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Meng Z, Tan B, Wang M, Zhu J, Qu C, Cheng Z. Development of a Cyclic TMTP1-Based PET Probe for Visualization of Hepatocellular Carcinoma. ACS Med Chem Lett 2025; 16:617-624. [PMID: 40236552 PMCID: PMC11995206 DOI: 10.1021/acsmedchemlett.5c00008] [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: 01/06/2025] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/17/2025] Open
Abstract
TMTP1 is a tumor-homing peptide that selectively targets highly metastatic tumor cells with XPNPEP2 identified as its potential targeting receptor. Although TMTP1-based molecular probes have been explored for imaging tumors such as hepatocellular carcinoma (HCC), their clinical translation has been hampered by factors including suboptimal tumor uptake and rapid systemic clearance. To study possible solution for addressing these challenges, a cyclic TMTP1 based positron emission tomography (PET) probe, [68Ga]Ga-DOTA-cTMTP1, was designed, synthesized, and evaluated for imaging HCC in small animal models. [68Ga]Ga-DOTA-cTMTP1 demonstrated favorable aqueous solubility, with a log D 7.4 value of -3.28 ± 0.05, and it exhibited excellent in vitro stability in phosphate buffered saline (PBS) and fetal bovine serum (FBS). Biodistribution studies revealed a certain level of tumor accumulation (0.98 ± 0.14%ID/g at 30 min) and retention (0.40 ± 0.11%ID/g at 120 min). Impressively, [68Ga]Ga-DOTA-cTMTP1 maintained high tumor-to-liver contrast over time, with ratios of 2.65 ± 0.45 at 30 min, 2.37 ± 0.07 at 60 min, and 2.14 ± 0.20 at 120 min. It also displayed capability of clear visualization of small HCC foci (<4 mm) in transgenic c-Myc liver tumor mice models, with tumor/liver ratios 2.20 ± 0.10 at 30 min, 2.26 ± 0.11 at 60 min, and 2.55 ± 0.44 at 120 min, respectively. Overall, this study highlights that [68Ga]Ga-DOTA-cTMTP1 has favorable pharmacokinetic and in vivo tumor imaging profile, and it is a highly promising probe for visualization of HCC microlesions. Development of PET probes based on cyclic TMTP1 is a promising approach for discovering novel imaging probes.
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Affiliation(s)
- Zihan Meng
- Shandong
First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- 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
| | - Boyu Tan
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School of
Biomedical Engineering, ShanghaiTech University, Shanghai 201210, China
- School of
Life Science and Technology, ShanghaiTech
University, Shanghai 201210, China
| | - Min Wang
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
| | - Jiamin Zhu
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
| | - Chunrong Qu
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
| | - Zhen Cheng
- Shandong
First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- 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
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
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Li Y, Wang Y, Wang Y, Huang J, Guo Z. Development and Evaluation of 68Ga-Labeled TMTP1-Based Cyclic Peptide Probes for Targeting Hepatocellular Carcinoma. Mol Pharm 2025; 22:1901-1910. [PMID: 39993946 DOI: 10.1021/acs.molpharmaceut.4c01123] [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: 02/26/2025]
Abstract
This study focused on the development and evaluation of four [68Ga]-labeled cyclic TMTP1 peptide-based probes for targeting highly metastatic hepatocellular carcinoma (HCC). The probes─[68Ga]Ga-N-G-NVvRQ, [68Ga]Ga-c[K(N)NVvRQ], [68Ga]Ga-c[K(N)NVVRQ], and [68Ga]Ga-c[K(N)NVvRQ]2─were designed using a head-to-tail cyclization strategy to enhance their stability, improve tumor targeting, and reduce uptake in nontarget organs. The microPET imaging results showed that although tumor uptake for all four probes was similar at each time point, renal evaluation revealed that [68Ga]Ga-c[K(N)NVvRQ] had the lowest value at 15 min (1.90 ± 0.87%ID/g), significantly outperforming linear analog [68Ga]Ga-N-G-NVvRQ (2.87 ± 0.86%ID/g) and dimeric peptide, [68Ga]Ga-c[K(N)NVvRQ]2 (3.92 ± 0.68%ID/g), and the probe exhibited the lowest physiological uptake across major organs. At 30 min, the liver uptake of [68Ga]Ga-c[K(N)NVvRQ] was 0.29 ± 0.08%ID/g, with a tumor-to-liver (T/L) ratio of 2.45 ± 0.03. This low nonspecific uptake in normal organs contributed to high-contrast PET imaging, facilitating the diagnosis of small tumor lesions. In addition, the probe demonstrated sustained low renal radioactivity retention, which may offer potential benefits for minimizing additional radioactive damage to the kidneys. Overall, [68Ga]Ga-c[K(N)NVvRQ] achieved a good balance between strong tumor uptake and low nonspecific uptake in organs (especially in kidneys), making it an ideal candidate for further investigation in HCC imaging applications.
