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Pougoue Ketchemen J, Njotu FN, Babeker H, Ahenkorah S, Tikum AF, Nwangele E, Henning N, Cleeren F, Fonge H. Effectiveness of [ 67Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer. Eur J Nucl Med Mol Imaging 2024; 51:2070-2084. [PMID: 38376808 DOI: 10.1007/s00259-024-06648-3] [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: 08/08/2023] [Accepted: 02/07/2024] [Indexed: 02/21/2024]
Abstract
PURPOSE To evaluate the imaging and therapeutic properties (theranostic) of 67Cu-labeled anti-human epidermal growth factor receptor II (HER2) monoclonal antibody trastuzumab against HER2-positive breast cancer (BC). METHODS We conjugated trastuzumab with p-SCN-Bn-NOTA, 3p-C-NETA-NCS, or p-SCN-Bn-DOTA, and radiolabeled with [67Cu]CuCl2. Immunoconjugate internalization was evaluated in BT-474, JIMT-1 and MCF-7 BC cells. In vitro stability was studied in human serum (HS) and Phosphate Buffered Saline (PBS). Flow cytometry, radioligand binding and immunoreactive fraction assays were carried out. ImmunoSPECT imaging of [67Cu]Cu-NOTA-trastuzumab was done in mice bearing BT-474, JIMT-1 and MCF-7 xenografts. Pharmacokinetic was studied in healthy Balb/c mice while dosimetry was done in both healthy Balb/c and in athymic nude mice bearing JIMT-1 xenograft. The therapeutic effectiveness of [67Cu]Cu-NOTA-trastuzumab was evaluated in mice bearing BT-474 and JIMT-1 xenografts after a single intravenous (i.v.) injection of ~ 16.8 MBq. RESULTS Pure immunoconjugates and radioimmunoconjugates (> 95%) were obtained. Internalization was HER2 density-dependent with highest internalization observed with NOTA-trastuzumab. After 5 days, in vitro stabilities were 97 ± 1.7%, 31 ± 6.2%, and 28 ± 4% in HS, and 79 ± 3.5%, 94 ± 1.2%, and 86 ± 2.3% in PBS for [67Cu]Cu-NOTA-trastuzumab, [67Cu]Cu-3p-C-NETA-trastuzumab and [67Cu]Cu-DOTA-trastuzumab, respectively. [67Cu]Cu-NOTA-trastuzumab was chosen for further evaluation. BT-474 flow cytometry showed low KD, 8.2 ± 0.2 nM for trastuzumab vs 26.5 ± 1.6 nM for NOTA-trastuzumab. There were 2.9 NOTA molecules per trastuzumab molecule. Radioligand binding assay showed a low KD of 2.1 ± 0.4 nM and immunoreactive fraction of 69.3 ± 0.9. Highest uptake of [67Cu]Cu-NOTA-trastuzumab was observed in JIMT-1 (33.9 ± 5.5% IA/g) and BT-474 (33.1 ± 10.6% IA/g) xenograft at 120 h post injection (p.i.). Effectiveness of the radioimmunoconjugate was also expressed as percent tumor growth inhibition (%TGI). [67Cu]Cu-NOTA-trastuzumab was more effective than trastuzumab against BT-474 xenografts (78% vs 54% TGI after 28 days), and JIMT-1 xenografts (90% vs 23% TGI after 19 days). Mean survival of [67Cu]Cu-NOTA-trastuzumab, trastuzumab and saline treated groups were > 90, 77 and 72 days for BT-474 xenografts, while that of JIMT-1 were 78, 24, and 20 days, respectively. CONCLUSION [67Cu]Cu-NOTA-trastuzumab is a promising theranostic agent against HER2-positive BC.
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Affiliation(s)
- Jessica Pougoue Ketchemen
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
| | - Fabrice Ngoh Njotu
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
- Department of Pathology and Lab. Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK, S7N 5A2, Canada
| | - Hanan Babeker
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
- Department of Pathology and Lab. Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK, S7N 5A2, Canada
| | - Stephen Ahenkorah
- NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium
- Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium
| | - Anjong Florence Tikum
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
| | - Emmanuel Nwangele
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
- Department of Pathology and Lab. Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK, S7N 5A2, Canada
| | - Nikita Henning
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada
| | - Frederik Cleeren
- Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium
| | - Humphrey Fonge
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada.
- Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon, SK, S7N 0W8, Canada.
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Shen Y, Zhou R, Bi L, Huang G, Yang M, Li Z, Yao J, Xian J, Qiu Y, Ye P, Liu Y, Hou Y, Jin H, Wang Y. Synthesis and Evaluation of [ 64Cu]Cu-NOTA-HFn for PET Imaging of Transferrin Receptor 1 Expression in Nasopharyngeal Carcinoma. ACS OMEGA 2024; 9:17423-17431. [PMID: 38645324 PMCID: PMC11024937 DOI: 10.1021/acsomega.4c00187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/29/2024] [Accepted: 03/20/2024] [Indexed: 04/23/2024]
Abstract
As recurrent and metastatic nasopharyngeal carcinoma (NPC) is the most common cause of death among patients with NPC, there is an urgent clinical need for the development of precision diagnosis to guide personalized treatment. Recent emerging evidence substantiates the increased expression of transferrin receptor 1 (also known as cluster of differentiation 71, CD71) within tumor tissues and the inherent targeting capability of natural heavy-chain ferritin (HFn) toward CD71. This study aimed to synthesize and assess a radiotracer ([64Cu]Cu-NOTA-HFn) designed to target CD71 for positron emission tomography (PET) imaging in an NPC tumor-bearing mouse model. The entire radiolabeling process of [64Cu]Cu-NOTA-HFn was completed within 15 min with high yield (>98.5%) and high molar activity (72.96 ± 21.33 GBq/μmol). The in vitro solubility and stability experiments indicated that [64Cu]Cu-NOTA-HFn had a high water solubility (log P = -2.42 ± 0.52, n = 6) and good stability in phosphate-buffered saline (PBS) for up to 48 h. The cell saturation binding assay indicated that [64Cu]Cu-NOTA-HFn had a nanomolar affinity (Kd = 10.9 ± 6.1 nM) for CD71-overexpressing C666-1 cells. To test the target engagement in vivo, prolonged-time PET imaging was performed at 1, 6, 12, 24, and 36 h postinjection (p.i.) of [64Cu]Cu-NOTA-HFn to C666-1 NPC tumor-bearing mice. The C666-1 tumors could be visualized by [64Cu]Cu-NOTA-HFn and blocked by nonradiolabeled HFn. PET imaging quantitative analysis demonstrated that the uptake of [64Cu]Cu-NOTA-HFn in C666-1 tumors peaked at 6 h p.i. and the best radioactive tumor-to-muscle ratio was 10.53 ± 3.11 (n = 3). Ex vivo biodistribution assay at 6 h p.i. showed that the tumor uptakes were 1.43 ± 0.23%ID/g in the nonblock group and 0.92 ± 0.2%ID/g in the block group (n = 3, p < 0.05). Immunohistochemistry and immunofluorescence staining confirmed positive expression of CD71 and the uptake of HFn in C666-1 tumor tissues. In conclusion, our experiments demonstrated that [64Cu]Cu-NOTA-HFn possesses a very high target engagement for CD71-positive NPC tumors and provided a fundamental basis for further clinical translation.
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Affiliation(s)
- Yanfang Shen
- Department
of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Renwei Zhou
- Department
of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Lei Bi
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Guolong Huang
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Min Yang
- Department
of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Zhijun Li
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Jijin Yao
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Jianzhong Xian
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Yifan Qiu
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Peizhen Ye
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Yongshan Liu
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Yuyi Hou
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Hongjun Jin
- Guangdong
Provincial Engineering Research Center of Molecular Imaging, The Fifth
Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
- Guangdong-Hong
Kong-Macao University Joint Laboratory of Interventional Medicine,
The Fifth Affiliated Hospital, Sun Yat-sen
University, Zhuhai 519000, China
| | - Ying Wang
- Department
of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
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Price T, Wagner L, Rosecker V, Havlíčková J, Prior TJ, Kubíček V, Hermann P, Stasiuk GJ. Inorganic Chemistry of the Tripodal Picolinate Ligand Tpaa with Gallium(III) and Radiolabeling with Gallium-68. Inorg Chem 2023; 62:20769-20776. [PMID: 37793007 PMCID: PMC10731648 DOI: 10.1021/acs.inorgchem.3c02459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Indexed: 10/06/2023]
Abstract
We report here the improved synthesis of the tripodal picolinate chelator Tpaa, with an overall yield of 41% over five steps, in comparison to the previously reported 6% yield. Tpaa was investigated for its coordination chemistry with Ga(III) and radiolabeling properties with gallium-68 (68Ga). The obtained crystal structure for [Ga(Tpaa)] shows that the three picolinate arms coordinate to the Ga(III) ion, fully occupying the octahedral coordination geometry. This is supported by 1H NMR which shows that the three arms are symmetrical when coordinated to Ga(III). Assessment of the thermodynamic stability through potentiometry gives log KGa-Tpaa = 21.32, with a single species being produced across the range of pH 3.5-7.5. Tpaa achieved >99% radiochemical conversion with 68Ga under mild conditions ([Tpaa] = 6.6 μM, pH 7.4, 37 °C) with a molar activity of 3.1 GBq μmol-1. The resulting complex, [68Ga][Ga(Tpaa)], showed improved stability over the previously reported [68Ga][Ga(Dpaa)(H2O)] in a serum challenge, with 32% of [68Ga][Ga(Tpaa)] remaining intact after 30 min of incubation with fetal bovine serum.
