
- Rita Noversa de Sousa
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Serviço de Medicina Interna, Hospital Pedro Hispano, Matosinhos, Portugal
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Koray Tascilar
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Giulia Corte
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Armin Atzinger
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Ioanna Minopoulou
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Sarah Ohrndorf
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maximilian Waldner
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Christian Schmidkonz
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Institute for Medical Engineering, Ostbayerische Technische Hochschule Amberg-Weiden, Amberg, Germany
| | - Torsten Kuwert
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Ferdinand Knieling
- Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arnd Kleyer
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Ramming
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - David Simon
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Filippo Fagni
- Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum fuer Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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Pan Q, Yang H, Zhou Z, Li M, Jiang X, Li F, Luo Y, Li M. [ 68 Ga]Ga-FAPI-04 PET/CT may be a predictor for early treatment response in rheumatoid arthritis. EJNMMI Res 2024; 14:2. [PMID: 38175339 PMCID: PMC10766931 DOI: 10.1186/s13550-023-01064-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND The identification of biomarkers predicting the treatment response of rheumatoid arthritis (RA) is important. [68 Ga]Ga-FAPI-04 showed markedly increased uptake in the joints of patients with RA. The purpose of this study is to investigate whether [68 Ga]Ga-FAPI-04 PET/CT can be a predictor of treatment response in RA. RESULTS Nineteen patients diagnosed with RA in the prospective cohort study were finally enrolled. Both total synovitis uptake (TSU) and metabolic synovitis volume (MSV) in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT of the responders were significantly higher than those in non-responders according to Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) response criteria at 3-months' follow-up (P < 0.05). The PET joint count (PJC) detected in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT were also significantly higher in CDAI responders than non-responders (P = 0.016 and 0.045, respectively). The clinical characteristics of disease activity at baseline did not show significant difference between the responders and non-responders, except CRP (P = 0.035 and 0.033 in CDAI and SDAI response criteria, respectively). The baseline PJCFAPI, TSUFAPI and MSVFAPI > cutoff values in [68 Ga]Ga-FAPI-04 PET/CT successfully discriminated CDAI and SDAI responders and non-responders at 3-months' follow-up. CONCLUSION [68 Ga]Ga-FAPI-04 uptake at baseline were significantly higher in early responders than those in non-responders. Trial registration ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register. CLINICALTRIALS gov/prs/app/action/SelectProtocol?sid=S000A4PN&selectaction=Edit&uid=U0001JRW&ts=2&cx=-x9t7cp.
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Affiliation(s)
- Qingqing Pan
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, 100730, China
| | - Huaxia Yang
- Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- State Key Laboratory of Difficult, Severe and Rare Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
| | - Ziyue Zhou
- Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- State Key Laboratory of Difficult, Severe and Rare Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
| | - Min Li
- Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xu Jiang
- State Key Laboratory of Difficult, Severe and Rare Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Fang Li
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, 100730, China
| | - Yaping Luo
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China.
- Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, 100730, China.
- State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing, China.
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
- State Key Laboratory of Difficult, Severe and Rare Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, Beijing, China
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Jardin B, Epstein JA. Emerging mRNA therapies for cardiac fibrosis. Am J Physiol Cell Physiol 2024; 326:C107-C111. [PMID: 38047297 PMCID: PMC11192469 DOI: 10.1152/ajpcell.00504.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/26/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
Cardiac fibrosis remains an unmet clinical need that has so far proven difficult to eliminate using current therapies. As such, novel technologies are needed that can target the pathological fibroblasts responsible for fibrosis and adverse tissue remodeling. mRNA encapsulated in lipid nanoparticles (LNPs) is an emerging technology that could offer a solution to this problem. Indeed, this strategy has already shown clinical success with the mRNA COVID-19 vaccines. In this AJP perspective, we discuss how this technology can be leveraged to specifically target cardiac fibrosis via several complementary strategies. First, we discuss the successful preclinical studies in a mouse model of cardiac injury to use T cell-targeted LNPs to produce anti-fibroblast chimeric antigen receptor T (CAR T) cells in vivo that could effectively reduce cardiac fibrosis. Next, we discuss how these T cell-targeted LNPs could be used to generate T regulatory cells (T-regs), which could migrate to areas of active fibrosis and dampen inflammation through paracrine effects as an alternative to active fibroblast killing by CAR T cells. Finally, we conclude with thoughts on directly targeting pathological fibroblasts to deliver RNAs that could interfere with fibroblast activation and activity. We hope this discussion serves as a catalyst for finding approaches that harness the power of mRNA and LNPs to eliminate cardiac fibrosis and treat other fibrotic diseases amenable to such interventions.NEW & NOTEWORTHY Cardiac fibrosis has few specific interventions available for effective treatment. mRNA encapsulated in lipid nanoparticles could provide a novel solution for treating cardiac fibrosis. This AJP perspective discusses what possible strategies could rely on this technology, from in vivo-produced CAR T cells that kill pathological fibroblasts to in vivo-produced T regulatory cells that dampen the concomitant profibrotic inflammatory cells contributing to remodeling, directly targeting fibroblasts and eliminating them or silencing profibrotic pathways.
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Affiliation(s)
- Blake Jardin
- Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Jonathan A Epstein
- Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
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Zhang XL, Xiao W, Qian JP, Yang WJ, Xu H, Xu XD, Zhang GW. The Role and Application of Fibroblast Activating Protein. Curr Mol Med 2024; 24:1097-1110. [PMID: 37259211 DOI: 10.2174/1566524023666230530095305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 06/02/2023]
Abstract
Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is rarely expressed in normal tissues but highly abundant in pathological diseases, including fibrosis, arthritis, and cancer. Ever since its discovery, we have deciphered its structure and biological properties and continue to investigate its roles in various diseases while attempting to utilize it for targeted therapy. To date, no significant breakthroughs have been made in terms of efficacy. However, in recent years, several practical applications in the realm of imaging diagnosis have been discovered. Given its unique expression in a diverse array of pathological tissues, the fundamental biological characteristics of FAP render it a crucial target for disease diagnosis and immunotherapy. To obtain a more comprehensive understanding of the research progress of FAP, its biological characteristics, involvement in diseases, and recent targeted application research have been reviewed. Moreover, we explored its development trend in the direction of clinical diagnoses and treatment.
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Affiliation(s)
- Xiao-Lou Zhang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wang Xiao
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian-Ping Qian
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wan-Jun Yang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Xu
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xing-da Xu
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guo-Wei Zhang
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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11
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Boswinkel M, Raavé R, Veltien A, Scheenen TWJ, Fransén Petterson N, in ‘t Zandt R, Olsson LE, von Wachenfeldt K, Heskamp S, Mahmutovic Persson I. Utilizing MRI, [ 18F]FDG-PET and [ 89Zr]Zr-DFO-28H1 FAP-PET tracer to assess inflammation and fibrogenesis in a reproducible lung injury rat model: a multimodal imaging study. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2023; 3:1306251. [PMID: 39355041 PMCID: PMC11440995 DOI: 10.3389/fnume.2023.1306251] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/20/2023] [Indexed: 10/03/2024]
Abstract
Objective Accurate imaging biomarkers that indicate disease progression at an early stage are highly important to enable timely mitigation of symptoms in progressive lung disease. In this context, reproducible experimental models and readouts are key. Here, we aim to show reproducibility of a lung injury rat model by inducing disease and assessing disease progression by multi-modal non-invasive imaging techniques at two different research sites. Furthermore, we evaluated the potential of fibroblast activating protein (FAP) as an imaging biomarker in the early stage of lung fibrosis. Methods An initial lung injury rat model was set up at one research site (Lund University, Lund, Sweden) and repeated at a second site (Radboudumc, Nijmegen, The Netherlands). To induce lung injury, Sprague-Dawley rats received intratracheal instillation of bleomycin as one single dose (1,000 iU in 200 µL) or saline as control. Thereafter, longitudinal images were acquired to track inflammation in the lungs, at 1 and 2 weeks after the bleomycin challenge by magnetic resonance imaging (MRI) and [18F]FDG-PET. After the final [18F]FDG-PET scan, rats received an intravenous tracer [89Zr]Zr-DFO-28H1 (anti-FAP antibody) and were imaged at day 15 to track fibrogenesis. Upon termination, bronchoalveolar lavage (BAL) was performed to assess cell and protein concentration. Subsequently, the biodistribution of [89Zr]Zr-DFO-28H1 was measured ex vivo and the spatial distribution in lung tissue was studied by autoradiography. Lung sections were stained and fibrosis assessed using the modified Ashcroft score. Results Bleomycin-challenged rats showed body weight loss and increased numbers of immune cells and protein concentrations after BAL compared with control animals. The initiation and progression of the disease were reproduced at both research sites. Lung lesions in bleomycin-exposed rats were visualized by MRI and confirmed by histology. [18F]FDG uptake was higher in the lungs of bleomycin-challenged rats compared with the controls, similar to that observed in the Lund study. [89Zr]Zr-DFO-28H1 tracer uptake in the lung was increased in bleomycin-challenged rats compared with control rats (p = 0.03). Conclusion Here, we demonstrate a reproducible lung injury model and monitored disease progression using conventional imaging biomarkers MRI and [18F]FDG-PET. Furthermore, we showed the first proof-of-concept of FAP imaging. This reproducible and robust animal model and imaging experimental set-up allows for future research on new therapeutics or biomarkers in lung disease.