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Affiliation(s)
- Yesen Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
| | - Yanjie Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yaoxuan Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jinxiong Huang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
| | - Zhide Guo
- State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China
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Zhang X, Yang B, Qin C, Song X, Lv X, Zeng D, Gai Y, Lan X. Clinical Translation of a Dual-Integrin αvβ3- and CD13-Targeting PET Tracer. Clin Nucl Med 2025; 50:332-337. [PMID: 39847870 DOI: 10.1097/rlu.0000000000005647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
PURPOSE Angiogenesis is essential in the development and progression of tumors. This study aimed to investigate the clinical application of 68 Ga-labeled heterodimeric peptide ( 68 Ga-HX01) targeting integrin αvβ3 and CD13 in tumor neovascularization. PATIENTS AND METHODS Six healthy volunteers were recruited to study the biodistribution, pharmacokinetics, and radiation of 68 Ga-HX01. Twelve patients with various malignancies were enrolled to seek the preliminary clinical value of 68 Ga-HX01. In healthy volunteers, SUVs of each major organ on 68 Ga-HX01 PET were measured. The clinical data, lesion numbers, and uptake were recorded in patients. The integrin αvβ3 and CD13 expression of the resected tumors was checked via immunohistochemistry staining. RESULTS With a mean injected dose of 167.98 ± 26.32 MBq, 68 Ga-HX01 was well tolerated and safe without side effects in 6 healthy volunteers. The radiation absorbed effective dose of 68 Ga-HX01 was 1.94 × 10 -2 mSv/MBq, and the urinary bladder wall held the highest absorbed effective dose (0.15 ± 5.87 × 10 -2 mSv/MBq). In 12 patients with various malignancies, 68 Ga-HX01 PET could clearly visualize the lesions from the surrounding tissues. The SUV max values in tumors were significantly higher than those in the surrounding tissues ( P < 0.05). A positive correlation trend between tumor SUV max and semiquantitative integrin αvβ3 and CD13 expression was determined ( P < 0.05). CONCLUSIONS For clinical use, 68 Ga-HX01 is safe with low radiation absorbed effective dose. It also indicates the efficiency of dual integrin αvβ3 and CD13-targeting PET radiotracer in tumor diagnosis, which may assist in patient prognosis and selecting eligible patients for antiangiogenic therapy.