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Affiliation(s)
- Thomas
W. Price
- Department
of Imaging Chemistry and Biology, School of Biomedical Engineering
and Imaging Sciences, King’s College
London, London SE1 7EH, United
Kingdom
| | - Laurène Wagner
- Department
of Imaging Chemistry and Biology, School of Biomedical Engineering
and Imaging Sciences, King’s College
London, London SE1 7EH, United
Kingdom
| | - Veronika Rosecker
- Department
of Imaging Chemistry and Biology, School of Biomedical Engineering
and Imaging Sciences, King’s College
London, London SE1 7EH, United
Kingdom
| | - Jana Havlíčková
- Department
of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague 2, Czech Republic
| | - Timothy J. Prior
- Chemistry,
School of Natural Sciences, University of
Hull, Cottingham Road, Hull HU6 7RX, United Kingdom
| | - Vojtěch Kubíček
- Department
of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague 2, Czech Republic
| | - Petr Hermann
- Department
of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 40 Prague 2, Czech Republic
| | - Graeme J. Stasiuk
- Department
of Imaging Chemistry and Biology, School of Biomedical Engineering
and Imaging Sciences, King’s College
London, London SE1 7EH, United
Kingdom
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Pang Y, Zhao L, Fang J, Chen J, Meng L, Sun L, Wu H, Guo Z, Lin Q, Chen H. Development of FAPI Tetramers to Improve Tumor Uptake and Efficacy of FAPI Radioligand Therapy. J Nucl Med 2023; 64:1449-1455. [PMID: 37321827 PMCID: PMC10478824 DOI: 10.2967/jnumed.123.265599] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/27/2023] [Indexed: 06/17/2023] Open
Abstract
Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) have shown promise as cancer diagnostic agents; however, the relatively short tumor retention of FAPIs may limit their application in radioligand therapy. In this paper, we report the design, synthesis, and evaluation of a FAPI tetramer. The aim of the study was to evaluate the tumor-targeting characteristics of radiolabeled FAPI multimers in vitro and in vivo, thereby providing information for the design of FAP-targeted radiopharmaceuticals based on the polyvalency principle. Methods: FAPI tetramers were synthesized on the basis of FAPI-46 and radiolabeled with 68Ga, 64Cu, and 177Lu. In vitro FAP-binding characteristics were identified using a competitive cell-binding experiment. To evaluate their pharmacokinetics, small-animal PET, SPECT, and ex vivo biodistribution analyses were performed on HT-1080-FAP and U87MG tumor-bearing mice. In addition, the 2 tumor xenografts received radioligand therapy with 177Lu-DOTA-4P(FAPI)4, and the antitumor efficacy of the 177Lu-FAPI tetramer was evaluated and compared with that of the 177Lu-FAPI dimer and monomer. Results: 68Ga-DOTA-4P(FAPI)4 and 177Lu-DOTA-4P(FAPI)4 were highly stable in phosphate-buffered saline and fetal bovine serum. The FAPI tetramer exhibited high FAP-binding affinity and specificity both in vitro and in vivo. 68Ga-, 64Cu-, and 177Lu-labeled FAPI tetramers exhibited higher tumor uptake, longer tumor retention, and slower clearance than FAPI dimers and FAPI-46 in HT-1080-FAP tumors. The uptake (percentage injected dose per gram) of 177Lu-DOTA-4P(FAPI)4, 177Lu-DOTA-2P(FAPI)2, and 177Lu-FAPI-46 in HT-1080-FAP tumors at 24 h was 21.4 ± 1.7, 17.1 ± 3.9, and 3.4 ± 0.7, respectively. Moreover, 68Ga-DOTA-4P(FAPI)4 uptake in U87MG tumors was approximately 2-fold the uptake of 68Ga-DOTA-2P(FAPI)2 (SUVmean, 0.72 ± 0.02 vs. 0.42 ± 0.03, P < 0.001) and more than 4-fold the uptake of 68Ga-FAPI-46 (0.16 ± 0.01, P < 0.001). In the radioligand therapy study, remarkable tumor suppression was observed with the 177Lu-FAPI tetramer in both HT-1080-FAP and U87MG tumor-bearing mice. Conclusion: The satisfactory FAP-binding affinity and specificity, as well as the favorable in vivo pharmacokinetics of the FAPI tetramer, make it a promising radiopharmaceutical for theranostic applications. Improved tumor uptake and prolonged retention of the 177Lu-FAPI tetramer resulted in excellent characteristics for FAPI imaging and radioligand therapy.
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Affiliation(s)
- Yizhen Pang
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Liang Zhao
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- 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
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and
| | - Jianyang Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China
| | - Jianhao Chen
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Lingxin Meng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China
| | - Long Sun
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Hua Wu
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Zhide Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics and Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China
| | - Qin Lin
- Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China;
| | - Haojun Chen
- Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China;
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Damerow H, Wängler B, Schirrmacher R, Fricker G, Wängler C. Synthesis of a Bifunctional Cross-Bridged Chelating Agent, Peptide Conjugation, and Comparison of 68 Ga Labeling and Complex Stability Characteristics with Established Chelators. ChemMedChem 2023; 18:e202200495. [PMID: 36259364 PMCID: PMC10100262 DOI: 10.1002/cmdc.202200495] [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: 09/14/2022] [Revised: 10/17/2022] [Indexed: 01/24/2023]
Abstract
[68 Ga]Ga3+ can be introduced into receptor-specific peptidic carriers via different chelators to obtain radiotracers for Positron Emission Tomography imaging and the chosen chelating agent considerably influences the in vivo pharmacokinetics of the corresponding radiopeptides. A chelator that should be a valuable alternative to established chelating agents for 68 Ga-radiolabeling of peptides would be a backbone-functionalized variant of the chelator CB-DO2A. Here, the bifunctional cross-bridged chelating agent CB-DO2A-GA was developed and compared to the established chelators DOTA, NODA-GA and DOTA-GA. For this purpose, CB-DO2A-GA(tBu)2 was introduced into the peptide Tyr3 -octreotate (TATE) and in direct comparison to the corresponding DOTA-, NODA-GA-, and DOTA-GA-modified TATE analogs, CB-DO2A-GA-TATE required harsher reaction conditions for 68 Ga-incorporation. Regarding the hydrophilicity profile of the resulting radiopeptides, a decrease in hydrophilicity from [68 Ga]Ga-DOTA-GA-TATE (logD(7.4) of -4.11±0.11) to [68 Ga]Ga-CB-DO2A-GA-TATE (-3.02±0.08) was observed. Assessing the stability against metabolic degradation and complex challenge, [68 Ga]Ga-CB-DO2A-GA demonstrated a very high kinetic inertness, exceeding that of [68 Ga]Ga-DOTA-GA. Therefore, CB-DO2A-GA is a valuable alternative to established chelating agents for 68 Ga-radiolabeling of peptides, especially when the formation of a very stable, positively charged 68 Ga-complex is pursued.
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Affiliation(s)
- Helen Damerow
- Clinic of Radiology and Nuclear Medicine, Biomedical ChemistryMedical Faculty Mannheim of Heidelberg University68167MannheimGermany
| | - Björn Wängler
- Clinic of Radiology and Nuclear Medicine, Molecular Imaging and RadiochemistryMedical Faculty Mannheim of Heidelberg University68167MannheimGermany
| | - Ralf Schirrmacher
- Department of Oncology, Division of Oncological ImagingUniversity of AlbertaEdmontonABT6G 1Z2Canada
| | - Gert Fricker
- Institute of Pharmacy and Molecular BiotechnologyUniversity of Heidelberg69120HeidelbergGermany
| | - Carmen Wängler
- Clinic of Radiology and Nuclear Medicine, Biomedical ChemistryMedical Faculty Mannheim of Heidelberg University68167MannheimGermany
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Modern Developments in Bifunctional Chelator Design for Gallium Radiopharmaceuticals. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010203. [PMID: 36615397 PMCID: PMC9822085 DOI: 10.3390/molecules28010203] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022]
Abstract
The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The synthesis of radiochemically pure gallium-68 radiopharmaceuticals relies on careful consideration of the coordination chemistry. The short half-life of 68 min necessitates rapid quantitative radiolabelling (≤10 min). Desirable radiolabelling conditions include near-neutral pH, ambient temperatures, and low chelator concentrations to achieve the desired apparent molar activity. This review presents a broad overview of the requirements of an efficient bifunctional chelator in relation to the aqueous coordination chemistry of gallium. Developments in bifunctional chelator design and application are then presented and grouped according to eight categories of bifunctional chelator: the macrocyclic chelators DOTA and TACN; the acyclic HBED, pyridinecarboxylates, siderophores, tris(hydroxypyridinones), and DTPA; and the mesocyclic diazepines.