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Affiliation(s)
- Milou Boswinkel
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | - René Raavé
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Andor Veltien
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Tom WJ Scheenen
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | | | - René in ‘t Zandt
- Lund University BioImaging Centre, Faculty of Medicine, Lund University, Lund, Sweden
| | - Lars E. Olsson
- Department of Translational Medicine, Medical Radiation Physics, Lund University, Malmö, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden
| | | | - Sandra Heskamp
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Irma Mahmutovic Persson
- Lund University BioImaging Centre, Faculty of Medicine, Lund University, Lund, Sweden
- Department of Translational Medicine, Medical Radiation Physics, Lund University, Malmö, Sweden
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Xu M, Chen J, Zhang P, Cai J, Song H, Li Z, Liu Z. An antibody-radionuclide conjugate targets fibroblast activation protein for cancer therapy. Eur J Nucl Med Mol Imaging 2023; 50:3214-3224. [PMID: 37318538 DOI: 10.1007/s00259-023-06300-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023]
Abstract
PURPOSE Fibroblast activation protein is one of the most attractive targets for tumor diagnosis and therapy. There have been many successful clinical translations with small molecules and peptides, yet only a few anti-FAP antibody diagnostic or therapeutic agents have been reported. Antibodies often feature good tumor selectivity and long tumor retention, which may be a better-match with therapeutic radionuclides (e.g.,177Lu, 225Ac) for cancer therapy. Here we report a 177Lu-labeled anti-FAP antibody, PKU525, as a therapeutic radiopharmaceutical for FAP-targeted radiotherapy. METHODS The anti-FAP antibody is produced as a derivative of sibrotuzumab. The pharmacokinetics and blocking study are performed with 89Zr-labeled antibody by PET imaging. The conjugation strategies have been screened and tested with SPECT imaging through 177Lu-labeling. The biodistribution and radiotherapy studies are performed on 177Lu-labeled anti-FAP antibody in NU/NU mice-bearing HT-1080-FAP tumors. RESULTS A multiple time-point PET imaging study shows that the tumor accumulation of [89Zr]Zr-DFO-PKU525 is intense, selective, and relatively rapid. The time activity curve indicates that the tumor uptake continually increases until reaches the highest uptake (SUVmax = 18.4 ± 2.3, n = 4) at 192 h, then gradually declines. Radioactivity rapidly cleared from the blood, liver, and other major organs, resulting in high tumor-to-background ratios. An in vivo blocking experiment suggests that [89Zr]Zr-DFO-PKU525 is FAP-specific and the uptake in FAP-negative tumors is almost negligible. Ex vivo biodistribution study shows that the tumor uptake of [177Lu]Lu-DOTA-NCS-PKU525 is 23.04 ± 5.11% ID/g, 33.2 ± 6.36% ID/g, 19.87 ± 6.84% ID/g and 19.02 ± 5.90% ID/g at 24 h, 96 h, 168 h, and 240 h after injection (n = 5), which is corroborated with the PET imaging. In therapeutic assays, multiple doses of [177Lu]Lu-DOTA-NCS-PKU525 have been tested in tumor-bearing mice, and the data suggests that 3.7 MBq may be sufficient to completely suppress the tumor growth in mice without showing observable side effects. CONCLUSION A FAP-targeted antibody-radionuclide conjugate was developed and evaluated in vitro and in vivo. Its tumor accumulation is rapid and high with a clean background. It remarkably suppresses the tumors in mice while the side effect is almost negligible, showing that it is promising for further clinical translational studies.
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Affiliation(s)
- Mengxin Xu
- Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
| | - Junyi Chen
- Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
| | - Pu Zhang
- Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
| | - Jie Cai
- Boomray Pharmaceuticals (Beijing) Co., Ltd., Beijing, China
| | - Hanbo Song
- Changping Laboratory, Beijing, 102206, China
| | - Zhu Li
- Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Zhibo Liu
- Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
- Changping Laboratory, Beijing, 102206, China.
- Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
- Peking University-Tsinghua University Center for Life Sciences, Beijing, 100871, China.
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Lai C, Cao R, Li R, He C, Wang X, Shi H, Qu C, Qian K, Song S, Chen WH, Cheng Z. Fibroblast Activation Protein Targeting Probe with Gly-Pro Sequence for PET of Glioblastoma. Mol Pharm 2023; 20:4120-4128. [PMID: 37487027 DOI: 10.1021/acs.molpharmaceut.3c00248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
As an important cancer-associated fibroblast-specific biomarker, fibroblast activation protein (FAP) has become an attractive target for tumor diagnosis and treatment. However, most FAP-based radiotracers showed inadequate uptake and short retention in tumors. In this study, we designed and synthesized a novel FAP ligand (DOTA-GPFAPI-04) through assembling three functional moieties: a quinoline-based FAP inhibitor for specifically targeting FAP, a FAP substrate Gly-Pro as a linker for increasing the FAP protein interaction, and a 2,2',2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) chelator for radiolabeling with different radionuclides. The FAP targeting ability of DOTA-GPFAPI-04 was investigated by molecular docking studies. DOTA-GPFAPI-04 was then radiolabeled with 68Ga to give [68Ga]Ga-DOTA-GPFAPI-04 for positron emission tomography (PET) imaging of glioblastoma. [68Ga]Ga-DOTA-GPFAPI-04 exhibited a purity of >98% and high stability analyzed by radio-HPLC in saline and mouse serum. Cell uptake studies demonstrated the targeting specificity of the probe. Further in vivo pharmacokinetic studies in normal mice demonstrated the quick clearance of the probe. Moreover, compared with the widely studied [68Ga]Ga-FAPI-04, [68Ga]Ga-DOTA-GPFAPI-04 showed much higher U87MG tumor uptake values (4.467 ± 0.379 for [68Ga]Ga-DOTA-GPFAPI-04 and 1.267 ± 0.208% ID/g for [68Ga]Ga-FAPI-04 at 0.5 h post-injection, respectively). The area under the curve based on time-activity curve (TAC) analysis for tumor radioactivity in small animal models was 422.5 for [68Ga]Ga-DOTA-GPFAPI-04 and 98.14 for [68Ga]Ga-FAPI-04, respectively, demonstrating that the former had longer tumor retention time. The tumor-to-muscle (T/M) ratio for [68Ga]Ga-DOTA-GPFAPI-04 reached 9.15 in a U87MG xenograft animal model. PET imaging and blocking assays showed that [68Ga]Ga-DOTA-GPFAPI-04 had specific tumor uptake. In summary, this study demonstrates the successful synthesis and evaluation of a novel FAPI targeting probe, [68Ga]Ga-DOTA-GPFAPI-04, with a Gly-Pro sequence. It shows favorable in vivo glioblastoma imaging properties and relatively long tumor retention, highlighting DOTA-GPFAPI-04 as a promising molecular scaffold for developing FAP targeting tumor theranostic agents.
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Affiliation(s)
- Chaoquan Lai
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong 529020, China
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Rui Cao
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Renda Li
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Chunfeng He
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiao Wang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Hui Shi
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Chunrong Qu
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Kun Qian
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Shaoli Song
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wen-Hua Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong 529020, China
| | - Zhen Cheng
- State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
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Outzen L, Münzmay M, Frangioni JV, Maison W. Synthesis of Modular Desferrioxamine Analogues and Evaluation of Zwitterionic Derivatives for Zirconium Complexation. ChemMedChem 2023; 18:e202300112. [PMID: 37057615 DOI: 10.1002/cmdc.202300112] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/15/2023]
Abstract
The natural siderophore desferrioxamine B (DFOB) has been used for targeted PET imaging with 89 Zr before. However, Zr-DFOB has a limited stability and a number of derivatives have been developed with improved chelation properties for zirconium. We describe the synthesis of pseudopeptidic analogues of DFOB with azido side chains. These are termed AZA-DFO (hexadentate) and AZA-DFO* (octadentate) and are assembled via a modular synthesis from Orn-β-Ala and Lys-β-Ala. Nine different chelators have been conjugated to zwitterionic moieties by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The resulting water-soluble chelators form Zr complexes under mild conditions (room temperature for 90 min). Transchelation assays with 1000-fold excess of EDTA and 300-fold excess of DFOB revealed that a short spacing of hydroxamates in (Orn-β-Ala)3-4 leads to improved complex stability compared to a longer spacing in (Lys-β-Ala)3-4 . We found that the alignment of amide groups in the pseudopeptide backbone and the presence of zwitterionic sidechains did not compromise the stability of the Zr-complexes with our chelators. We believe that the octadentate derivative AZA-DFO* is particularly valuable for the preparation of new Zr-chelators for targeted imaging which combine tunable pharmacokinetic properties with high complex stability and fast Zr-complexation kinetics.
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Affiliation(s)
- Lasse Outzen
- Department of Chemistry, University of Hamburg, Bundesstrasse 45, 20146, Hamburg, Germany
| | - Moritz Münzmay
- Department of Chemistry, University of Hamburg, Bundesstrasse 45, 20146, Hamburg, Germany
| | | | - Wolfgang Maison
- Department of Chemistry, University of Hamburg, Bundesstrasse 45, 20146, Hamburg, Germany
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Zhang X, Jozic A, Song P, Xu Q, Shi X, Wang H, Bishop L, Struthers HM, Rutledge J, Chen S, Xu F, Hancock MH, Zhu D, Sahay G, Chu CQ. mRNA vaccine against fibroblast activation protein ameliorates murine models of inflammatory arthritis. RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2023; 4:90-97. [PMID: 37818347 PMCID: PMC10561064 DOI: 10.2478/rir-2023-0013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 06/15/2023] [Indexed: 10/12/2023]
Abstract
Objective Synovial fibroblasts in patients with rheumatoid arthritis (RA) contribute substantially to the perpetuation of synovitis and invasion to cartilage and bone, and are potential therapeutic targets. Fibroblast activation protein (FAP) is highly expressed by RA synovial fibroblasts and the expression is relatively specific. We tested whether FAP can serve as a molecular target to modulate synovial fibroblasts for therapy in experimental arthritis. Methods mRNA encoding consensus FAP (cFAP) was encapsulated in lipid nanoparticles (LNP) and was injected intramuscularly as vaccine prior to induction of collagen-induced arthritis (CIA) and collagen antibody induced arthritis (CAIA) in mice. Development of CIA and CAIA was assessed clinically and by histology. Results cFAP mRNA-LNP vaccine provoked immune response to cFAP and mouse FAP (mFAP); prevented onset of CIA in 40% of mice and significantly reduced the severity of arthritis. In CAIA, cFAP mRNA-LNP did not prevent onset of arthritis but significantly reduced the severity of arthritis. Conclusion cFAP mRNA-LNP vaccine was able to provoke immune response to mFAP and suppress inflammatory arthritis.