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Affiliation(s)
| | | | | | | | | | - Dexing Zeng
- Hexin (Suzhou) Pharmaceutical Technology Co, Ltd, Taicang, China
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Therapeutic Performance Evaluation of 213Bi-Labelled Aminopeptidase N (APN/CD13)-Affine NGR-Motif ([ 213Bi]Bi-DOTAGA-cKNGRE) in Experimental Tumour Model: A Treasured Tailor for Oncology. Pharmaceutics 2023; 15:pharmaceutics15020491. [PMID: 36839813 PMCID: PMC9968005 DOI: 10.3390/pharmaceutics15020491] [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: 01/09/2023] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Since NGR-tripeptides (asparagine-glycine-arginine) selectively target neoangiogenesis-associated Aminopeptidase N (APN/CD13) on cancer cells, we aimed to evaluate the in vivo tumour targeting capability of radiolabelled, NGR-containing, ANP/CD13-selective [213Bi]Bi-DOTAGA-cKNGRE in CD13pos. HT1080 fibrosarcoma-bearing severe combined immunodeficient CB17 mice. 10 ± 1 days after cancer cell inoculation, positron emission tomography (PET) was performed applying [68Ga]Ga-DOTAGA-cKNGRE for tumour verification. On the 7th, 8th, 10th and 12th days the treated group of tumourous mice were intraperitoneally administered with 4.68 ± 0.10 MBq [213Bi]Bi-DOTAGA-cKNGRE, while the untreated tumour-bearing animals received 150 μL saline solution. In addition to body weight (BW) and tumour volume measurements, ex vivo biodistribution studies were conducted 30 and 90 min postinjection (pi.). The following quantitative standardised uptake values (SUV) confirmed the detectability of the HT1080 tumours: SUVmean and SUVmax: 0.37 ± 0.09 and 0.86 ± 0.14, respectively. Although no significant difference (p ≤ 0.05) was encountered between the BW of the treated and untreated mice, their tumour volumes measured on the 9th, 10th and 12th days differed significantly (p ≤ 0.01). Relatively higher [213Bi]Bi-DOTAGA-cKNGRE accumulation of the HT1080 neoplasms (%ID/g: 0.80 ± 0.16) compared with the other organs at 90 min time point yields better tumour-to-background ratios. Therefore, the therapeutic application of APN/CD13-affine [213Bi]Bi-DOTAGA- cKNGRE seems to be promising in receptor-positive fibrosarcoma treatment.
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Kan X, Ren Y, Li X, Kong X, Zhang Y, Li Q, Liu F, Zhang Y, Zheng C. Value of 18F-FDG PET/MRI in the early evaluation of treatment response following radiofrequency ablation of liver cancer in a rabbit model. J Vasc Interv Radiol 2021; 33:452-459.e3. [PMID: 34607002 DOI: 10.1016/j.jvir.2021.09.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/24/2021] [Accepted: 09/08/2021] [Indexed: 11/17/2022] Open
Abstract
PURPOSE To test the hypothesis that 18F-fluorodeoxyglucose positron emission tomography and MRI (18F-FDG PET/MRI) can detect early residual tumor following radiofrequency ablation (RFA) of liver cancer using a VX2 tumor model. METHODS Twenty-four rabbits with VX2 liver tumors were randomly divided into three groups (n = 8/group): group 1 without RFA treatment, group 2 with complete ablation, and group 3 with partial ablation. 18F-FDG PET/MRI scan was obtained in three animal groups within 2 hours post-RFA. The maximum standardized uptake value (SUVmax) of non-treated liver tumor, benign peri-ablational enhancement (BPE), residual tumor, ablated tumor, adjacent liver parenchyma, and mean SUV of normal liver were measured, respectively. The ratios of SUVmax for these targets to mean SUV of normal liver (TNR) were calculated and statistically compared. RESULTS The mean TNR of non-treated liver tumors in group 1 was significantly greater than that of adjacent liver parenchyma (8.68 ± 0.71 vs 1.89 ± 0.26, p < 0.001). In group 2, the mean TNR of BPE was significantly greater than that of adjacent liver parenchyma (2.85 ± 0.20 vs 1.86 ± 0.25, p < 0.001). In group 3, the mean TNR of residual tumor was significantly greater than that of BPE (8.64 ± 0.59 vs 2.78 ± 0.23, p < 0.001), which was significantly greater than that of completely ablated tumor (2.78 ± 0.23 vs 0.50 ± 0.06, p < 0.001). CONCLUSION 18F-FDG PET/MRI may serve as a promising imaging tool for early detection of viable residual tumors due to incomplete tumor ablation.
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Affiliation(s)
- Xuefeng Kan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Xin Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Xiangchuang Kong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yanrong Zhang
- Neuroradiology Section, Department of Radiology, Stanford University, Stanford, California, USA
| | - Qian Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Fang Liu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yajing Zhang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Provinve Key Laboratory of Molecular Imaging, Wuhan 430022, China.