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Refardt J, Hofland J, Wild D, Christ E. Molecular Imaging of Neuroendocrine Neoplasms. J Clin Endocrinol Metab 2022; 107:e2662-e2670. [PMID: 35380158 DOI: 10.1210/clinem/dgac207] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Indexed: 12/17/2022]
Abstract
The key for molecular imaging is the use of a radiotracer with a radioactive and a functional component. While the functional component targets a specific feature of the tumor, the radioactive component makes the target visible. Neuroendocrine neoplasms (NEN) are a diverse group of rare tumors that arise from neuroendocrine cells found mainly in the gastroenteropancreatic system, lung, thyroid, and adrenal glands. They are characterized by the expression of specific hormone receptors on the tumor cell surface, which makes them ideal targets for radiolabeled peptides. The most commonly expressed hormone receptors on NEN cells are the somatostatin receptors. They can be targeted for molecular imaging with various radiolabeled somatostatin analogs, but also with somatostatin antagonists, which have shown improved imaging quality. 18F-DOPA imaging has become a second-line imaging modality in NENs, with the exception of the evaluation of advanced medullary thyroid carcinoma. Alternatives for NENs with insufficient somatostatin receptor expression due to poor differentiation involve targeting glucose metabolism, which can also be used for prognosis. For the localization of the often-small insulinoma, glucagon-like peptide-1 (GLP-1) receptor imaging has become the new standard. Other alternatives involve metaiodobenzylguanidine and the molecular target C-X-C motif chemokine receptor-4. In addition, new radiopeptides targeting the fibroblast activation protein, the glucose-dependent insulinotropic polypeptide receptor and cholecystokinin-2 receptors have been identified in NENs and await further evaluation. This mini-review aims to provide an overview of the major molecular imaging modalities currently used in the field of NENs, and also to provide an outlook on future developments.
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Affiliation(s)
- Julie Refardt
- Department of Internal Medicine, Section of Endocrinology, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, the Netherlands
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland
| | - Johannes Hofland
- Department of Internal Medicine, Section of Endocrinology, ENETS Center of Excellence, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Damian Wild
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Emanuel Christ
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland
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8
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Kubinec J, Širůčková V, Havlíčková J, Kotek J, Kubicek V, Lubal P, Hermann P. Complexes of NOTA‐monoamides with CuII ion: Structural, equilibrium and kinetic study. Eur J Inorg Chem 2022. [DOI: 10.1002/ejic.202200173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Jan Kubinec
- Univerzita Karlova Přírodovědecká fakulta: Univerzita Karlova Prirodovedecka fakulta Department of Inorganic Chemistry CZECH REPUBLIC
| | - Viktorie Širůčková
- Masarykova univerzita Přírodovědecká fakulta: Masarykova univerzita Prirodovedecka Fakulta Department of Chemistry CZECH REPUBLIC
| | - Jana Havlíčková
- PřF UK: Univerzita Karlova Prirodovedecka fakulta Department of Inorganic Chemistry CZECH REPUBLIC
| | - Jan Kotek
- Univerzita Karlova Prirodovedecka fakulta Department of Inorganic Chemistry CZECH REPUBLIC
| | - Vojtech Kubicek
- Charles University in Prague, Faculty of Science Department of Inorganic Chemistry Hlavova 2030 128 40 Prague 2 CZECH REPUBLIC
| | - Přemysl Lubal
- Masarykova univerzita Přírodovědecká fakulta: Masarykova univerzita Prirodovedecka Fakulta Department of Chemistry CZECH REPUBLIC
| | - Petr Hermann
- Univerzita Karlova Přírodovědecká fakulta: Univerzita Karlova Prirodovedecka fakulta Departmnet of Inorganic Chemistry CZECH REPUBLIC
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9
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Ariztia J, Solmont K, Moïse NP, Specklin S, Heck MP, Lamandé-Langle S, Kuhnast B. PET/Fluorescence Imaging: An Overview of the Chemical Strategies to Build Dual Imaging Tools. Bioconjug Chem 2022; 33:24-52. [PMID: 34994545 DOI: 10.1021/acs.bioconjchem.1c00503] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Molecular imaging is a biomedical research discipline that has quickly emerged to afford the observation, characterization, monitoring, and quantification of biomarkers and biological processes in living organism. It covers a large array of imaging techniques, each of which provides anatomical, functional, or metabolic information. Multimodality, as the combination of two or more of these techniques, has proven to be one of the best options to boost their individual properties, hence offering unprecedented tools for human health. In this review, we will focus on the combination of positron emission tomography and fluorescence imaging from the specific perspective of the chemical synthesis of dual imaging agents. Based on a detailed analysis of the literature, this review aims at giving a comprehensive overview of the chemical strategies implemented to build adequate imaging tools considering radiohalogens and radiometals as positron emitters, fluorescent dyes mostly emitting in the NIR window and all types of targeting vectors.
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Affiliation(s)
- Julen Ariztia
- Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, 91401, Orsay, France
| | - Kathleen Solmont
- Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, 91401, Orsay, France
| | | | - Simon Specklin
- Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, 91401, Orsay, France
| | - Marie Pierre Heck
- Université Paris-Saclay, INRAE, Département Médicaments et Technologies pour la santé (DMTS), SCBM, 91191, Gif-sur-Yvette cedex, France
| | | | - Bertrand Kuhnast
- Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, 91401, Orsay, France
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10
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von Guggenberg E, Kolenc P, Rottenburger C, Mikołajczak R, Hubalewska-Dydejczyk A. Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals. Cancers (Basel) 2021; 13:5776. [PMID: 34830930 PMCID: PMC8616406 DOI: 10.3390/cancers13225776] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 11/16/2022] Open
Abstract
The cholecystokinin-2 receptor (CCK2R) has been a target of interest for molecular imaging and targeted radionuclide therapy for two decades. However, so far CCK2R targeted imaging and therapy has not been introduced in clinical practice. Within this review the recent radiopharmaceutical development of CCK2R targeting compounds and the ongoing clinical trials are presented. Currently, new gastrin derivatives as well as nonpeptidic substances are being developed to improve the properties for clinical use. A team of specialists from the field of radiopharmacy and nuclear medicine reviewed the available literature and summarized their own experiences in the development and clinical testing of CCK2R targeting radiopharmaceuticals. The recent clinical trials with novel radiolabeled minigastrin analogs demonstrate the potential for both applications, imaging as well as targeted radiotherapy, and reinforce the clinical applicability within a theranostic concept. The intense efforts in optimizing CCK2R targeting radiopharmaceuticals has led to new substances for clinical use, as shown in first imaging studies in patients with advanced medullary thyroid cancer. The first clinical results suggest that the wider clinical implication of CCK2R-targeted radiopharmaceuticals is reasonable.
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Affiliation(s)
| | - Petra Kolenc
- Department of Nuclear Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
- Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
| | | | - Renata Mikołajczak
- National Centre for Nuclear Research, Radioisotope Centre POLATOM, 05-400 Otwock-Świerk, Poland;
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11
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Jauregui-Osoro M, De Robertis S, Halsted P, Gould SM, Yu Z, Paul RL, Marsden PK, Gee AD, Fenwick A, Blower PJ. Production of copper-64 using a hospital cyclotron: targetry, purification and quality analysis. Nucl Med Commun 2021; 42:1024-1038. [PMID: 34397988 PMCID: PMC8357037 DOI: 10.1097/mnm.0000000000001422] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/09/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVES To construct and evaluate a 64Cu production system that minimises the amount of costly 64Ni, radionuclidic impurities and nonradioactive metal contamination and maximises radiochemical and radionuclidic purity and molar activity; and to report analytical and quality control methods that can be used within typical PET radiochemistry production facilities to measure metal ion concentrations and radiometal molar activities. METHODS Low volume was ensured by dissolving the irradiated nickel in a low volume of hydrochloric acid (<1 mL) using the concave gold target backing as a reaction vessel in a custom-built target holder. Removal of contaminating 55Co and nonradioactive trace metals was ensured by adding an intermediate hydrochloric acid concentration step during the conventional ion-exchange elution process. The radionuclidic purity of the product was determined by half-life measurements, gamma spectroscopy and ion radiochromatography. Trace metal contamination and molar activity were determined by ion chromatography. RESULTS AND CONCLUSIONS On a small scale, suitable for preclinical research, the process produced typically 3.2 GBq 64Cu in 2 mL solution from 9.4 ± 2.1 mg nickel-64 electroplated onto a gold target backing. The product had high molar activity (121.5 GBq/µmol), was free of trace metal contamination detectable by ion chromatography and has been used for many preclinical and clinical PET imaging applications.