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Affiliation(s)
- Xiaowei Zhang
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
| | - Antony Jozic
- Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon97201, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon97239, USA
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon97239, USA
| | - Pingfang Song
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
| | - Qiang Xu
- Department of Rheumatology, The First Hospital, Guangzhou University of Chinese Medicine, Guangzhou51405, Guangdong Province, China
| | - Xiaofei Shi
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
- Department of Rheumatology, The First Hospital, Henan University of Science and Technology, Luoyang471003, Henan Province, China
| | - Hong Wang
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
- Department of Rheumatology, The Second Hospital, Wenzhou Medical University, Wenzhou362000, Zhejiang Province, China
| | - Lindsey Bishop
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon97006, USA
| | - Hillary M Struthers
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon97006, USA
| | - John Rutledge
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
- Portland VA Research Foundation, Portland, Oregon97239, USA
| | - Shuang Chen
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
- Department of Internal Medicine, Oregon Health & Science University, Portland, Oregon97239, USA
| | - Fei Xu
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
- Department of Hematology and Oncology, General Hospital of Ningxia Medical University, Yinchuan750004, Ningxia Hui Autonomous Region, China
| | - Meaghan H Hancock
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon97006, USA
| | - Daocheng Zhu
- Shanghai Kexin Biotechnology, Co., Ltd., Shanghai, 201203, China
| | - Gaurav Sahay
- Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon97201, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon97239, USA
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon97239, USA
| | - Cong-Qiu Chu
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, VA Portland Health Care System, Portland, Oregon97239, USA
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Zhang Q, Lin X, Wang W, Zhang X, Lü M, Shao Z, Shi D, Zhang R, Shi H, Zhang Y, Pan J, Song G, Cheng K, Ge L, Wang L, Han J. Evaluation of 18F-FAPI-04 Imaging in Assessing the Therapeutic Response of Rheumatoid Arthritis. Mol Imaging Biol 2023:10.1007/s11307-023-01817-6. [PMID: 37020126 DOI: 10.1007/s11307-023-01817-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 04/07/2023]
Abstract
PURPOSE Fibroblast activating protein (FAP) is highly expressed in the synovial tissues of rheumatoid arthritis (RA) patients. The aim of this study was to determine the feasibility of PET imaging with an Al[18F] F-NOTA-labeled FAP inhibitor 04(18F-FAPI-04) for the evaluation of arthritic progression and therapeutic response in experimental arthritis. METHODS Fibroblast-like synoviocytes (FLSs) were obtained from patients with RA or osteoarthritis (OA), and the relationship between 18F-FAPI-04 uptake and the inflammatory activity of RA FLSs was investigated. Collagen-induce arthritis (CIA) mice models were established and treated with methotrexate (MTX) or etanercept (ETC). Then, PET imaging was performed 24 h following 18F-FAPI-04 injection. The imaging results were compared by assessing macroscopic arthritis scores and histological staining. RESULTS 18F-FAPI-04 uptake was obvious in RA FLSs that characterizing FAP activation. The higher the uptake of 18F-FAPI-04, the more severity of the inflammatory phenotype in RA FLS. Furthermore, the uptake of 18F-FAPI-04 in inflamed joints could be found even before the deformity of the parental joints could be observed by histological examination. Both MTX and ETC were effective in inhibiting the progression of arthritis in CIA mice was confirmed by macroscopic, histological, and radiographic pathology scores. Importantly, 18F-FAPI-04 uptake declined accordingly in CIA models following MTX and ETC treatment. CONCLUSIONS These findings suggest that PET imaging of 18F-FAPI-04 can be used to monitor treatment response in RA, and is more sensitive in disease speculation than macroscopic arthritis scoring.
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Affiliation(s)
- Qingyun Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Xuehong Lin
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Weiqi Wang
- College of Preventive Medical Sciences (Institute of Radiation Medicine), Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, China
| | - Xiaofan Zhang
- Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Mengxue Lü
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Zhurui Shao
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Dandan Shi
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Ruojia Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Haojun Shi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuang Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Jihong Pan
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China
| | - Guanhua Song
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Kai Cheng
- Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan 250117, Shandong, China
| | - Luna Ge
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China.
| | - Lin Wang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China.
| | - Jinxiang Han
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China; Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, #6699, Qingdao Road, Jinan, 250017, China.
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Wang Z, Wang J, Lan T, Zhang L, Yan Z, Zhang N, Xu Y, Tao Q. Role and mechanism of fibroblast-activated protein-α expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis. Front Immunol 2023; 14:1135384. [PMID: 37006278 PMCID: PMC10064071 DOI: 10.3389/fimmu.2023.1135384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
Fibroblast-activated protein-α (FAP) is a type II integrated serine protease expressed by activated fibroblasts during fibrosis or inflammation. Fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) synovial sites abundantly and stably overexpress FAP and play important roles in regulating the cellular immune, inflammatory, invasion, migration, proliferation, and angiogenesis responses in the synovial region. Overexpression of FAP is regulated by the initial inflammatory microenvironment of the disease and epigenetic signaling, which promotes RA development by regulating FLSs or affecting the signaling cross-linking FLSs with other cells at the local synovium and inflammatory stimulation. At present, several treatment options targeting FAP are in the process of development. This review discusses the basic features of FAP expressed on the surface of FLSs and its role in RA pathophysiology and advances in targeted therapies.
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Affiliation(s)
- Zihan Wang
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
- Graduate school, Beijing University of Chinese Medicine, Beijing, China
| | - Jinping Wang
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Tianyi Lan
- Graduate school, Beijing University of Chinese Medicine, Beijing, China
| | - Liubo Zhang
- Graduate school, Beijing University of Chinese Medicine, Beijing, China
| | - Zeran Yan
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Nan Zhang
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Yuan Xu
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Yuan Xu, ; Qingwen Tao,
| | - Qingwen Tao
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Yuan Xu, ; Qingwen Tao,
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18
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Luo Y, Pan Q, Zhou Z, Li M, Wei Y, Jiang X, Yang H, Li F. 68Ga-FAPI PET/CT for Rheumatoid Arthritis: A Prospective Study. Radiology 2023; 307:e222052. [PMID: 36853178 DOI: 10.1148/radiol.222052] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Background In rheumatoid arthritis (RA), fibroblast-like synoviocyte cells, which are involved in inflammation of the articular cartilage and bone, overexpress fibroblast activation protein (FAP). This is a feature that could be leveraged to improve imaging assessment of disease. Purpose To determine the performance of gallium 68 (68Ga)-labeled FAP inhibitor (FAPI) in assessing joint disease activity of RA and to compare with fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging. Materials and Methods Twenty participants with RA (15 women; mean age, 55 years ± 10 [SD]) were prospectively enrolled from September 2020 to December 2021 and underwent clinical and laboratory assessment of disease activity and dual-tracer PET/CT (68Ga-FAPI and 18F-FDG) imaging. Imaging-derived variables of PET joint count (the number of joints positive for RA at PET) and PET articular index (a sum of the points of the joints using a three-point scale) were correlated to clinical and laboratory variables of disease activity. Results The combined output of both PET/CT techniques helped detect 244 affected joints, all of which showed positive results at 68Ga-FAPI PET/CT. However, fifteen of 244 (6.1%) FAPI-avid joints in six of 20 (30%) participants were not detected at 18F-FDG PET/CT. The maximum standardized uptake value of the most affected joint in each participant was higher in 68Ga-FAPI than in 18F-FDG PET/CT (9.54 ± 4.92 vs 5.85 ± 2.81, respectively; P = .001). The maximum standardized uptake values of the joints at both 68Ga-FAPI and 18F-FDG PET/CT were positively correlated with laboratory evaluation of C-reactive protein levels (r = 0.49 [P = .03] and 0.54 [P = .01], respectively). The PET joint count and PET articular index scores at 68Ga-FAPI PET/CT were also positively correlated with most clinical disease activity variables and radiographic progression of joint damage (P < .05). Conclusion In participants with rheumatoid arthritis who underwent gallium 68 fibroblast activation protein inhibitor PET/CT, the extent of joint involvement correlated with clinical and laboratory variables of disease activity and showed a greater amount and degree of affected joints than at fluorine 18 fluorodeoxyglucose PET/CT. Clinical trial registration no. NCT04514614 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Williams and Ahlman in this issue.
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Affiliation(s)
- Yaping Luo
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Qingqing Pan
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Ziyue Zhou
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Min Li
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Yanping Wei
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Xu Jiang
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Huaxia Yang
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
| | - Fang Li
- From the Department of Nuclear Medicine (Y.L., Q.P., F.L.), Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, the Ministry of Education Key Laboratory (Z.Z., M.L., H.Y.), and State Key Laboratory of Difficult, Severe and Rare Diseases (Z.Z., Y.W., X.J., H.Y.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, PR China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, PR China (Y.L., Q.P., F.L.); Department of Endocrinology and Rheumatology, Taihe Hospital, Hubei University of Medicine, Shiyan, PR China (M.L.); and Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, PR China (Y.W., X.J.)
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Dong Y, Zhou H, Alhaskawi A, Wang Z, Lai J, Yao C, Liu Z, Hasan Abdullah Ezzi S, Goutham Kota V, Hasan Abdulla Hasan Abdulla M, Lu H. The Superiority of Fibroblast Activation Protein Inhibitor (FAPI) PET/CT Versus FDG PET/CT in the Diagnosis of Various Malignancies. Cancers (Basel) 2023; 15:1193. [PMID: 36831535 PMCID: PMC9954090 DOI: 10.3390/cancers15041193] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Cancer represents a major cause of death worldwide and is characterized by the uncontrolled proliferation of abnormal cells that escape immune regulation. It is now understood that cancer-associated fibroblasts (CAFs), which express specific fibroblast activation protein (FAP), are critical participants in tumor development and metastasis. Researchers have developed various FAP-targeted probes for imaging of different tumors from antibodies to boronic acid-based inhibitor molecules and determined that quinoline-based FAP inhibitors (FAPIs) are the most appropriate candidate as the radiopharmaceutical for FAPI PET/CT imaging. When applied clinically, FAPI PET/CT yielded satisfactory results. Over the past few years, the utility and effectiveness of tumor detection and staging of FAPI PET/CT have been compared with FDG PET/CT in various aspects, including standardized uptake values (SUVs), rate of absorbance and clearance. This review summarizes the development and clinical application of FAPI PET/CT, emphasizing the diagnosis and management of various tumor types and the future prospects of FAPI imaging.