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Zhu L, Ding Z, Li X, Wei H, Chen Y. Research Progress of Radiolabeled Asn-Gly-Arg (NGR) Peptides for Imaging and Therapy. Mol Imaging 2021; 19:1536012120934957. [PMID: 32862776 PMCID: PMC7466889 DOI: 10.1177/1536012120934957] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Asn-Gly-Arg (NGR) motifs have vasculature-homing properties via interactions with the aminopeptidase N (CD13) expressed on tumor neovasculature. Numerous NGR peptides with different molecular scaffolds have been exploited for targeted delivery of different compounds for imaging and therapy. When conjugated with NGR, complexes recognize the CD13 receptor expressed on the tumor vasculature, which improves the specificity to tumor and avoids systematic toxic reactions. Both preclinical and clinical studies performed with these products suggest that NGR-mediated vascular targeting is an effective strategy for delivering bioactive amounts of cytokines to tumor endothelial cells. For molecular imaging, radiolabeled peptides have been the most successful approach and have been translated into clinic. This review describes current data on radiolabeled tumor vasculature-homing NGR peptides for imaging and therapy.
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Affiliation(s)
- Liqin Zhu
- Department of Nuclear Medicine, 556508The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Zhikai Ding
- Department of Nuclear Medicine, 556508The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Xingliang Li
- Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, Sichuan, People's Republic of China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People's Republic of China
| | - Hongyuan Wei
- Department of Nuclear Medicine, 556508The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, Sichuan, People's Republic of China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People's Republic of China
| | - Yue Chen
- Department of Nuclear Medicine, 556508The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People's Republic of China
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Florea A, Mottaghy FM, Bauwens M. Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status. Int J Mol Sci 2021; 22:5544. [PMID: 34073992 PMCID: PMC8197399 DOI: 10.3390/ijms22115544] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
Angiogenesis is an active process, regulating new vessel growth, and is crucial for the survival and growth of tumours next to other complex factors in the tumour microenvironment. We present possible molecular imaging approaches for tumour vascularisation and vitality, focusing on radiopharmaceuticals (tracers). Molecular imaging in general has become an integrated part of cancer therapy, by bringing relevant insights on tumour angiogenic status. After a structured PubMed search, the resulting publication list was screened for oncology related publications in animals and humans, disregarding any cardiovascular findings. The tracers identified can be subdivided into direct targeting of angiogenesis (i.e., vascular endothelial growth factor, laminin, and fibronectin) and indirect targeting (i.e., glucose metabolism, hypoxia, and matrix metallo-proteases, PSMA). Presenting pre-clinical and clinical data of most tracers proposed in the literature, the indirect targeting agents are not 1:1 correlated with angiogenesis factors but do have a strong prognostic power in a clinical setting, while direct targeting agents show most potential and specificity for assessing tumour vascularisation and vitality. Within the direct agents, the combination of multiple targeting tracers into one agent (multimers) seems most promising. This review demonstrates the present clinical applicability of indirect agents, but also the need for more extensive research in the field of direct targeting of angiogenesis in oncology. Although there is currently no direct tracer that can be singled out, the RGD tracer family seems to show the highest potential therefore we expect one of them to enter the clinical routine.
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Affiliation(s)
- Alexandru Florea
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX Maastricht, The Netherlands
| | - Felix M. Mottaghy
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229HX Maastricht, The Netherlands
| | - Matthias Bauwens
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany; (A.F.); (M.B.)