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Affiliation(s)
- Maite Jauregui-Osoro
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Simona De Robertis
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Philip Halsted
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Sarah-May Gould
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Zilin Yu
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Rowena L Paul
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Paul K Marsden
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Antony D Gee
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
| | - Andrew Fenwick
- National Physical Laboratory, Teddington, Middlesex, London, UK
| | - Philip J. Blower
- School of Biomedical Engineering and Imaging Sciences, King’s College London, School of Biomedical Engineering and Imaging Sciences, St Thomas’ Hospital
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12
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Le Fur M, Ross A, Pantazopoulos P, Rotile N, Zhou I, Caravan P, Medarova Z, Yoo B. Radiolabeling and PET-MRI microdosing of the experimental cancer therapeutic, MN-anti-miR10b, demonstrates delivery to metastatic lesions in a murine model of metastatic breast cancer. Cancer Nanotechnol 2021; 12:16. [PMID: 34531932 PMCID: PMC8442631 DOI: 10.1186/s12645-021-00089-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/01/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND In our earlier work, we identified microRNA-10b (miR10b) as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR10b-targeted therapeutic consisting of anti-miR10b and ultrasmall iron oxide magnetic nanoparticles (MN), termed MN-anti-miR10b. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b caused durable regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. RESULTS In this study, we devised a method to efficiently radiolabel MN-anti-miR10b with Cu-64 (64Cu) and evaluated the pharmacokinetics and biodistribution of the radiolabeled product at two different doses: a therapeutic dose, referred to as macrodose, corresponding to 64Cu-MN-anti-miR10b co-injected with non-labeled MN-anti-miR10b, and a tracer level dose of 64Cu-MN-anti-miR10b, referred to as microdose. In addition, we evaluated the uptake of 64Cu-MN-anti-miR10b by metastatic lesions using both in vivo and ex vivo positron emission tomography-magnetic resonance imaging (PET-MRI). A comparable distribution of the therapeutic was observed after administration of a microdose or macrodose. Uptake of the therapeutic by metastatic lymph nodes, lungs, and bone was also demonstrated by PET-MRI with a significantly higher PET signal than in the same organs devoid of metastatic lesions. CONCLUSION Our results demonstrate that PET-MRI following a microdose injection of the agent will accurately reflect the innate biodistribution of the therapeutic. The tools developed in the present study lay the groundwork for the clinical testing of MN-anti-miR10b and other similar therapeutics in patients with cancer.
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Affiliation(s)
- Mariane Le Fur
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
- Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02129 USA
| | - Alana Ross
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
| | - Pamela Pantazopoulos
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
| | - Nicholas Rotile
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
- Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02129 USA
| | - Iris Zhou
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
- Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02129 USA
| | - Peter Caravan
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
- Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02129 USA
| | - Zdravka Medarova
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
| | - Byunghee Yoo
- MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129 USA
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13
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Renard E, Moreau M, Bellaye PS, Guillemin M, Collin B, Prignon A, Denat F, Goncalves V. Positron Emission Tomography Imaging of Neurotensin Receptor-Positive Tumors with 68Ga-Labeled Antagonists: The Chelate Makes the Difference Again. J Med Chem 2021; 64:8564-8578. [PMID: 34107209 DOI: 10.1021/acs.jmedchem.1c00523] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Neurotensin receptor 1 (NTS1) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS1 antagonist, named [177Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [68Ga]Ga-bisNODAGA-16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS1-positive human pancreatic adenocarcinoma.
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Affiliation(s)
- Emma Renard
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université Bourgogne Franche-Comté, Dijon 21000, France
| | - Mathieu Moreau
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université Bourgogne Franche-Comté, Dijon 21000, France
| | | | - Mélanie Guillemin
- Georges-François LECLERC Cancer Center - UNICANCER, Dijon 21000, France
| | - Bertrand Collin
- Georges-François LECLERC Cancer Center - UNICANCER, Dijon 21000, France
| | - Aurélie Prignon
- UMS28 Laboratoire d'Imagerie Moléculaire Positonique (LIMP), Sorbonne Université, Paris 75020, France
| | - Franck Denat
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université Bourgogne Franche-Comté, Dijon 21000, France
| | - Victor Goncalves
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université Bourgogne Franche-Comté, Dijon 21000, France
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14
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Corlett A, Sani MA, Van Zuylekom J, Ang CS, von Guggenberg E, Cullinane C, Blyth B, Hicks RJ, Roselt PD, Thompson PE, Hutton CA, Haskali MB. A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer. J Med Chem 2021; 64:4841-4856. [PMID: 33826325 DOI: 10.1021/acs.jmedchem.0c02213] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Proteins adopt unique folded secondary and tertiary structures that are responsible for their remarkable biological properties. This structural complexity is key in designing efficacious peptides that can mimic the three-dimensional structure needed for biological function. In this study, we employ different chemical strategies to induce and stabilize a β-hairpin fold of peptides targeting cholecystokinin-2 receptors for theranostic application (combination of a targeted therapeutic and a diagnostic companion). The newly developed peptides exhibited enhanced folding capacity as demonstrated by circular dichroism (CD) spectroscopy, ion-mobility spectrometry-mass spectrometry, and two-dimensional (2D) NMR experiments. Enhanced folding characteristics of the peptides led to increased biological potency, affording four optimal Ga-68 labeled radiotracers ([68Ga]Ga-4b, [68Ga]Ga-11b-13b) targeting CCK-2R. In particular, [68Ga]Ga-12b and [68Ga]Ga-13b presented improved metabolic stability, enhanced cell internalization, and up to 6 fold increase in tumor uptake. These peptides hold great promise as next-generation theranostic radiopharmaceuticals.
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Affiliation(s)
- Alicia Corlett
- Department of Nuclear Medicine, The Royal Melbourne Hospital, Melbourne, VIC 3000, Australia
| | | | - Jessica Van Zuylekom
- The Centre for Molecular Imaging and Translational Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Ching-Seng Ang
- The Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville 3010, Australia
| | | | - Carleen Cullinane
- The Centre for Molecular Imaging and Translational Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Benjamin Blyth
- The Centre for Molecular Imaging and Translational Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Rodney J Hicks
- The Centre for Molecular Imaging and Translational Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Peter D Roselt
- The Radiopharmaceutical Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Philip E Thompson
- Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University (Parkville Campus), Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville VIC 3052, Australia
| | | | - Mohammad B Haskali
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.,The Radiopharmaceutical Research Laboratory, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
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15
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Bergmann R, Chollet C, Els-Heindl S, Ullrich M, Berndt N, Pietzsch J, Máthé D, Bachmann M, Beck-Sickinger AG. Development of a ghrelin receptor inverse agonist for positron emission tomography. Oncotarget 2021; 12:450-474. [PMID: 33747360 PMCID: PMC7939532 DOI: 10.18632/oncotarget.27895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/01/2021] [Indexed: 12/21/2022] Open
Abstract
Imaging of Ghrelin receptors in vivo provides unique potential to gain deeper understanding on Ghrelin and its receptors in health and disease, in particular, in cancer. Ghrelin, an octanoylated 28-mer peptide hormone activates the constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) with nanomolar activity. We developed novel compounds, derived from the potent inverse agonist K-(D-1-Nal)-FwLL-NH2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), palmitic acid and/or diethylene glycol (PEG2) to allow radiolabeling and improve pharmacokinetics, respectively. All compounds were tested for receptor binding, potency and efficacy in vitro, for biodistribution and -kinetics in rats and in preclinical prostate cancer models on mice. Radiolabeling with Cu-64 and Ga-68 was successfully achieved. The Cu-64- or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiotracer were specifically accumulated by the GHS-R1a in xenotransplanted human prostate tumor models (PC-3, DU-145) in mice. The tumors were clearly delineated by PET. The radiotracer uptake was also partially blocked by K-(D-1-Nal)-FwLL-NH2 in stomach and thyroid. The presence of the GHS-R1a was also confirmed by immunohistology. In the arterial rat blood plasma, only the original compounds were found. The Cu-64 or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiolabeled inverse agonists turned out to be potent and safe. Due to their easy synthesis, high affinity, medium potency, metabolic stability, and the suitable pharmacokinetic profiles, they are excellent tools for imaging and quantitation of GHS-R1a expression in normal and cancer tissues by PET. These compounds can be used as novel biomarkers of the Ghrelin system in precision medicine.
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Affiliation(s)
- Ralf Bergmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.,Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.,These authors contributed equally to this work
| | - Constance Chollet
- Institute of Biochemistry, Faculty of Life Sciences, Universität Leipzig, Leipzig, Germany.,These authors contributed equally to this work
| | - Sylvia Els-Heindl
- Institute of Biochemistry, Faculty of Life Sciences, Universität Leipzig, Leipzig, Germany
| | - Martin Ullrich
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Nicole Berndt
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.,Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany
| | - Domokos Máthé
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Michael Bachmann
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.,Tumor Immunology, University Cancer Center, Carl Gustav Carus Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Carl Gustav Carus Technische Universität Dresden, Dresden, Germany
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16
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Rouchota M, Adamiano A, Iafisco M, Fragogeorgi E, Pilatis I, Doumont G, Boutry S, Catalucci D, Zacharioudaki A, Kagadis GC. Optimization of In Vivo Studies by Combining Planar Dynamic and Tomographic Imaging: Workflow Evaluation on a Superparamagnetic Nanoparticles System. Mol Imaging 2021; 2021:6677847. [PMID: 33746630 PMCID: PMC7953590 DOI: 10.1155/2021/6677847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/16/2020] [Indexed: 11/18/2022] Open
Abstract
Molecular imaging holds great promise in the noninvasive monitoring of several diseases with nanoparticles (NPs) being considered an efficient imaging tool for cancer, central nervous system, and heart- or bone-related diseases and for disorders of the mononuclear phagocytic system (MPS). In the present study, we used an iron-based nanoformulation, already established as an MRI/SPECT probe, as well as to load different biomolecules, to investigate its potential for nuclear planar and tomographic imaging of several target tissues following its distribution via different administration routes. Iron-doped hydroxyapatite NPs (FeHA) were radiolabeled with the single photon γ-emitting imaging agent [99mTc]TcMDP. Administration of the radioactive NPs was performed via the following four delivery methods: (1) standard intravenous (iv) tail vein, (2) iv retro-orbital injection, (3) intratracheal (it) instillation, and (4) intrarectal installation (pr). Real-time, live, fast dynamic screening studies were performed on a dedicated bench top, mouse-sized, planar SPECT system from t = 0 to 1 hour postinjection (p.i.), and consequently, tomographic SPECT/CT imaging was performed, for up to 24 hours p.i. The administration routes that have been studied provide a wide range of possible target tissues, for various diseases. Studies can be optimized following this workflow, as it is possible to quickly assess more parameters in a small number of animals (injection route, dosage, and fasting conditions). Thus, such an imaging protocol combines the strengths of both dynamic planar and tomographic imaging, and by using iron-based NPs of high biocompatibility along with the appropriate administration route, a potential diagnostic or therapeutic effect could be attained.