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Affiliation(s)
- Yanzhao Dong
- Department of Orthopedics, The First Affiliated Hospital of Zhejiang University, #79 Qingchun Road, Hangzhou 310003, China
| | - Haiying Zhou
- Department of Orthopedics, The First Affiliated Hospital of Zhejiang University, #79 Qingchun Road, Hangzhou 310003, China
| | - Ahmad Alhaskawi
- Department of Orthopedics, The First Affiliated Hospital of Zhejiang University, #79 Qingchun Road, Hangzhou 310003, China
| | - Zewei Wang
- School of Medicine, Zhejiang University, #866 Yuhangtang Road, Hangzhou 310058, China
| | - Jingtian Lai
- School of Medicine, Zhejiang University, #866 Yuhangtang Road, Hangzhou 310058, China
| | - Chengjun Yao
- School of Medicine, Zhejiang University, #866 Yuhangtang Road, Hangzhou 310058, China
| | - Zhenfeng Liu
- Department of Nuclear Medicine, The First Affiliated Hospital of Zhejiang University, #79 Qingchun Road, Hangzhou 310003, China
| | - Sohaib Hasan Abdullah Ezzi
- Department of Orthopaedics, Third Xiangya Hospital of Central South University, #138 Tongzipo Road, Changsha 410013, China
| | - Vishnu Goutham Kota
- School of Medicine, Zhejiang University, #866 Yuhangtang Road, Hangzhou 310058, China
| | | | - Hui Lu
- Department of Orthopedics, The First Affiliated Hospital of Zhejiang University, #79 Qingchun Road, Hangzhou 310003, China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, #866 Yuhangtang Road, Hangzhou 310058, China
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20
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Cheung SK, Chen S, Wong YH, Wu KK, Ho CL. Diagnosis of Seronegative Rheumatoid Arthritis by 68 Ga-FAPI PET/CT. Nucl Med Mol Imaging 2023; 57:44-45. [PMID: 36643942 PMCID: PMC9832189 DOI: 10.1007/s13139-022-00779-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 09/18/2022] [Accepted: 09/22/2022] [Indexed: 01/18/2023] Open
Abstract
Early diagnosis of rheumatoid arthritis with the initiation of disease-modifying antirheumatic drugs is important to prevent future disability. Seronegative rheumatoid arthritis lacks the classical immunological markers, thus imposing clinical diagnostic difficulty. In this case, we reported 68 Ga-FAPI PET/CT findings of seronegative rheumatoid arthritis in a 60-year-old lady. This case illustrates how 68 Ga-FAPI PET/CT aids in the diagnosis of seronegative rheumatoid arthritis.
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Affiliation(s)
- Shing Kee Cheung
- Department of Nuclear Medicine & PET, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China
| | - Sirong Chen
- Department of Nuclear Medicine & PET, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China
- Research Department, Hong Kong Sanatorium & Hospital, Hong Kong, China
| | - Yuet Hung Wong
- Department of Nuclear Medicine & PET, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China
| | - Kwan Kit Wu
- Department of Nuclear Medicine & PET, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China
| | - Chi Lai Ho
- Department of Nuclear Medicine & PET, Hong Kong Sanatorium & Hospital, 2 Village Road, Happy Valley, Hong Kong, China
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21
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Lee IK, Noguera-Ortega E, Xiao Z, Todd L, Scholler J, Song D, Liousia M, Lohith K, Xu K, Edwards KJ, Farwell MD, June CH, Albelda SM, Puré E, Sellmyer MA. Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74. Clin Cancer Res 2022; 28:5330-5342. [PMID: 35972732 PMCID: PMC9771904 DOI: 10.1158/1078-0432.ccr-22-1379] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/28/2022] [Accepted: 08/12/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response. EXPERIMENTAL DESIGN We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer. RESULTS [18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses. CONCLUSIONS This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy. See related commentary by Weber et al., p. 5241.
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Affiliation(s)
- Iris K. Lee
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Estela Noguera-Ortega
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Zebin Xiao
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pensnsylvania, Philadelphia, PA, USA
| | - Leslie Todd
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pensnsylvania, Philadelphia, PA, USA
| | - John Scholler
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Decheng Song
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maria Liousia
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Katheryn Lohith
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kexiang Xu
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kimberly J. Edwards
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael D. Farwell
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Carl H. June
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Steven M. Albelda
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ellen Puré
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pensnsylvania, Philadelphia, PA, USA
| | - Mark A. Sellmyer
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- The Deparment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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22
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Damerow H, Cheng X, von Kiedrowski V, Schirrmacher R, Wängler B, Fricker G, Wängler C. Toward Optimized 89Zr-Immuno-PET: Side-by-Side Comparison of [ 89Zr]Zr-DFO-, [ 89Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [ 89Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable? Pharmaceutics 2022; 14:pharmaceutics14102114. [PMID: 36297549 PMCID: PMC9611803 DOI: 10.3390/pharmaceutics14102114] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 11/21/2022] Open
Abstract
89Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the 89Zr4+ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for 89Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable 89Zr-complexation. The chelators were introduced into cetuximab, and an optical analysis method was developed, enabling the efficient quantification of derivatization sites per protein. The cetuximab conjugates were efficiently obtained and radiolabeled with 89Zr at 37 °C within 30 min, giving the [89Zr]Zr-cetuximab derivatives in high radiochemical yields and purities of >99% as well as specific activities of 50 MBq/mg. The immunoreactive fraction of all 89Zr-labeled cetuximab derivatives was determined to be in the range of 86.5−88.1%. In vivo PET imaging and ex vivo biodistribution studies in tumor-bearing animals revealed a comparable and significantly higher kinetic inertness for both [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab and [89Zr]Zr-DFO*-cetuximab, compared to [89Zr]Zr-DFO-cetuximab. Of these, [89Zr]Zr-DFO*-cetuximab showed a considerably more favorable pharmacokinetic profile with significantly lower liver and spleen retention than [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab. Since [89Zr]Zr-DFO* demonstrates a very high kinetic inertness, paired with a highly favorable pharmacokinetic profile of the resulting antibody conjugate, DFO* currently represents the most suitable chelator candidate for stable 89Zr-radiolabeling of antibodies and clinical translation.
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Affiliation(s)
- Helen Damerow
- Biomedical Chemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Xia Cheng
- Molecular Imaging and Radiochemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Valeska von Kiedrowski
- Molecular Imaging and Radiochemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Ralf Schirrmacher
- Division of Oncologic Imaging, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada
| | - Björn Wängler
- Molecular Imaging and Radiochemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
| | - Carmen Wängler
- Biomedical Chemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Correspondence:
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23
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Clausen AS, Christensen C, Christensen E, Cold S, Kristensen LK, Hansen AE, Kjaer A. Development of a 64Cu-labeled CD4+ T cell targeting PET tracer: evaluation of CD4 specificity and its potential use in collagen-induced arthritis. EJNMMI Res 2022; 12:62. [PMID: 36114433 PMCID: PMC9481863 DOI: 10.1186/s13550-022-00934-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background CD4+ T cells are central inflammatory mediators in the pathogenesis of autoimmune rheumatoid arthritis (RA), as they are one of the dominating cell types in synovial inflammation. Molecular imaging of CD4+ T cells has potential role for early detection and monitoring of RA. Here, we developed a new radiotracer for in vivo immunoPET imaging of murine CD4+ T cells and tested it in the collagen-induced arthritis (CIA) mouse model of human RA. Results The tracer, [64Cu]Cu-NOTA-CD4-F(ab)’2 ([64Cu]Cu-NOTA-CD4), was generated from F(ab)’2 fragments of R-anti-mouse CD4 antibodies conjugated to the 2-S-(isothiocyanatbenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) chelator and radiolabeled with copper-64. Accumulation of the tracer and isotype control was evaluated in the CIA model and mice receiving whole-body irradiation (WBI) (5 Gy). The potential of [64Cu]Cu-NOTA-CD4 for response assessment was evaluated in CIA induced mice treated with dexamethasone (DXM). Imaging data were compared with flow cytometry and immunohistochemistry (IHC) of inflammatory cells including CD4+ T cells. [64Cu]Cu-NOTA-CD4 showed increased accumulation in T cell-rich tissues compared with isotype control (p < 0.0001). In addition, reduced accumulation of [64Cu]Cu-NOTA-CD4 was observed in T cell-depleted tissue (p < 0.0001). Flow cytometry and IHC confirmed the increased infiltration of CD4+ T cells in CIA mice. Conclusions We developed and evaluated a new radiotracer, [64Cu]Cu-NOTA-CD4, for immunoPET imaging of murine CD4+ T cells. [64Cu]Cu-NOTA-CD4 was successfully synthesized by F(ab)’2 fragments of R-anti-mouse CD4 antibodies conjugated to a chelator and radiolabeled with copper-64. We found that our novel CD4 PET tracer can be used for noninvasive visualization of murine CD4+ T cells. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-022-00934-7.
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24
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Meng Y, Yu J, Zhu M, Zhou J, Li N, Liu F, Zhang H, Fang X, Li J, Feng X, Wang L, Jiang H, Lu J, Shao C, Bian Y. CT radiomics signature: a potential biomarker for fibroblast activation protein expression in patients with pancreatic ductal adenocarcinoma. Abdom Radiol (NY) 2022; 47:2822-2834. [PMID: 35451626 DOI: 10.1007/s00261-022-03512-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 01/18/2023]
Abstract
PURPOSE To develop and validate a radiomics model to predict fibroblast activation protein (FAP) expression in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS This retrospective study included consecutive 152 patients with PDAC who underwent MDCT scan and surgical resection from January 2017 to December 2017 (training set) and from January 2018 to April 2018 (validation set). In the training set, 1409 portal radiomic features were extracted from each patient's preoperative imaging. Optimal features were selected using the least absolute shrinkage and selection operator (LASSO) logistic regression algorithm, whereupon the extreme gradient boosting (XGBoost) was developed using the radiomics features. The performance of the XGBoost classifier performance was assessed by its calibration, discrimination, and clinical usefulness. RESULTS The patients were divided into FAP-low (n = 91; 59.87%) and FAP-high (n = 61; 40.13%) groups according to the optimal FAP cutoff (45.71%). Patients in the FAP-low group showed longer survival. The XGBoost classifier comprised 13 selected radiomics features and showed good discrimination in the training set [area under the curve (AUC), 0.97] and the validation set (AUC, 0.75). It also performed well in the calibration test and decision-curve analysis, demonstrating its potential clinical value. CONCLUSIONS The XGBoost classifier based on CT radiomics in the portal venous phase can non-invasively predict FAP expression and may help to improve clinical decision-making in patients with PDAC.