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229HX Maastricht, The Netherlands
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Yang Y, Zhang J, Zou H, Shen Y, Deng S, Wu Y. Synthesis and evaluation of 68Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft. J Cancer 2021; 12:244-252. [PMID: 33391421 PMCID: PMC7738837 DOI: 10.7150/jca.49628] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/24/2020] [Indexed: 12/17/2022] Open
Abstract
Introduction: Previous studies have shown that peptides containing the asparagine-glycine-arginine (NGR) sequence can specifically bind to CD13 (aminopeptidase N) receptor, a tumor neovascular biomarker that is over-expressed on the surface of angiogenic blood vessels and various tumor cells, and it plays an important role in angiogenesis and tumor progression. In the present study, we aimed to evaluate the efficacy of a gallium-68 (68Ga)-labeled dimeric cyclic NGR (cNGR) peptide as a new molecular probe that binds to CD13 in vitro and in vivo. Materials and Methods: A dimeric cNGR peptide conjugated with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) was synthesized and labeled with 68Ga. In vitro uptake and binding analyses of the 68Ga- DOTA-c(NGR)2 were performed in two ovarian tumor cell lines, ES2 and SKOV3, which had different CD13 expression patterns. An in vivo biodistribution study was performed in normal mice, and micro positron emission tomography (PET) imaging was conducted in nude mice bearing ES2 and SKOV3 tumors. Results:68Ga-DOTA-c(NGR)2 was prepared with high radiochemical purity (>95%), and it was stable both in saline at room temperature and in bovine serum at 37°C for 3 h. In vitro studies showed that the uptake of 68Ga-DOTA-c(NGR)2 in ES2 cells was higher compared with SKOV3 cells, and such uptake could be blocked by the cold DOTA-c(NGR)2. Biodistribution studies demonstrated that 68Ga-DOTA-c(NGR)2 was rapidly cleared from blood and mainly excreted from the kidney. MicroPET imaging of ES2 tumor xenografts showed the focal uptake of 68Ga-DOTA-c(NGR)2 in tumors from 1 to 1.5 h post-injection. The high-contrast tumor visualization occurred at 1 h, corresponding to the highest tumor/background ratio of 10.30±0.26. The CD13-specific tumor targeting of the 68Ga-DOTA-c(NGR)2 was further supported by the reduced uptake of the probe in ES2 tumors by co-injection of the unlabeled cold peptide. In SKOV3 tumor models, the tumor was not obviously visible under the same imaging conditions. Conclusions:68Ga-DOTA-c(NGR)2 was easily synthesized, and it showed favorable CD13-specific targeting ability by in vitro data and microPET imaging with ovarian cancer xenografts. Collectively, 68Ga-DOTA-c(NGR)2 might be a potential PET imaging probe for non-invasive evaluation of the CD13 receptor expression in tumors.
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Affiliation(s)
- Yi Yang
- Department of Nuclear Medicine, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.,Department of Nuclear Medicine, the Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu 215153, China
| | - Jun Zhang
- Department of Nuclear Medicine, Taizhou People's Hospital, Taizhou, Jiangsu 225300, China
| | - Huifeng Zou
- Department of Nuclear Medicine, the Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu 215153, China
| | - Yang Shen
- Department of Nuclear Medicine, the Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu 215153, China
| | - Shengming Deng
- Department of Nuclear Medicine, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Yiwei Wu
- Department of Nuclear Medicine, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
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9
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Kis A, Dénes N, Szabó JP, Arató V, Jószai I, Enyedi KN, Lakatos S, Garai I, Mező G, Kertész I, Trencsényi G. In vivo assessment of aminopeptidase N (APN/CD13) specificity of different 68Ga-labelled NGR derivatives using PET/MRI imaging. Int J Pharm 2020; 589:119881. [PMID: 32946975 DOI: 10.1016/j.ijpharm.2020.119881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/07/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023]
Abstract
Aminopeptidase N (APN/CD13) plays an important role in neoangiogenic process in malignancies. Our previous studies have already shown that 68Ga-labelled NOTA conjugated asparagine-glycine-arginine peptide (c[KNGRE]-NH2) specifically bind to APN/CD13 expressing tumors. The aim of this study was to evaluate and compare the APN/CD13 specificity of newly synthesized 68Ga-labelled NGR derivatives in vivo by PET/MRI imaging using hepatocellular carcinoma (He/De) and mesoblastic nephroma (Ne/De) tumor models. PET/MRI and ex vivo biodistribution studies were performed 11 ± 1 days after subcutaneous injection of tumor cells and 90 min after intravenous injection of 68Ga-NOTA-c(NGR), 68Ga-NODAGA-c(NGR), 68Ga-NODAGA-c(NGR) (MG1) or 68Ga-NODAGA-c(NGR) (MG2). The APN/CD13 selectivity was confirmed by blocking experiments and the APN/CD13 expression was verified by immunohistochemistry. 68Ga-labelled c(NGR) derivatives were produced with high specific activity and radiochemical purity. In control animals, low radiotracer accumulation was found in abdominal and thoracic organs. Using tumor-bearing animals we found that the 68Ga-NOTA-c(NGR), 68Ga-NODAGA-c(NGR), and 68Ga-NODAGA-c(NGR) (MG1) derivatives showed higher uptake in He/De and Ne/De tumors, than that of the accumulation of 68Ga-NODAGA-c(NGR) (MG2). APN/CD13 is a very promising target in PET imaging, however, the selection of the appropriate 68Ga-labelled NGR-based radiopharmaceutical is critical for the precise detection of tumor neo-angiogenesis and for monitoring the efficacy of anticancer therapy.