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Affiliation(s)
- Maritina Rouchota
- 3dmi Research Group, Department of Medical Physics, School of Medicine, University of Patras, Greece
| | - Alessio Adamiano
- Institute of Science and Technology for Ceramics (ISTEC), National Research Council (CNR), Italy
| | - Michele Iafisco
- Institute of Science and Technology for Ceramics (ISTEC), National Research Council (CNR), Italy
| | - Eirini Fragogeorgi
- Institute of Nuclear & Radiological Sciences, Technology, Energy & Safety, NCSR “Demokritos”, Greece
| | - Irineos Pilatis
- Department of Biomedical Engineering, University of West Attica, Greece
| | - Gilles Doumont
- Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
| | - Sébastien Boutry
- Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), Rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
| | - Daniele Catalucci
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), UOS Milan, Italy
- Humanitas Clinical and Research Center, IRCCS, Rozzano (Milan), Italy
| | | | - George C. Kagadis
- 3dmi Research Group, Department of Medical Physics, School of Medicine, University of Patras, Greece
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17
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Yordanova A, Biersack HJ, Ahmadzadehfar H. Advances in Molecular Imaging and Radionuclide Therapy of Neuroendocrine Tumors. J Clin Med 2020; 9:E3679. [PMID: 33207788 PMCID: PMC7697910 DOI: 10.3390/jcm9113679] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms make up a heterogeneous group of tumors with inter-patient and intra-patient variabilities. Molecular imaging can help to identify and characterize neuroendocrine tumors (NETs). Furthermore, imaging and treatment with novel theranostics agents offers a new, tailored approach to managing NETs. Recent advances in the management of NETs aim to enhance the effectiveness of targeted treatment with either modifications of known substances or the development of new substances with better targeting features. There have been several attempts to increase the detectability of NET lesions via positron emission tomography (PET) imaging and improvements in pretreatment planning using dosimetry. Especially notable is PET imaging with the radionuclide Copper-64. Increasing interest is also being paid to theranostics of grade 3 and purely differentiated NETs, for example, via targeting of the C-X-C motif chemokine receptor 4 (CXCR4). The aim of this review is to summarize the most relevant recent studies, which present promising new agents in molecular imaging and therapy for NETs, novel combination therapies and new applications of existing molecular imaging modalities in nuclear medicine.
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Affiliation(s)
- Anna Yordanova
- Department of Radiology, St. Marien Hospital Bonn, 53115 Bonn, Germany;
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Abstract
PURPOSE OF REVIEW Thyroid cancer is the most common endocrine cancer in adults with rising incidence. Challenges in imaging thyroid cancer are twofold: distinguishing thyroid cancer from benign thyroid nodules, which occur in 50% of the population over 50 years; and correct staging of thyroid cancer to facilitate appropriate radical surgery in a single session. The clinical management of thyroid cancer patients has been covered in detail by the 2015 guidelines of the American Thyroid Association (ATA). The purpose of this review is to state the principles underlying optimal multimodal imaging of thyroid cancer and aid clinicians in avoiding important pitfalls. RECENT FINDINGS Recent additions to the literature include assessment of ultrasound-based scoring systems to improve selection of nodules for fine needle biopsy (FNB) and the evaluation of new radioactive tracers for imaging thyroid cancer. SUMMARY The mainstay of diagnosing thyroid cancer is thyroid ultrasound with ultrasound-guided FNB. Contrast-enhanced computed tomography and PET with [F]-fluorodeoxyglucose (FDG) and MRI are reserved for advanced and/or recurrent cases of differentiated thyroid cancer and anaplastic thyroid cancer, while [F]FDOPA and [Ga]DOTATOC are the preferred tracers for medullary thyroid cancer.
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Affiliation(s)
- Katrin Brauckhoff
- Department of Breast and Endocrine Surgery, Haukeland University Hospital
- Department of Clinical Science, University of Bergen
| | - Martin Biermann
- Nuclear Medicine/PET-center, Department of Radiology, Haukeland University Hospital
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Martinelli J, Remotti D, Tei L. Selective functionalization of 6-amino-6-methyl-1,4-perhydrodiazepine for the synthesis of a library of polydentate chelators. Org Biomol Chem 2020; 18:5245-5252. [PMID: 32614034 DOI: 10.1039/d0ob00980f] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Polydentate chelators are an important part of an imaging probe, which consists of an agent that usually produces signals for imaging purposes connected to a targeting moiety. The goal of this study was to set up a generic protocol to prepare a library of polydentate ligands having a 6-amino-6-methyl-1,4-perhydrodiazepine (AMPED) core and able to chelate metal ions of interest for various diagnostic imaging techniques, including Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT). These ions, among which we can include Mn(ii), Cu(ii), Al(iii) or Ga(iii), require penta- or hexa-dentate chelators for this purpose, and the AMPED scaffold has considerable potential to support various pendant arms for coordination of such ions. AMPED already has three amino nitrogen donors; thus, only two or three additional arms should be introduced to obtain penta- or hexa-dentate systems. This condition implies that symmetrical or asymmetrical structures have to be developed, depending on the functionalization of cyclic and exocyclic amines. Starting from easily available materials, we have designed a convenient protocol for the preparation of multiple AMPED-based ligands endowed with different characteristics, several of which were synthesized as examples.
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Affiliation(s)
- Jonathan Martinelli
- Dipartimento di Scienze e Innovazione Tecnologica (DiSIT), Università del Piemonte Orientale "A. Avogadro", Viale Michel 11, 15121 Alessandria, Italy.
| | - Davide Remotti
- Dipartimento di Scienze e Innovazione Tecnologica (DiSIT), Università del Piemonte Orientale "A. Avogadro", Viale Michel 11, 15121 Alessandria, Italy.
| | - Lorenzo Tei
- Dipartimento di Scienze e Innovazione Tecnologica (DiSIT), Università del Piemonte Orientale "A. Avogadro", Viale Michel 11, 15121 Alessandria, Italy.
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20
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Lepage ML, Kuo H, Roxin Á, Huh S, Zhang Z, Kandasamy R, Merkens H, Kumlin JO, Limoges A, Zeisler SK, Lin K, Bénard F, Perrin DM. Toward18F‐Labeled Theranostics: A Single Agent that Can Be Labeled with18F,64Cu, or177Lu. Chembiochem 2020; 21:943-947. [DOI: 10.1002/cbic.201900632] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Indexed: 12/21/2022]
Affiliation(s)
- Mathieu L. Lepage
- Chemistry DepartmentUniversity of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | | | - Áron Roxin
- Chemistry DepartmentUniversity of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
- BC Cancer 675 W 10th Avenue Vancouver BC V5Z 1L3 Canada
- Department of RadiologyUniversity of British Columbia 2775 Laurel Street Vancouver BC V5Z 1M9 Canada
| | - Sungjoon Huh
- Chemistry DepartmentUniversity of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Zhengxing Zhang
- BC Cancer 675 W 10th Avenue Vancouver BC V5Z 1L3 Canada
- Department of RadiologyUniversity of British Columbia 2775 Laurel Street Vancouver BC V5Z 1M9 Canada
| | - Rajaguru Kandasamy
- Chemistry DepartmentUniversity of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
| | - Helen Merkens
- BC Cancer 675 W 10th Avenue Vancouver BC V5Z 1L3 Canada
- Department of RadiologyUniversity of British Columbia 2775 Laurel Street Vancouver BC V5Z 1M9 Canada
| | | | - Alan Limoges
- TRIUMF 4004 Wesbrook Mall Vancouver BC V6T 2A3 Canada
| | | | - Kuo‐Shyan Lin
- BC Cancer 675 W 10th Avenue Vancouver BC V5Z 1L3 Canada
| | - François Bénard
- BC Cancer 675 W 10th Avenue Vancouver BC V5Z 1L3 Canada
- Department of RadiologyUniversity of British Columbia 2775 Laurel Street Vancouver BC V5Z 1M9 Canada
| | - David M. Perrin
- Chemistry DepartmentUniversity of British Columbia 2036 Main Mall Vancouver BC V6T 1Z1 Canada
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Poret B, Desrues L, Bonin MA, Pedard M, Dubois M, Leduc R, Modzelewski R, Decazes P, Morin F, Vera P, Castel H, Bohn P, Gandolfo P. Development of Novel 111-In-Labelled DOTA Urotensin II Analogues for Targeting the UT Receptor Overexpressed in Solid Tumours. Biomolecules 2020; 10:E471. [PMID: 32204509 PMCID: PMC7175314 DOI: 10.3390/biom10030471] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/11/2022] Open
Abstract
Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111In-DOTA-hUII or 111In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools.