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Affiliation(s)
- Yinghao Meng
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Radiology, No. 971 Hospital of Navy, Qingdao, Shandong, China
| | - Jieyu Yu
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mengmeng Zhu
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jian Zhou
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Na Li
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fang Liu
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hao Zhang
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xu Fang
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jing Li
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaocheng Feng
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Li Wang
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hui Jiang
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jianping Lu
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chengwei Shao
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China.
- Department of Radiology, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
| | - Yun Bian
- Department of Radiology, Changhai Hospital, Naval Medical University, Shanghai, China.
- Department of Radiology, Changhai Hospital, 168 Changhai Road, Shanghai, 200433, China.
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25
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Ge L, Song G, Zhang Y, Pan J, Zhang Y, Wang L, Cheng K. PET imaging to assess fibroblast activation protein inhibitor biodistribution: A training program adapted to pharmacology education. Pharmacol Res Perspect 2022; 10:e00997. [PMID: 35950835 PMCID: PMC9367699 DOI: 10.1002/prp2.997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/23/2022] [Indexed: 11/17/2022] Open
Abstract
In the process of pharmacology education, practical teaching is an important complement to theoretical teaching. These activities include the use of experimental animals to obtain certain pharmacological parameters or to help students understand certain classical concepts. However, the growing interest in laboratory animal welfare, the rapid development of pharmacology research and the challenges of cultivating innovative pharmacy talent create a need for innovative and flexible in vitro experiments for teaching purposes. Here, we report the application of positron emission tomography (PET) imaging of 18 F-labeled fibroblast activation protein inhibitor (18 F-FAPi) to practical pharmacology teaching, enabling dynamic visualization of the distribution and excretion process of FAPi in mice. Students can quantitatively analyze the distribution of FAPi in various tissues and organs without sacrificing the mice. Furthermore, the newly implemented method resulted in highly reproducible results and was generally appreciated by the students. Additionally, the application of PET imaging in pharmacokinetic teaching can not only greatly reduce the use of experimental animals but also need not sacrificing animals. Of note is that dynamic scanning data from this project can be used for online practical teaching during COVID-19 pandemic.
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Affiliation(s)
- Luna Ge
- Biomedical Sciences College & Shandong Medicinal Biotechnology CentreShandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong ProvinceJi'nanShandongChina
| | - Guanhua Song
- Institute of Basic MedicineShandong First Medical University & Shandong Academy of Medical SciencesJi'nanShandongChina
| | - Yuang Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology CentreShandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong ProvinceJi'nanShandongChina
| | - Jihong Pan
- Biomedical Sciences College & Shandong Medicinal Biotechnology CentreShandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong ProvinceJi'nanShandongChina
| | - Yihang Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology CentreShandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong ProvinceJi'nanShandongChina
| | - Lin Wang
- Biomedical Sciences College & Shandong Medicinal Biotechnology CentreShandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong ProvinceJi'nanShandongChina
| | - Kai Cheng
- Department of PET/CT CenterShandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical SciencesJi'nanShandongChina
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26
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Ge L, Fu Z, Wei Y, Shi D, Geng Y, Fan H, Zhang R, Zhang Y, Li S, Wang S, Shi H, Song G, Pan J, Cheng K, Wang L. Preclinical evaluation and pilot clinical study of [ 18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis. Eur J Nucl Med Mol Imaging 2022; 49:4025-4036. [PMID: 35715613 DOI: 10.1007/s00259-022-05836-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 05/08/2022] [Indexed: 11/04/2022]
Abstract
PURPOSE Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[18F]-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid-conjugated FAP inhibitor 04 ([18F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. METHODS RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro-binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [18F]AlF-NOTA-FAPI-04 and 18F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye-labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [18F]AlF-NOTA-FAPI-04. Additionally, [18F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. RESULTS The binding of [18F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/105 cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/105 cells). Compared to 18F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [18F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [18F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [18F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [18F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. CONCLUSION [18F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.
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Affiliation(s)
- Luna Ge
- Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China.,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Zheng Fu
- Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China
| | - Yuchun Wei
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China
| | - Dandan Shi
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Yun Geng
- Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China
| | - Huancai Fan
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Ruojia Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Yuang Zhang
- Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China.,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Shufeng Li
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China
| | - Shijie Wang
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China
| | - Haojun Shi
- The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China
| | - Guanhua Song
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China
| | - Jihong Pan
- Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China.,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China
| | - Kai Cheng
- Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, 250117, Shandong, China.
| | - Lin Wang
- Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China. .,Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences; NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences); Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, 250117, Shandong, China.
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27
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Meng L, Fang J, Zhao L, Wang T, Yuan P, Zhao Z, Zhuang R, Lin Q, Chen H, Chen X, Zhang X, Guo Z. Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein. J Med Chem 2022; 65:8245-8257. [PMID: 35658448 DOI: 10.1021/acs.jmedchem.1c02162] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The fibroblast activation protein (FAP), overexpressed on cancer-associated fibroblasts (CAFs), has become a valuable target for tumor diagnosis and therapy. However, most FAP-based radioligands show insufficient tumor uptake and retention. In this study, three novel albumin-binding FAP ligands (denoted as FSDD0I, FSDD1I, and FSDD3I) were labeled with 68Ga and 177Lu to overcome these limitations. Cell-based studies and molecular docking assays were performed to identify the specificity and protein-binding properties for FAP. Positron emission tomography (PET) scans in human hepatocellular carcinoma patient-derived xenografts (HCC-PDXs) animal models revealed longer blood retention of 68Ga-FSDD0I than 68Ga-FAPI-04, 68Ga-FSDD1I, and 68Ga-FSDD3I. Remarkably, 68Ga-FSDD3I had prominent tumor-to-nontarget (T/NT) ratios. The prominent tumor retention properties of 177Lu-FSDD0I in single photon emission computed tomography (SPECT) imaging and biodistribution studies were demonstrated. In summary, this study reports a proof-of-concept study of albumin-binding radioligands for FAP-targeted imaging and targeted radionuclide therapy (TRT).
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Affiliation(s)
- Lingxin Meng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jianyang Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Liang Zhao
- Department of Nuclear Medicine & Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.,Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Tingting Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Pu Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zuoquan Zhao
- Department of Nuclear Medicine, Cardiovascular Institute and FuWai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, China
| | - Rongqiang Zhuang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Qin Lin
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Haojun Chen
- Department of Nuclear Medicine & Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 119074, Singapore.,Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.,Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Xianzhong Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zhide Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
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Erol Fenercioğlu Ö, Beyhan E, Ergül N, Arslan E, Çermik TF. 18F-FDG PET/CT and 68Ga-FAPI-4 PET/CT Findings of Bilateral Knee Osteoarthritis in a Patient With Uveal Malignant Melanoma. Clin Nucl Med 2022; 47:e144-e146. [PMID: 34319962 DOI: 10.1097/rlu.0000000000003854] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT We present the findings of 68Ga-FAPI-4 PET/CT and 18F-FDG PET/CT of a metastatic malignant melanoma patient with osteoarthritis. A 65-year-old woman with a history of metastatic uveal malignant melanoma was referred to 18F-FDG PET/CT for restaging after enucleation and chemotherapy. 18F-FDG PET/CT imaging showed high radiotracer uptake in liver metastases; additionally mild uptake due to osteoarthritis was observed in both knees. However, although 68Ga-FAPI-4 showed lower uptake in liver lesions, it showed a more prominent uptake in both knee joints compared with 18F-FDG.
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Affiliation(s)
- Özge Erol Fenercioğlu
- From the Clinic of Nuclear Medicine, Istanbul Training and Research Hospital, Istanbul, Turkey
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29
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Peng D, He J, Liu H, Cao J, Wang Y, Chen Y. FAPI PET/CT research progress in digestive system tumours. Dig Liver Dis 2022; 54:164-169. [PMID: 34364808 DOI: 10.1016/j.dld.2021.07.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
18F-fluorodeoxyglucose positron emission tomography/computed tomography has been used in clinical practice for many years. This modality is of great value for tumour diagnosis, staging, and efficacy evaluations, but it has many limitations in the diagnosis and treatment of digestive system tumours. Fibroblast activation protein is highly expressed in gastrointestinal tumours. Various isotope-labelled fibroblast activation protein inhibitors are widely used in clinical research. These inhibitors have low background uptake in the brain, liver and oral/pharyngeal mucosa and show good contrast between the tumour and background, which makes up for the lack of fluorodeoxyglucose in the diagnosis of digestive system tumours. It better displays the primary tumours, metastases and regional lymph nodes of digestive system tumours, such as oesophageal cancer, gastric cancer and liver cancer, and also provides a new method for treating these tumours. Based on this background, this article introduces the current research status of fibroblast activation protein inhibitor positron emission tomography/computed tomography in various types of digestive system malignant tumours to provide more valuable information for diagnosing and treating digestive system tumours.