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Key Words
- (68)Ga
- Aminopeptidase N
- Angiogenesis
- CD13
- CID: 2796029, 1-hydroxybenzotriazole (HOBt)
- CID: 3036142, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)
- CID: 33032, L-Glutamic acid
- CID: 5962, L-Lysine
- CID: 6228, N,N-dimethylformamide (DMF)
- CID: 6267, L-Asparagine
- CID: 6322, L-Arginine
- CID: 6422, triflouroacetic acid (TFA)
- CID: 750, Glyicine
- NGR
- PET/MRI imaging
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Affiliation(s)
- Adrienn Kis
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Doctoral School of Clinical Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Noémi Dénes
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Gyula Petrányi Doctoral School of Allergy and Clinical Immunology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Judit P Szabó
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Doctoral School of Clinical Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Viktória Arató
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary
| | - István Jószai
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary
| | - Kata Nóra Enyedi
- Eötvös Loránd University, Faculty of Science, Institute of Chemistry, Budapest, Hungary
| | - Szilvia Lakatos
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary
| | - Ildikó Garai
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Scanomed LTD, Nagyerdei St. 98, H-4032 Debrecen, Hungary
| | - Gábor Mező
- Eötvös Loránd University, Faculty of Science, Institute of Chemistry, Budapest, Hungary; MTA-ELTE, Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest, Hungary
| | - István Kertész
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary
| | - György Trencsényi
- Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Doctoral School of Clinical Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Gyula Petrányi Doctoral School of Allergy and Clinical Immunology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
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In Vivo Imaging of Hypoxia and Neoangiogenesis in Experimental Syngeneic Hepatocellular Carcinoma Tumor Model Using Positron Emission Tomography. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4952372. [PMID: 32832549 PMCID: PMC7428931 DOI: 10.1155/2020/4952372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 06/29/2020] [Accepted: 07/11/2020] [Indexed: 12/19/2022]
Abstract
Introduction Hypoxia-induced ανβ3 integrin and aminopeptidase N (APN/CD13) receptor expression play an important role in tumor neoangiogenesis. APN/CD13-specific 68Ga-NOTA-c(NGR), ανβ3 integrin-specific 68Ga-NODAGA-[c(RGD)]2, and hypoxia-specific 68Ga-DOTA-nitroimidazole enable the in vivo detection of the neoangiogenic process and the hypoxic regions in the tumor mass using positron emission tomography (PET) imaging. The aim of this study was to evaluate whether 68Ga-NOTA-c(NGR) and 68Ga-DOTA-nitroimidazole allow the in vivo noninvasive detection of the temporal changes of APN/CD13 expression and hypoxia in experimental He/De tumors using positron emission tomography. Materials and Methods 5 × 106 hepatocellular carcinoma (He/De) cells were used for the induction of a subcutaneous tumor model in Fischer-344 rats. He/De tumor-bearing animals were anaesthetized, and 90 min after intravenous injection of 10.2 ± 1.1 MBq 68Ga-NOTA-c(NGR) or 68Ga-NODAGA-[c(RGD)]2 (as angiogenesis tracers) or 68Ga-DOTA-nitroimidazole (for hypoxia imaging), whole-body PET/MRI scans were performed. Results Hypoxic regions and angiogenic markers (αvβ3 integrin and APN/CD13) were determined using 68Ga-NOTA-c(NGR), 68Ga-DOTA-nitroimidazole, and 68Ga-NODAGA-[c(RGD)]2 in subcutaneously growing He/De tumors in rats. 68Ga-NOTA-c(NGR) showed the strong APN/CD13 positivity of He/De tumors in vivo, by which observation was confirmed by western blot analysis. By the qualitative analysis of PET images, heterogenous accumulation was found inside He/De tumors using all radiotracers. Significantly (p ≤ 0.01) higher SUVmean and SUVmax values were found in the radiotracer avid regions of the tumors than those of the nonavid areas using hypoxia and angiogenesis-specific radiopharmaceuticals. Furthermore, a strong correlation was found between the presence of angiogenic markers, the appearance of hypoxic regions, and the tumor volume using noninvasive in vivo PET imaging. Conclusion 68Ga-DOTA-nitroimidazole and 68Ga-NOTA-c(NGR) are suitable diagnostic radiotracers for the detection of the temporal changes of hypoxic areas and neoangiogenic molecule (CD13) expression, which vary during tumor growth in a hepatocellular carcinoma model.