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Affiliation(s)
- Benjamin Poret
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Department of Physiology & Pharmacology, Institute of Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC J1H 5N4, Canada; (M.-A.B.); (R.L.)
| | - Laurence Desrues
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Marc-André Bonin
- Department of Physiology & Pharmacology, Institute of Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC J1H 5N4, Canada; (M.-A.B.); (R.L.)
| | - Martin Pedard
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Martine Dubois
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Richard Leduc
- Department of Physiology & Pharmacology, Institute of Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC J1H 5N4, Canada; (M.-A.B.); (R.L.)
| | - Romain Modzelewski
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Pierre Decazes
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Fabrice Morin
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Pierre Vera
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Hélène Castel
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Pierre Bohn
- EA 4108, Laboratory of Computer Science, Information Processing and Systems (LITIS), team “QuantIF”, Centre Henri Becquerel, 76000 Rouen, France; (R.M.); (P.D.); (P.V.); (P.B.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
| | - Pierrick Gandolfo
- Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, INSERM U1239, DC2N, 76000 Rouen, France; (B.P.); (L.D.); (M.P.); (M.D.); (F.M.); (P.G.)
- Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France
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Wu R, Liu S, Liu Y, Sun Y, Xiao H, Huang Y, Yang Z, Wu Z. PET probe with Aggregation Induced Emission characteristics for the specific turn-on of aromatase. Talanta 2020; 208:120412. [DOI: 10.1016/j.talanta.2019.120412] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/04/2019] [Accepted: 09/30/2019] [Indexed: 12/14/2022]
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Klingler M, Hörmann AA, Guggenberg EV. Cholecystokinin-2 Receptor Targeting with Radiolabeled Peptides: Current Status and Future Directions. Curr Med Chem 2020; 27:7112-7132. [PMID: 32586246 PMCID: PMC7116483 DOI: 10.2174/0929867327666200625143035] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/01/2020] [Accepted: 05/13/2020] [Indexed: 02/08/2023]
Abstract
A wide variety of radiolabeled peptide analogs for specific targeting of cholecystokinin- 2 receptors (CCK2R) has been developed in the last decades. Peptide probes based on the natural ligands Minigastrin (MG) and Cholecystokinin (CCK) have a high potential for molecular imaging and targeted radiotherapy of different human tumors, such as Medullary Thyroid Carcinoma (MTC) and Small Cell Lung Cancer (SCLC). MG analogs with high persistent uptake in CCK2R expressing tumors have been preferably used for the development of radiolabeled peptide analogs. The clinical translation of CCK2R targeting has been prevented due to high kidney uptake or low metabolic stability of the different radiopeptides developed. Great efforts in radiopharmaceutical development have been undertaken to overcome these limitations. Various modifications in the linear peptide sequence of MG have been introduced mainly with the aim to reduce kidney retention. Furthermore, improved tumor uptake could be obtained by in situ stabilization of the radiopeptide against enzymatic degradation through coinjection of peptidase inhibitors. Recent developments focusing on the stabilization of the Cterminal receptor binding sequence (Trp-Met-Asp-Phe-NH2) have led to new radiolabeled MG analogs with highly improved tumor uptake and tumor-to-kidney ratio. In this review, all the different aspects in the radiopharmaceutical development of CCK2R targeting peptide probes are covered, giving also an overview on the clinical investigations performed so far. The recent development of radiolabeled MG analogs, which are highly stabilized against enzymatic degradation in vivo, promises to have a high impact on the clinical management of patients with CCK2R expressing tumors in the near future.
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Affiliation(s)
- Maximilian Klingler
- Department of Nuclear Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria
| | - Anton Amadeus Hörmann
- Department of Nuclear Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria
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Abstract
Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101-amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin-17 and gastrin-34. The C-terminal active site of gastrin (Trp-Met-Asp-Phe-NH2 ) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine-containing enterochromaffin-like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2 -receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid-peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197-228, 2020.
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Affiliation(s)
- Mitchell L Schubert
- Division of Gastroenterology, Department of Medicine, Virginia Commonwealth University Health System, Richmond, Virginia, USA.,Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Zhang J, Ma Y, Yang W, Xue J, Ding Y, Xie C, Luo W, Gao F, Zhang Z, Zhao Y, Chai Z, He X. Comparative study of core- and surface-radiolabeling strategies for the assembly of iron oxide nanoparticle-based theranostic nanocomposites. NANOSCALE 2019; 11:5909-5913. [PMID: 30888363 DOI: 10.1039/c9nr00428a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
This work highlights the superiority of the surface-radiolabeling strategy over the core-labeling strategy in the assembly of radioactive iron oxide nanoparticle (IONP)-based nanocomposites for use in multimodal imaging and targeted therapy. It also implies a possible overestimation of the labeling stability in previous studies and points out directions for further optimization.
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Affiliation(s)
- Junzhe Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
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Kobayashi M, Kato T, Washiyama K, Ihara M, Mizutani A, Nishi K, Flores LG, Nishii R, Kawai K. The pharmacological properties of 3-arm or 4-arm DOTA constructs for conjugation to α-melanocyte-stimulating hormone analogues for melanoma imaging. PLoS One 2019; 14:e0213397. [PMID: 30901323 PMCID: PMC6430397 DOI: 10.1371/journal.pone.0213397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 02/20/2019] [Indexed: 11/19/2022] Open
Abstract
Background Although a 3-arm DOTA construct, which has three carboxylic acids, h has been applied for conjugation to many peptides, we investigated if a 4-arm DOTA construct conjugated to peptides improves chemical properties for melanoma imaging of the melanocortin 1 receptor compared to 3-arm DOTA-conjugated peptides. Methods Specific activities, radiolabeling efficiencies, and partition coefficients were evaluated using 111In-labeled 3-arm and 4-arm DOTA-α-melanocyte-stimulating hormone (MSH). For assessment of MC1-R affinity and accumulation in tumor cells in vitro, B16-F1 melanoma and/or 4T1 breast cancer cells were incubated with 111In-labeled 3-arm and 4-arm DOTA-α-MSH with and without α-MSH as a substrate. The stability was evaluated using mouse liver homogenates and plasma. Biological distribution and whole-body single photon emission computed tomography imaging of 111In-labeled 3-arm and 4-arm DOTA-α-MSH were obtained using B16-F1 melanoma-bearing mice. Results Specific activities and radiolabeling efficiencies of both radiotracers were about 1.2 MBq/nM and 90–95%, respectively. The partition coefficients were −0.28 ± 0.03 for 111In-labeled 3-arm DOTA-α-MSH and −0.13 ± 0.04 for 111In-labeled 4-arm DOTA-α-MSH. Although accumulation was significantly inhibited by α-MSH in B16-F1 cells, the inhibition rate of 111In-labeled 4-arm DOTA-α-MSH was lower than that of 111In-labeled 3-arm DOTA-α-MSH. 111In-labeled 4-arm DOTA-α-MSH was taken up early into B16-F1 cells and showed higher accumulation than 111In-labeled 3-arm DOTA-α-MSH after 10 min of incubation. Although these stabilities were relatively high, the stability of 111In-labeled 4-arm DOTA-α-MSH was higher than that of 111In-labeled 3-arm DOTA-α-MSH. Regarding biological distribution, 111In-labeled 4-arm DOTA-α-MSH showed significantly lower average renal accumulation (1.38-fold) and significantly higher average melanoma accumulation (1.32-fold) than 111In-labeled 3-arm DOTA-α-MSH at all acquisition times. 111In-labeled 4-arm DOTA-α-MSH showed significantly higher melanoma-to-kidney, melanoma-to-blood, and melanoma-to-muscle ratios than 111In-labeled 3-arm DOTA-α-MSH. Conclusions The 4-arm DOTA construct has better chemical properties for peptide radiotracers than the 3-arm DOTA construct.
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Affiliation(s)
- Masato Kobayashi
- Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
- * E-mail:
| | - Toshitaka Kato
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Kohshin Washiyama
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Masaaki Ihara
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Asuka Mizutani
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Kodai Nishi
- Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Leo G. Flores
- Department of Pediatrics, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ryuichi Nishii
- Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
| | - Keiichi Kawai
- Department of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
- Biomedical Imaging Research Center, University of Fukui, Fukui, Japan
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Thomas G, Boudon J, Maurizi L, Moreau M, Walker P, Severin I, Oudot A, Goze C, Poty S, Vrigneaud JM, Demoisson F, Denat F, Brunotte F, Millot N. Innovative Magnetic Nanoparticles for PET/MRI Bimodal Imaging. ACS OMEGA 2019; 4:2637-2648. [PMID: 31459499 PMCID: PMC6648431 DOI: 10.1021/acsomega.8b03283] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 01/14/2019] [Indexed: 05/21/2023]
Abstract
Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (-NH2 and -COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further 64Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r 2 and r 2* (T 2 and T 2* relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI.