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Affiliation(s)
- Dengsai Peng
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No 25 TaiPing St, Jiangyang District, Luzhou, Sichuan 646000, PR China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, PR China; Academician (Expert) Workstation of Sichuan Province, 646000, PR China
| | - Jing He
- Department of Ultrasonography, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, PR China
| | - Hanxiang Liu
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No 25 TaiPing St, Jiangyang District, Luzhou, Sichuan 646000, PR China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, PR China; Academician (Expert) Workstation of Sichuan Province, 646000, PR China
| | - Jianpeng Cao
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No 25 TaiPing St, Jiangyang District, Luzhou, Sichuan 646000, PR China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, PR China; Academician (Expert) Workstation of Sichuan Province, 646000, PR China
| | - Yingwei Wang
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No 25 TaiPing St, Jiangyang District, Luzhou, Sichuan 646000, PR China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, PR China; Academician (Expert) Workstation of Sichuan Province, 646000, PR China
| | - Yue Chen
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No 25 TaiPing St, Jiangyang District, Luzhou, Sichuan 646000, PR China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, PR China; Academician (Expert) Workstation of Sichuan Province, 646000, PR China.
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30
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Krache A, Fontan C, Pestourie C, Bardiès M, Bouvet Y, Payoux P, Chatelut E, White-Koning M, Salabert AS. Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model. Front Med (Lausanne) 2022; 8:741855. [PMID: 35174180 PMCID: PMC8841431 DOI: 10.3389/fmed.2021.741855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022] Open
Abstract
Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression.MethodsPharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (μPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans.ResultsOrgan distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 μSv/MBq.ConclusionThe predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.
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Affiliation(s)
- Anis Krache
- CRCT, UMR 1037, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
- ToNIC, Toulouse NeuroImaging Center, UMR 1214, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
- General-Electric - Zionexa, Targeting Imaging and Therapy, Buc, France
- Anis Krache
| | - Charlotte Fontan
- General-Electric - Zionexa, Targeting Imaging and Therapy, Buc, France
| | - Carine Pestourie
- CREFRE (Centre Régional D'Exploration Fonctionnelle et Ressources Expérimentales) – INSERM UMS006, Plateforme GénoToul-Anexplo, Toulouse, France
- ENVT (Ecole Nationale Vétérinaire de Toulouse), Toulouse, France
| | - Manuel Bardiès
- IRCM (Institut de Recherche en Cancérologie de Montpellier), UMR 1194 INSERM, Université de Montpellier and ICM, Montpellier, France
- Département de Médecine Nucléaire, ICM (Institut du Cancer de Montpellier), Montpellier, France
| | - Yann Bouvet
- General-Electric - Zionexa, Targeting Imaging and Therapy, Buc, France
| | - Pierre Payoux
- ToNIC, Toulouse NeuroImaging Center, UMR 1214, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
- Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
| | - Etienne Chatelut
- CRCT, UMR 1037, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
| | - Melanie White-Koning
- CRCT, UMR 1037, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
| | - Anne-Sophie Salabert
- ToNIC, Toulouse NeuroImaging Center, UMR 1214, Université de Toulouse, INSERM, Université Paul-Sabatier, Toulouse, France
- Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
- *Correspondence: Anne-Sophie Salabert
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31
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Li XG, Velikyan I, Viitanen R, Roivainen A. PET radiopharmaceuticals for imaging inflammatory diseases. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00075-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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32
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Mukkamala R, Lindeman SD, Kragness KA, Shahriar I, Srinivasarao M, Low PS. Design and Characterization of Fibroblast Activation Protein Targeted Pan-Cancer Imaging Agent for Fluorescence-Guided Surgery of Solid Tumors. J Mater Chem B 2022; 10:2038-2046. [PMID: 35255116 DOI: 10.1039/d1tb02651h] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Tumor-targeted fluorescent dyes have been shown to significantly improve a surgeon's ability to locate and resect occult malignant lesions, thereby enhancing a patient’s chances of long term survival. Although several...
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Affiliation(s)
- Ramesh Mukkamala
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
| | - Spencer D Lindeman
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
| | - Kate A Kragness
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
| | - Imrul Shahriar
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
| | - Madduri Srinivasarao
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
| | - Philip S Low
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, USA.
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33
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Rangarajan V, Choudhury S, Agrawal A, Puranik A, Shah S, Purandare N. Fibroblast activation protein inhibitors: New frontier of molecular imaging and therapy. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00113-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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34
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Photodynamic Therapy Targeting Macrophages Using IRDye700DX-Liposomes Decreases Experimental Arthritis Development. Pharmaceutics 2021; 13:pharmaceutics13111868. [PMID: 34834283 PMCID: PMC8621465 DOI: 10.3390/pharmaceutics13111868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/31/2022] Open
Abstract
Macrophages play a crucial role in the initiation and progression of rheumatoid arthritis (RA). Liposomes can be used to deliver therapeutics to macrophages by exploiting their phagocytic ability. However, since macrophages serve as the immune system’s first responders, it is inadvisable to systemically deplete these cells. By loading the liposomes with the photosensitizer IRDye700DX, we have developed and tested a novel way to perform photodynamic therapy (PDT) on macrophages in inflamed joints. PEGylated liposomes were created using the film method and post-inserted with micelles containing IRDye700DX. For radiolabeling, a chelator was also incorporated. RAW 264.7 cells were incubated with liposomes with or without IRDye700DX and exposed to 689 nm light. Viability was determined using CellTiterGlo. Subsequently, biodistribution and PDT studies were performed on mice with collagen-induced arthritis (CIA). PDT using IRDye700DX-loaded liposomes efficiently induced cell death in vitro, whilst no cell death was observed using the control liposomes. Biodistribution of the two compounds in CIA mice was comparable with excellent correlation of the uptake with macroscopic and microscopic arthritis scores. Treatment with 700DX-loaded liposomes significantly delayed arthritis development. Here we have shown the proof-of-principle of performing PDT in arthritic joints using IRDye700DX-loaded liposomes, allowing locoregional treatment of arthritis.
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Klasen B, Lemcke D, Mindt TL, Gasser G, Rösch F. Development and in vitro evaluation of new bifunctional 89Zr-chelators based on the 6-amino-1,4-diazepane scaffold for immuno-PET applications. Nucl Med Biol 2021; 102-103:12-23. [PMID: 34242949 DOI: 10.1016/j.nucmedbio.2021.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/15/2021] [Accepted: 06/25/2021] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Combination of hydroxamate bearing side chains with the 6-amino-1,4-diazepane scaffold provides a promising strategy for fast and stable 89Zr-labeling of antibodies. Following this approach, we hereby present the development, labeling kinetics and in vitro complex stability of three resulting bifunctional chelator derivatives both stand-alone and coupled to a model protein in comparison to different linear deferoxamine (DFO) derivatives. METHODS The novel 89Zr-chelator Hy3ADA5 was prepared via amide-coupling of separately synthesized 6-amino-1,4-diazepane-6-pentanoic acid and hydroxamate-containing side chains. Two further bifunctional derivatives were synthesized by extending the resulting system with either a squaramide- or p-isothiocyanatophenyl moiety for simplified binding to proteins. After coupling to a model antibody and purification, the resulting immunoconjugates as well as the unbound chelator derivatives were 89Zr-labeled at room temperature (RT) and neutral pH. For comparison, different DFO derivatives were analogously coupled, purified and radiolabeled. In vitro complex stability of the resulting radioconjugates was investigated in phosphate buffered saline (PBS) and human serum at 37 °C over a period of 7 days. RESULTS 89Zr-labeling of the novel unbound Hy3ADA5 derivatives indicated rapid complexation kinetics resulting in high radiochemical conversions (RCC) of 84-94% after 90 min. Similar or even faster radiolabeling with slightly increased maximum yields was obtained using the DFO-analogues. Initially, [89Zr]Zr-DFO*-p-Ph-NCS showed a delayed formation, nevertheless reaching almost quantitative complexation. Radiolabeling of the corresponding immunoconjugates Hy3ADA5-SA-mAb and Hy3ADA5-p-Ph-NCS-mAb resulted in 82.0 ± 1.1 and 89.2 ± 0.7% RCC, respectively after 90 min representing high but slightly lower labeling efficiency compared to the DFO- and DFO*-functionalized analogues. All examined radioimmunoconjugates showed very high in vitro complex stability both in human serum and PBS, providing no significant release of the radiometal. In the case of unbound chelators, however, the p-Ph-NCS-functionalized derivatives indicated considerable instability in human serum already after 1 h. CONCLUSION The novel chelator derivatives based on hydroxamate-functionalized 6-amino-1,4-diazepane revealed fast and high yielding 89Zr-labeling kinetics as well as high in vitro complex stability both stand-alone and coupled to an antibody. Therefore, Hy3ADA5 represents a promising tool for radiolabeling of biomolecules such as antibodies at mild conditions for immuno-PET applications.
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Affiliation(s)
- Benedikt Klasen
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, Germany.
| | - Daniel Lemcke
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, Germany
| | - Thomas L Mindt
- Ludwig Boltzmann Institute Applied Diagnostics, General Hospital Vienna, Austria; Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Austria
| | - Gilles Gasser
- Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, Paris, France
| | - Frank Rösch
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, Germany.
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Imlimthan S, Moon ES, Rathke H, Afshar-Oromieh A, Rösch F, Rominger A, Gourni E. New Frontiers in Cancer Imaging and Therapy Based on Radiolabeled Fibroblast Activation Protein Inhibitors: A Rational Review and Current Progress. Pharmaceuticals (Basel) 2021; 14:1023. [PMID: 34681246 PMCID: PMC8540221 DOI: 10.3390/ph14101023] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/29/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022] Open
Abstract
Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted-as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation.
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Affiliation(s)
- Surachet Imlimthan
- Department of Nuclear Medicine, the Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland; (S.I.); (H.R.); (A.A.-O.); (A.R.)
| | - Euy Sung Moon
- Department of Chemistry—TRIGA Site, Johannes Gutenberg—University Mainz, 55128 Mainz, Germany; (E.S.M.); (F.R.)
| | - Hendrik Rathke
- Department of Nuclear Medicine, the Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland; (S.I.); (H.R.); (A.A.-O.); (A.R.)
| | - Ali Afshar-Oromieh
- Department of Nuclear Medicine, the Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland; (S.I.); (H.R.); (A.A.-O.); (A.R.)
| | - Frank Rösch
- Department of Chemistry—TRIGA Site, Johannes Gutenberg—University Mainz, 55128 Mainz, Germany; (E.S.M.); (F.R.)
| | - Axel Rominger
- Department of Nuclear Medicine, the Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland; (S.I.); (H.R.); (A.A.-O.); (A.R.)
| | - Eleni Gourni
- Department of Nuclear Medicine, the Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland; (S.I.); (H.R.); (A.A.-O.); (A.R.)