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Lu RC, She B, Gao WT, Ji YH, Xu DD, Wang QS, Wang SB. Positron-emission tomography for hepatocellular carcinoma: Current status and future prospects. World J Gastroenterol 2019; 25:4682-4695. [PMID: 31528094 PMCID: PMC6718031 DOI: 10.3748/wjg.v25.i32.4682] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/30/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality worldwide. Various imaging modalities provide important information about HCC for its clinical management. Since positron-emission tomography (PET) or PET-computed tomography was introduced to the oncologic setting, it has played crucial roles in detecting, distinguishing, accurately staging, and evaluating local, residual, and recurrent HCC. PET imaging visualizes tissue metabolic information that is closely associated with treatment. Dynamic PET imaging and dual-tracer have emerged as complementary techniques that aid in various aspects of HCC diagnosis. The advent of new radiotracers and the development of immuno-PET and PET-magnetic resonance imaging have improved the ability to detect lesions and have made great progress in treatment surveillance. The current PET diagnostic capabilities for HCC and the supplementary techniques are reviewed herein.
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Affiliation(s)
- Ren-Cai Lu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Bo She
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Wen-Tao Gao
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Yun-Hai Ji
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Dong-Dong Xu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Quan-Shi Wang
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shao-Bo Wang
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650093, Yunnan Province, China
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Molecular Imaging of Aminopeptidase N in Cancer and Angiogenesis. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:5315172. [PMID: 30046296 PMCID: PMC6036854 DOI: 10.1155/2018/5315172] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023]
Abstract
This review focuses on recent advances in the molecular imaging of aminopeptidase N (APN, also known as CD13), a zinc metalloenzyme that cleaves N-terminal neutral amino acids. It is overexpressed in multiple cancer types and also on the surface of vasculature undergoing angiogenesis, making it a promising target for molecular imaging and targeted therapy. Molecular imaging probes for APN are divided into two large subgroups: reactive and nonreactive. The structures of the reactive probes (substrates) contain a reporter group that is cleaved and released by the APN enzyme. The nonreactive probes are not cleaved by the enzyme and contain an antibody, peptide, or nonpeptide for targeting the enzyme exterior or active site. Multivalent homotopic probes utilize multiple copies of the same targeting unit, whereas multivalent heterotopic molecular probes are equipped with different targeting units for different receptors. Several recent preclinical cancer imaging studies have shown that multivalent APN probes exhibit enhanced tumor specificity and accumulation compared to monovalent analogues. The few studies that have evaluated APN-specific probes for imaging angiogenesis have focused on cardiac regeneration. These promising results suggest that APN imaging can be expanded to detect and monitor other diseases that are associated with angiogenesis.
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