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Affiliation(s)
- Guillaume Thomas
- ICB
UMR 6303 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Julien Boudon
- ICB
UMR 6303 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Lionel Maurizi
- ICB
UMR 6303 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Mathieu Moreau
- ICMUB
UMR 6302 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Paul Walker
- Département
de Spectroscopie par Résonance Magnétique, CHU Dijon, 21000 Dijon, France
| | - Isabelle Severin
- UBFC-AgrosupDijon-INSERM
U 1231, 1 Esplanade Erasme, 21000 Dijon, France
| | - Alexandra Oudot
- Plateforme
d’Imagerie Préclinique, Service de Médecine Nucléaire, Centre Georges François Leclerc, 21000 Dijon, France
| | - Christine Goze
- ICMUB
UMR 6302 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Sophie Poty
- ICMUB
UMR 6302 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Jean-Marc Vrigneaud
- Plateforme
d’Imagerie Préclinique, Service de Médecine Nucléaire, Centre Georges François Leclerc, 21000 Dijon, France
| | - Fréderic Demoisson
- ICB
UMR 6303 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - Franck Denat
- ICMUB
UMR 6302 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
| | - François Brunotte
- Plateforme
d’Imagerie Préclinique, Service de Médecine Nucléaire, Centre Georges François Leclerc, 21000 Dijon, France
| | - Nadine Millot
- ICB
UMR 6303 CNRS-Université Bourgogne Franche-Comté, 21000 Dijon, France
- E-mail:
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28
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Practical Application of Periostin as a Biomarker for Pathological Conditions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1132:195-204. [PMID: 31037636 DOI: 10.1007/978-981-13-6657-4_18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In physiological condition, periostin is expressed in limited tissues such as periodontal ligament, periosteum, and heart valves. Periostin protein is mainly localized on extracellular collagen bundles and in matricellular space. On the other hand, in pathological condition, expression of periostin is induced in disordered tissues of human patients. In tumor development and progression, periostin is elevated mainly in its microenvironment and stromal tissue rich in extracellular matrix. Tumor stromal fibroblasts highly express periostin and organize the tumor-surrounding extracellular matrix architecture. In fibrosis in lung, liver, and kidney, proliferating activated fibroblasts express periostin and replace normal functional tissues with dense connective tissues. In inflammation and allergy, inflammatory cytokines such as IL-4 and IL-13 induce expression of periostin that plays important roles in pathogenesis of these diseases. The elevated levels of periostin in human patients could be detected not only in tissue biopsy samples but also in peripheral bloods using specific antibodies against periostin, because periostin secreted from the disordered tissues is transported into blood vessels and circulates in the cardiovascular system. In this chapter, I introduce the elevated expression of periostin in pathological conditions, and discuss how periostin could be utilized as a biomarker in disease diagnosis.
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Mitran B, Güler R, Roche FP, Lindström E, Selvaraju RK, Fleetwood F, Rinne SS, Claesson-Welsh L, Tolmachev V, Ståhl S, Orlova A, Löfblom J. Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model. Theranostics 2018; 8:4462-4476. [PMID: 30214632 PMCID: PMC6134937 DOI: 10.7150/thno.24395] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 04/21/2018] [Indexed: 01/09/2023] Open
Abstract
Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (ZVEGFR2-Bp2) for in vivo visualization of VEGFR2 expression in GBM. Methods: ZVEGFR2-Bp2 coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed. Results: [111In]In-NODAGA-ZVEGFR2-Bp2 bound specifically to VEGFR2 (KD=33±18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 µg [111In]In-NODAGA-ZVEGFR2-Bp2 were significantly higher than the ratios observed for the 40 µg injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images. Conclusion: The anti-VEGFR2 affibody conjugate [111In]In-NODAGA-ZVEGFR2-Bp2 specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [111In]In-NODAGA-ZVEGFR2-Bp2 were higher compared to other VEGFR2 imaging probes. [111In]In-NODAGA-ZVEGFR2-Bp2 appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.
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30
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Woo SK, Jang SJ, Seo MJ, Park JH, Kim BS, Kim EJ, Lee YJ, Lee TS, An GI, Song IH, Seo Y, Kim KI, Kang JH. Development of 64Cu-NOTA-Trastuzumab for HER2 Targeting: A Radiopharmaceutical with Improved Pharmacokinetics for Human Studies. J Nucl Med 2018; 60:26-33. [PMID: 29777007 DOI: 10.2967/jnumed.118.210294] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 05/14/2018] [Indexed: 01/12/2023] Open
Abstract
The purpose of this study was to develop 64Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2 (HER2). Methods: Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with 64Cu. Serum stability and immunoreactivity of 64Cu-NOTA-trastuzumab were tested. Small-animal PET imaging and biodistribution studies were performed in a HER2-positive breast cancer xenograft model (BT-474). The internal dosimetry for experimental animals was determined using the image-based approach with the Monte Carlo N-particle code. Results: 64Cu-NOTA-trastuzumab was prepared with high radiolabeling yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of 64Cu-NOTA-trastuzumab was highest at 48 h after injection as determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations of 64Cu-NOTA-trastuzumab decreased biexponentially with time in both mice with and mice without BT-474 tumor xenografts. The calculated absorbed dose of 64Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 mGy/MBq for the liver, and 0.047 mGy/MBq for the spleen. Conclusion: 64Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor in vitro and in vivo, and it exhibited a relatively low absorbed dose due to a short residence time. Therefore, 64Cu-NOTA-trastuzumab could be applied to select the right patients and right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread.
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Affiliation(s)
- Sang-Keun Woo
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Su Jin Jang
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Min-Jung Seo
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Ju Hui Park
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Byoung Soo Kim
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Eun Jung Kim
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Yong Jin Lee
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Tae Sup Lee
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Gwang Il An
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - In Ho Song
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Youngho Seo
- Department of Radiology, University of California San Francisco School of Medicine, San Francisco, California
| | - Kwang Il Kim
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
| | - Joo Hyun Kang
- Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; and
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31
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Klingler M, Decristoforo C, Rangger C, Summer D, Foster J, Sosabowski JK, von Guggenberg E. Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting. Am J Cancer Res 2018; 8:2896-2908. [PMID: 29896292 PMCID: PMC5996369 DOI: 10.7150/thno.24378] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 03/01/2018] [Indexed: 12/12/2022] Open
Abstract
Minigastrin (MG) analogs show high affinity to the cholecystokinin-2 receptor (CCK2R) and have therefore been intensively studied to find a suitable analog for imaging and treatment of CCK2R-expressing tumors. The clinical translation of the radioligands developed thus far has been hampered by high kidney uptake or low enzymatic stability. In this study, we aimed to develop new MG analogs with improved targeting properties stabilized against degradation through site-specific amino acid modifications. Method: Based on the lead structure of a truncated MG analog, four new MG derivatives with substitutions in the C-terminal part of the peptide (Trp-Met-Asp-Phe-NH2) were synthesized and derivatized with DOTA at the N-terminus for radiolabeling with trivalent radiometals. The in vitro properties of the new analogs were characterized by analyzing the lipophilicity, the protein binding, and the stability of the Indium-111 (111In)-labeled analogs in different media. Two different cell lines, AR42J cells physiologically expressing the rat CCK2R and A431 cells transfected with human CCK2R (A431-CCK2R), were used to study the receptor affinity and cell uptake. For the two most promising MG analogs, metabolic studies in normal BALB/c mice were carried out as well as biodistribution and imaging studies in tumor xenografted athymic BALB/c nude mice. Results: Two out of four synthesized peptide analogs (DOTA-MGS1 and DOTA-MGS4) showed retained receptor affinity and cell uptake when radiolabeled with 111In. These two peptide analogs, however, showed a different stability against enzymatic degradation in vitro and in vivo. When injected to normal BALB/c mice, for 111In-DOTA-MGS1 at 10 min post injection (p.i.) no intact radiopeptide was found in the blood, whereas for 111In-DOTA-MGS4 more than 75% was still intact. 111In-DOTA-MGS4 showed a clear increase in injected activity per gram tissue (IA/g) for A431-CCK2R xenografts (10.40±2.21% IA/g 4 h p.i.) when compared to 111In-DOTA-MGS1 (1.23±0.15% IA/g 4 h p.i.). The tumor uptake of 111In-DOTA-MGS4 was also combined with a low uptake in stomach and kidney leading to high-contrast NanoSPECT/CT images. Conclusion: Of the four new MG analogs developed, the best results in terms of enzymatic stability and increased tumor targeting were obtained with 111In-DOTA-MGS4 showing two substitutions with N-methylated amino acids. 111In-DOTA-MGS4 was also superior to other MG analogs reported thus far and seems therefore an extremely promising targeting molecule for theranostic use with alternative radiometals.
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32
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Lipiński PFJ, Garnuszek P, Maurin M, Stoll R, Metzler-Nolte N, Wodyński A, Dobrowolski JC, Dudek MK, Orzełowska M, Mikołajczak R. Structural studies on radiopharmaceutical DOTA-minigastrin analogue (CP04) complexes and their interaction with CCK2 receptor. EJNMMI Res 2018; 8:33. [PMID: 29663167 PMCID: PMC5902437 DOI: 10.1186/s13550-018-0387-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 04/06/2018] [Indexed: 12/16/2022] Open
Abstract
Background The cholecystokinin receptor subtype 2 (CCK-2R) is an important target for diagnostic imaging and targeted radionuclide therapy (TRNT) due to its overexpression in certain cancers (e.g., medullary thyroid carcinoma (MTC)), thus matching with a theranostic principle. Several peptide conjugates suitable for the TRNT of MTC have been synthesized, including a very promising minigastrin analogue DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04). In this contribution, we wanted to see whether CP04 binding affinity for CCK-2R is sensitive to the type of the complexed radiometal, as well as to get insights into the structure of CP04-CCK2R complex by molecular modeling. Results In vitro studies demonstrated that there is no significant difference in CCK-2R binding affinity and specific cellular uptake between the CP04 conjugates complexed with [68Ga]Ga3+ or [177Lu]Lu3+. In order to investigate the background of this observation, we proposed a binding model of CP04 with CCK-2R based on homology modeling and molecular docking. In this model, the C-terminal part of the molecule enters the cavity formed between the receptor helices, while the N-terminus (including DOTA and the metal) is located at the binding site outlet, exposed in large extent to the solvent. The radiometals do not influence the conformation of the molecule except for the direct neighborhood of the chelating moiety. Conclusions The model seems to be in agreement with much of structure-activity relationship (SAR) studies reported for cholecystokinin and for CCK-2R-targeting radiopharmaceuticals. It also explains relative insensitivity of CCK-2R affinity for the change of the metal. The proposed model partially fits the reported site-directed mutagenesis data.