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37
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Aarntzen EHJG, Noriega-Álvarez E, Artiko V, Dias AH, Gheysens O, Glaudemans AWJM, Lauri C, Treglia G, van den Wyngaert T, van Leeuwen FWB, Terry SYA. EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases. EJNMMI Res 2021; 11:85. [PMID: 34487263 PMCID: PMC8421483 DOI: 10.1186/s13550-021-00820-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/02/2021] [Indexed: 11/26/2022] Open
Abstract
Inflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings.
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Affiliation(s)
- Erik H J G Aarntzen
- Inflammation and Infection Committee EANM, Vienna, Austria
- Department of Medical Imaging, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands
| | - Edel Noriega-Álvarez
- Inflammation and Infection Committee EANM, Vienna, Austria
- Department of Nuclear Medicine, General University Hospital of Ciudad Real, Ciudad Real, Spain
| | - Vera Artiko
- Inflammation and Infection Committee EANM, Vienna, Austria
- Center for Nuclear Medicine Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000, Belgrade, Serbia
| | - André H Dias
- Inflammation and Infection Committee EANM, Vienna, Austria
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark
| | - Olivier Gheysens
- Inflammation and Infection Committee EANM, Vienna, Austria
- Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc and Institute of Clinical and Experimental Research (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Andor W J M Glaudemans
- Inflammation and Infection Committee EANM, Vienna, Austria.
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen Medical Imaging Center, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
| | - Chiara Lauri
- Inflammation and Infection Committee EANM, Vienna, Austria
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, "Sapienza" University of Rome, 00161, Rome, Italy
| | - Giorgio Treglia
- Inflammation and Infection Committee EANM, Vienna, Austria
- Clinic of Nuclear Medicine, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Faculty of Biology and Medicine, Università Della Svizzera Italiana, Lugano, Switzerland
| | - Tim van den Wyngaert
- Bone and Joint Committee EANM, Vienna, Austria
- Antwerp University Hospital Belgium, Edegem, Belgium
- Molecular Imaging Center Antwerp (MICA) - IPPON, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Fijs W B van Leeuwen
- Translational Molecular Imaging and Therapy Committee EANM, Vienna, Austria
- Department of Radiology, Interventional Molecular Imaging Laboratory, Leiden University Medical Center, Leiden, The Netherlands
| | - Samantha Y A Terry
- Inflammation and Infection Committee EANM, Vienna, Austria.
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor Lambeth Wing, St Thomas' Hospital, London, SE1 7EH, UK.
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Dorst DN, Rijpkema M, Buitinga M, Walgreen B, Helsen MMA, Brennan E, Klein C, Laverman P, Ramming A, Schmidkonz C, Kuwert T, Schett G, van der Kraan PM, Gotthardt M, Koenders MI. Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy. Rheumatology (Oxford) 2021; 61:2999-3009. [PMID: 34450633 PMCID: PMC9258553 DOI: 10.1093/rheumatology/keab664] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/20/2021] [Indexed: 12/21/2022] Open
Abstract
Objective Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
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Affiliation(s)
- Daphne N Dorst
- Department of medical imaging: Nuclear medicine, Radboudumc, Nijmegen, The Netherlands.,Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - Mark Rijpkema
- Department of medical imaging: Nuclear medicine, Radboudumc, Nijmegen, The Netherlands
| | - Mijke Buitinga
- Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, The Netherlands.,Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Birgitte Walgreen
- Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - Monique M A Helsen
- Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - Evan Brennan
- Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands
| | - Christian Klein
- Roche Pharmaceutical Research and Early Development, Innovation Center Zurich, Schlieren, Switzerland
| | - Peter Laverman
- Department of medical imaging: Nuclear medicine, Radboudumc, Nijmegen, The Netherlands
| | - Andreas Ramming
- Department of medicine 3, Friedrich Alexander University Erlangen-Nürnberg and Universtitätsklinikum Erlangen, Germany.,Deutsches Zentrum für Immuntherapie, Erlangen, Germany
| | | | - Torsten Kuwert
- Clinic of Nuclear Medicine, University Hospital Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of medicine 3, Friedrich Alexander University Erlangen-Nürnberg and Universtitätsklinikum Erlangen, Germany.,Deutsches Zentrum für Immuntherapie, Erlangen, Germany
| | | | - Martin Gotthardt
- Department of medical imaging: Nuclear medicine, Radboudumc, Nijmegen, The Netherlands
| | - Marije I Koenders
- Department of Experimental Rheumatology, Radboudumc, Nijmegen, The Netherlands
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Grus T, Lahnif H, Klasen B, Moon ES, Greifenstein L, Roesch F. Squaric Acid-Based Radiopharmaceuticals for Tumor Imaging and Therapy. Bioconjug Chem 2021; 32:1223-1231. [PMID: 34170116 DOI: 10.1021/acs.bioconjchem.1c00305] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Targeting vectors bound to a chelator represent a significant fraction of radiopharmaceuticals used nowadays for diagnostic and therapeutic purposes in nuclear medicine. The use of squaramides as coupling units for chelator and targeting vector helps to circumvent the disadvantages of several common coupling methods. This review gives an overview of the use of squaric acid diesters (SADE) as linking agents. It focuses on the conjugation of cyclic chelators, e.g., DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), as well as hybrid chelators like AAZTA5 (6-pentanoic acid-6-amino-1,4-diazepine tetracetic acid) or DATA5m (6-pentanoic acid-6-amino-1,4-diazapine-triacetate) to different targeting vectors, e.g., prostate-specific membrane antigen inhibitors (KuE; PSMAi), fibroblast activation protein inhibitors (FAPi), and monoclonal antibodies (mAbs). An overview of the synthesis, radiolabeling, and in vitro and in vivo behavior of the described structures is given. The unique properties of SADE enable a fast and simple conjugation of chelators to biomolecules, peptides, and small molecules under mild conditions. Furthermore, SA-containing conjugates could not only display similar in vitro characteristics in terms of binding affinity when compared to reference compounds, but may even induce beneficial effects on the pharmacokinetic properties of these radiopharmaceuticals.
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Affiliation(s)
- Tilmann Grus
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
| | - Hanane Lahnif
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
| | - Benedikt Klasen
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
| | - Euy-Sung Moon
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
| | - Lukas Greifenstein
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
| | - Frank Roesch
- Department of Chemistry - TRIGA site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
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Abstract
Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.
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Affiliation(s)
- Joel G Rurik
- Department of Cell and Developmental Biology, Department of Medicine, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
| | - Haig Aghajanian
- Department of Cell and Developmental Biology, Department of Medicine, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
| | - Jonathan A Epstein
- Department of Cell and Developmental Biology, Department of Medicine, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
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41
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Zhang X, Chen D, Babich JW, Green SJE, Deng XH, Rodeo SA. In Vivo Imaging of Fibroblast Activity Using a 68Ga-Labeled Fibroblast Activation Protein Alpha (FAP-α) Inhibitor: Study in a Mouse Rotator Cuff Repair Model. J Bone Joint Surg Am 2021; 103:e40. [PMID: 33587512 DOI: 10.2106/jbjs.20.00831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Rotator cuff repair site failure is a well-established clinical concern. Tendon-to-bone healing is initiated by inflammatory mediators followed by matrix synthesis by fibroblasts. The kinetics of fibroblast accumulation and activity are currently poorly understood. METHODS Ninety-six mice underwent supraspinatus tendon repair. Six were used for imaging using a novel 68Gallium (Ga)-labeled fibroblast activation protein alpha (FAP-α) inhibitor and positron emission tomography-computed tomography (PET/CT) at days 0 (before surgery), 3, 7, 14, and 28. Sixty-eight animals were divided into 4 groups to be evaluated at 3, 7, 14, or 28 days. Twenty-two native shoulders from mice without surgery were used as the control group (intact tendon). Six animals from each group were used for histological analysis; 6 from each group were used for evaluation of fibroblastic response-related gene expression; and 10 mice each from the intact, 14-day, and 28-day groups were used for biomechanical testing. RESULTS There was minimal localization of 68Ga-labeled FAP-α inhibitor in the shoulders at day 0 (before surgery). There was significantly increased uptake in the shoulders with surgery compared with the contralateral sides without surgery at 3, 7, and 14 days. 68Ga-labeled FAP-α inhibitor uptake in the surgically treated shoulders increased gradually and peaked at 14 days followed by a decrease at 28 days. Gene expression for smooth muscle alpha (α)-2 (acta2), FAP-α, and fibronectin increased postsurgery followed by a drop at 28 days. Immunohistochemical analysis showed that FAP-α-positive cell density followed a similar temporal trend, peaking at 14 days. All trends matched closely with the PET/CT results. Biomechanical testing demonstrated a gradual increase in failure load during the healing process. CONCLUSIONS 68Ga-labeled FAP-α inhibitor PET/CT allows facile, high-contrast in vivo 3-dimensional imaging of fibroblastic activity in a mouse rotator cuff repair model. CLINICAL RELEVANCE Noninvasive imaging of activated fibroblasts using labeled radiotracers may be a valuable tool to follow the progression of healing at the bone-tendon interface.
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Affiliation(s)
- Xueying Zhang
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, NY.,Department of Sports Medicine & Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, People's Republic of, China
| | - Daoyun Chen
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, NY
| | - John W Babich
- Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY
| | - Samuel J E Green
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, NY
| | - Xiang-Hua Deng
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, NY
| | - Scott A Rodeo
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, NY
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42
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Slania SL, Das D, Lisok A, Du Y, Jiang Z, Mease RC, Rowe SP, Nimmagadda S, Yang X, Pomper MG. Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules. J Med Chem 2021; 64:4059-4070. [PMID: 33730493 PMCID: PMC8214312 DOI: 10.1021/acs.jmedchem.0c02171] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [111In]QCP02, using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity in vivo. QCP01 and [111In]QCP02 demonstrated nanomolar inhibition of FAP at Ki values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically in vivo. [111In]QCP02 showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration.
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Affiliation(s)
- Stephanie L Slania
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Deepankar Das
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Ala Lisok
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Yong Du
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Zirui Jiang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Ronnie C Mease
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Steven P Rowe
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Sridhar Nimmagadda
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Xing Yang
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
| | - Martin G Pomper
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States
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Kelly JM, Jeitner TM, Ponnala S, Williams C, Nikolopoulou A, DiMagno SG, Babich JW. A Trifunctional Theranostic Ligand Targeting Fibroblast Activation Protein-α (FAPα). Mol Imaging Biol 2021; 23:686-696. [PMID: 33721173 DOI: 10.1007/s11307-021-01593-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 01/05/2021] [Accepted: 02/16/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE Fibroblast activation protein-α (FAPα) is uniquely expressed in activated fibroblasts, including cancer-associated fibroblasts that populate tumor stroma and contribute to proliferation and immunosuppression. Radiolabeled FAPα inhibitors enable imaging of multiple human cancers, but time-dependent clearance from tumors currently limits their utility as FAPα-targeted radiotherapeutics. We sought to increase the area under the curve (AUC) by constructing a trifunctional ligand that binds FAPα with high affinity and also binds albumin and theranostic radiometals. PROCEDURES RPS-309 comprised a FAPα-targeting moiety, an albumin-binding group, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Inhibition of recombinant human FAPα (rhFAPα) was determined by colorimetric assay. Affinity for human serum albumin (HSA) was determined by high-performance affinity chromatography. The tissue distribution of [68Ga]Ga-RPS-309 in SW872 tumor xenograft-bearing mice was imaged by microPET/CT and quantified by biodistribution studies performed from 30 min to 3 h post injection (p.i.). The biodistribution of [177Lu]Lu-RPS-309 was determined at 4, 24, and 96 h p.i. RESULTS RPS-309 inhibits rhFAPα with IC50 = 7.3 ± 1.4 nM. [68Ga]Ga-RPS-309 is taken up specifically by FAPα-expressing cells and binds HSA with Kd = 4.6 ± 0.1 μM. Uptake of the radiolabeled ligand in tumors was evident from 30 min p.i. (> 5 %ID/g) and was significantly reduced by co-injection of RPS-309. Specific skeletal uptake was also observed. Activity in tumors was constant through 4 h p.i., but cleared significantly by 24 h. The AUC in this period was 127 (%ID/g) × h. CONCLUSIONS RPS-309 is a high-affinity FAPα inhibitor with prolonged plasma residence. Introduction of the albumin-binding group did not compromise FAPα binding. Although initial tumor uptake was high and FAPα-specific, RPS-309 also progressively cleared from tumors. Nevertheless, RPS-309 incorporates multiple sites in which structural diversity can be introduced, and therefore serves as a platform for future structure-activity relationship studies.
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Affiliation(s)
- James M Kelly
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Thomas M Jeitner
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Shashikanth Ponnala
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
- Angion Biomedica Corp., Uniondale, NY, 11553, USA
| | - Clarence Williams
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Anastasia Nikolopoulou
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA
- Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA
- The Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, PA, 19477, USA
| | - Stephen G DiMagno
- Departments of Pharmaceutical Sciences and Chemistry, UIC College of Pharmacy, Chicago, IL, USA
| | - John W Babich
- Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.
- Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
- Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 E 69th St, New York, NY, 10021, USA.
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Sharma P, Singh SS, Gayana S. Fibroblast Activation Protein Inhibitor PET/CT: A Promising Molecular Imaging Tool. Clin Nucl Med 2021; 46:e141-e150. [PMID: 33351507 DOI: 10.1097/rlu.0000000000003489] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE Fibroblast activation protein (FAP) is a cell membrane-bound serine peptidase, overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Recently, molecular PET/CT imaging with radiolabeled FAP inhibitor (FAPI) has been evaluated in different diseases. We aimed to assess its potential role based on the available literature. PATIENTS AND METHODS We conducted a comprehensive review of the available preclinical and clinical data on FAPI PET/CT in an attempt to summarize its current status and potential future role. Based on that, we have discussed the pathophysiology behind FAP-based imaging, followed by a discussion of FAPI radiopharmaceuticals including their synthesis, biodistribution, and dosimetry. Next, we have discussed studies evaluating FAPI PET/CT in different oncological and nononcological pathologies. The potential of FAPI PET/CT in theranostics has also been addressed. RESULTS Based on the early scientific evidence available, including preclinical and clinical studies, FAPI PET/CT seems to be a promising molecular imaging tool, especially in oncology. It can be used for imaging different types of cancers and outperforms 18F-FDG PET/CT in some of these. Its potential as a theranostic tool warrants special attention. CONCLUSIONS Fibroblast activation protein inhibitor PET/CT has the potential to emerge as a powerful molecular imaging tool in the future. However, as of yet, the available evidence is limited, warranting further research and trials in this field.
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Affiliation(s)
- Punit Sharma
- From the Department of Nuclear Medicine and PET/CT, Apollo Gleneagles Hospital, Kolkata
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45
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Imaging Inflammation with Positron Emission Tomography. Biomedicines 2021; 9:biomedicines9020212. [PMID: 33669804 PMCID: PMC7922638 DOI: 10.3390/biomedicines9020212] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 01/28/2021] [Accepted: 02/12/2021] [Indexed: 12/19/2022] Open
Abstract
The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings.
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46
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Abstract
Fibroblast activation protein-α (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions including fibrosis, arthritis, and cancer. Across most cancer types, elevated FAP is associated with worse clinical outcomes. Despite the clear association between FAP and disease severity, the biological reasons underlying these clinical observations remain unclear. Here we review basic FAP biology and FAP's role in non-oncologic and oncologic disease. We further explore how FAP may worsen clinical outcomes via its effects on extracellular matrix remodeling, intracellular signaling regulation, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. Lastly, we discuss the potential to exploit FAP biology to improve clinical outcomes.
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Affiliation(s)
- Allison A Fitzgerald
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3870 Reservoir Road NW, Washington, DC, 20057, USA
| | - Louis M Weiner
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3870 Reservoir Road NW, Washington, DC, 20057, USA.
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47
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Dorst DN, Rijpkema M, Boss M, Walgreen B, Helsen MMA, Bos DL, Brom M, Klein C, Laverman P, van der Kraan PM, Gotthardt M, Koenders MI, Buitinga M. Targeted photodynamic therapy selectively kills activated fibroblasts in experimental arthritis. Rheumatology (Oxford) 2021; 59:3952-3960. [PMID: 32734285 PMCID: PMC7733717 DOI: 10.1093/rheumatology/keaa295] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/30/2020] [Indexed: 12/11/2022] Open
Abstract
Objective In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX. Methods After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis. Results 28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT. Conclusion Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.
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Affiliation(s)
- Daphne N Dorst
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mark Rijpkema
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marti Boss
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Birgitte Walgreen
- Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Monique M A Helsen
- Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Desirée L Bos
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maarten Brom
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Christian Klein
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Peter Laverman
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Peter M van der Kraan
- Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marije I Koenders
- Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mijke Buitinga
- Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
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van der Krogt JMA, van Binsbergen WH, van der Laken CJ, Tas SW. Novel positron emission tomography tracers for imaging of rheumatoid arthritis. Autoimmun Rev 2021; 20:102764. [PMID: 33476822 DOI: 10.1016/j.autrev.2021.102764] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 10/28/2020] [Indexed: 11/30/2022]
Abstract
Positron emission tomography (PET) is a nuclear imaging modality that relies on visualization of molecular targets in tissues, which is nowadays combined with a structural imaging modality such as computed tomography (CT) or Magnetic Resonance Imaging (MRI) and referred to as hybrid PET imaging. This technique allows to image specific immunological targets in rheumatoid arthritis (RA). Moreover, quantification of the PET signal enables highly sensitive monitoring of therapeutic effects on the molecular target. PET may also aid in stratification of the immuno-phenotype at baseline in order to develop personalized therapy. In this systematic review we will provide an overview of novel PET tracers, investigated in the context of RA, either pre-clinically, or clinically, that specifically visualize immune cells or stromal cells, as well as other factors and processes that contribute to pathology. The potential of these tracers in RA diagnosis, disease monitoring, and prediction of treatment outcome will be discussed. In addition, novel PET tracers established within the field of oncology that may be of use in RA will also be reviewed in order to expand the future opportunities of PET imaging in RA.
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Affiliation(s)
- Jeffrey M A van der Krogt
- Amsterdam UMC, Location AMC, Amsterdam Rheumatology & Immunology Center (ARC), University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Amsterdam UMC/University of Amsterdam, Amsterdam, the Netherlands
| | - Wouter H van Binsbergen
- Amsterdam UMC, Location VUmc, Amsterdam Rheumatology and Immunology Center (ARC), VU University, Amsterdam, the Netherlands
| | - Conny J van der Laken
- Amsterdam UMC, Location VUmc, Amsterdam Rheumatology and Immunology Center (ARC), VU University, Amsterdam, the Netherlands
| | - Sander W Tas
- Amsterdam UMC, Location AMC, Amsterdam Rheumatology & Immunology Center (ARC), University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Amsterdam UMC/University of Amsterdam, Amsterdam, the Netherlands.
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Zheng J, Chen H, Lin K, Yao S, Miao W. [ 68Ga]Ga-FAPI and [ 18F]FDG PET/CT images in a patient with juvenile polymyositis. Eur J Nucl Med Mol Imaging 2021; 48:2051-2052. [PMID: 33462628 DOI: 10.1007/s00259-020-05185-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 12/27/2020] [Indexed: 11/28/2022]
Affiliation(s)
- Jieling Zheng
- Department of Nuclear Medicine, Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Huaning Chen
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Kaixian Lin
- Department of Nuclear Medicine, Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Shaobo Yao
- Department of Nuclear Medicine, Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China.
| | - Weibing Miao
- Department of Nuclear Medicine, Fujian Provincial Key Laboratory of Precision Medicine for Cancer, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China.
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50
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Molecular Imaging of Autoimmune Diseases. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00055-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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