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Affiliation(s)
- Piotr F J Lipiński
- Neuropeptides Department, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 Str., 02-106, Warszawa, Poland.
| | - Piotr Garnuszek
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, A. Sołtana 7 Str, 05-400, Otwock, Poland
| | - Michał Maurin
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, A. Sołtana 7 Str, 05-400, Otwock, Poland
| | - Raphael Stoll
- Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Universitätsstr. 150, 44780, Bochum, Germany
| | - Nils Metzler-Nolte
- Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Universitätsstr. 150, 44780, Bochum, Germany
| | - Artur Wodyński
- Świerk Computing Centre, National Centre for Nuclear Research, A. Sołtana 7 Str., 05-400, Otwock, Poland.,Institut für Chemie, Theoretische Chemie/Quantenchemie, Technische Universität Berlin, Sekr. C7, Strasse des 17. Juni 135, 10623, Berlin, Germany
| | - Jan Cz Dobrowolski
- Institute of Nuclear Chemistry and Technology, Dorodna 16 Street, 03-195, Warszawa, Poland.,National Medicines Institute, Chełmska 30/34 Str., 00-725, Warszawa, Poland
| | - Marta K Dudek
- Centre of Molecular and Macromolecular Studies Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland
| | - Monika Orzełowska
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, A. Sołtana 7 Str, 05-400, Otwock, Poland
| | - Renata Mikołajczak
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, A. Sołtana 7 Str, 05-400, Otwock, Poland
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33
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Huang Y, Liu Y, Liu S, Wu R, Wu Z. An Efficient Synthesis of N
,N
,N
-Substituted 1,4,7-Triazacyclononane. European J Org Chem 2018. [DOI: 10.1002/ejoc.201800048] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Yong Huang
- Brain Institute for Brain Disorders; Capital Medical University; 100069 Beijing China
| | - Yajing Liu
- School of Pharmaceutical Science; Capital Medical University; 100069 Beijing China
| | - Song Liu
- Brain Institute for Brain Disorders; Capital Medical University; 100069 Beijing China
| | - Renbo Wu
- Brain Institute for Brain Disorders; Capital Medical University; 100069 Beijing China
| | - Zehui Wu
- Brain Institute for Brain Disorders; Capital Medical University; 100069 Beijing China
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34
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Burks J, Nadella S, Mahmud A, Mankongpaisarnrung C, Wang J, Hahm JI, Tucker RD, Shivapurkar N, Stern ST, Smith JP. Cholecystokinin Receptor-Targeted Polyplex Nanoparticle Inhibits Growth and Metastasis of Pancreatic Cancer. Cell Mol Gastroenterol Hepatol 2018; 6:17-32. [PMID: 29928669 PMCID: PMC6008260 DOI: 10.1016/j.jcmgh.2018.02.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 02/28/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) remains the most aggressive malignancy with the lowest 5-year survival rate of all cancers in part owing to the lack of tumor-specific therapy and the rapid metastatic nature of this cancer. The gastrointestinal peptide gastrin is a trophic peptide that stimulates growth of PDAC in an autocrine fashion by interaction with the cholecystokinin receptor that is overexpressed in this malignancy. METHODS We developed a therapeutic novel polyplex nanoparticle (NP) that selectively targets the cholecystokinin receptor on PDAC. The NP was characterized in vitro and stability testing was performed in human blood. The effects of the target-specific NP loaded with gastrin small interfering RNA (siRNA) was compared with an untargeted NP and with an NP loaded with a scrambled siRNA in vitro and in 2 orthotopic models of PDAC. A polymerase chain reaction metastasis array examined differentially expressed genes from control tumors compared with tumors of mice treated with the targeted polyplex NP. RESULTS The polyplex NP forms a micelle that safely delivers specific gastrin siRNA to the tumor without off-target toxicity. Consistent with these findings, cellular uptake was confirmed only with the targeted fluorescently labeled NP by confocal microscopy in vitro and by IVIS fluorescent based imaging in mice bearing orthotopic pancreatic cancers but not found with untargeted NPs. Tumor uptake and release of the gastrin siRNA NP was verified by decreased cellular gastrin gene expression by quantitative reverse-transcription polymerase chain reaction and peptide expression by immunohistochemistry. Growth of PDAC was inhibited in a dose-related fashion in cell culture and in vivo. The targeted NP therapy completely blocked tumor metastasis and altered tumor-specific genes. CONCLUSIONS Our polyplex nanoparticle platform establishes both a strong foundation for the development of receptor-targeted therapeutics and a unique approach for the delivery of siRNA in vivo, thus warranting further exploration of this approach in other types of cancers.
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Key Words
- CCK Receptor
- CCK, cholecystokinin
- Ex/Em, maximal excitation and emission wavelengths
- Ga-10, gastrin 10 peptide
- Gastrin
- Gene Therapy
- MW, molecular weight
- N/P, ratio of “amines” of poly (L-lysine) unit and “phosphates” of siRNA complexed in the polyplex
- NMR, nuclear magnetic resonance
- NP, nanoparticle
- Nanotechnology
- Orthotopic
- PBS, phosphate-buffered saline
- PDAC, pancreatic ductal adenocarcinoma
- PEG, polyethylene glycol
- PanIN, pancreatic intraepithelial neoplasia
- mRNA, messenger RNA
- qRT-PCR, quantitative reverse-transcription polymerase chain reaction
- siRNA, small interfering RNA
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Affiliation(s)
- Julian Burks
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Sandeep Nadella
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Abdullah Mahmud
- National Institutes of Health Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | | | - Juan Wang
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Jong-In Hahm
- Department of Chemistry, Georgetown University, Washington, District of Columbia
| | - Robin D. Tucker
- Department of Comparative Medicine, Georgetown University, Washington, District of Columbia
| | - Narayan Shivapurkar
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | - Stephan T. Stern
- National Institutes of Health Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Jill P. Smith
- Department of Medicine, Georgetown University, Washington, District of Columbia,Correspondence Address correspondence to: Jill P. Smith, MD, Department of Medicine, Georgetown University, 4000 Reservoir Road, NW, Building D, Room 338, Washington, District of Columbia 20007.
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35
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Bailly C, Gouard S, Lacombe M, Remaud-Le Saëc P, Chalopin B, Bourgeois M, Chouin N, Tripier R, Halime Z, Haddad F, Faivre-Chauvet A, Kraeber-Bodéré F, Chérel M, Bodet-Milin C. Comparison of Immuno-PET of CD138 and PET imaging with 64CuCl 2 and 18F-FDG in a preclinical syngeneic model of multiple myeloma. Oncotarget 2018; 9:9061-9072. [PMID: 29507674 PMCID: PMC5823645 DOI: 10.18632/oncotarget.23886] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 11/10/2017] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Although recent data from the literature suggest that PET imaging with [18]-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker in many laboratories for the identification and purification of myeloma cells, and could be used in phenotype tumor imaging. In this study, we evaluated a 64Cu-labeled anti-CD138 murine antibody (64Cu-TE2A-9E7.4) and a metabolic tracer (64CuCl2) for PET imaging in a MM syngeneic mouse model. EXPERIMENTAL DESIGN AND RESULTS 64Cu-TE2A-9E7.4 antibody and 64CuCl2 were evaluated via PET imaging and biodistribution studies in C57BL / KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions. These results were compared to 18F-FDG-PET imaging. Autoradiography and histology of representative tumors were secondly conducted. In biodistribution and PET studies, 64Cu-TE2A-9E7.4 displayed good tumor uptake of subcutaneous and intra-medullary lesions, greater than that demonstrated with 18F-FDG-PET. In control experiments, only low-level, non-specific uptake of 64Cu-labeled isotype IgG was observed in tumors. Similarly, low activity concentrations of 64CuCl2 were accumulated in MM lesions. Histopathologic analysis of the immuno-PET-positive lesions revealed the presence of plasma cell infiltrates within the bone marrow. CONCLUSIONS 64Cu-labeled anti-CD138 antibody can detect subcutaneous MM tumors and bone marrow lesions with high sensitivity, outperforming 18F-FDG-PET and 64CuCl2 in this preclinical model. These data support 64Cu-anti-CD138 antibody as a specific and promising new imaging radiopharmaceutical agent in MM.
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Affiliation(s)
- Clément Bailly
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
| | - Sébastien Gouard
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
| | - Marie Lacombe
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nuclear Medicine Department, ICO-René Gauducheau Cancer Center, Saint-Herblain, France
| | - Patricia Remaud-Le Saëc
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
| | - Benjamin Chalopin
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
| | - Mickaël Bourgeois
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
- Groupement d’Intérêt Public ARRONAX, Saint-Herblain, France
| | - Nicolas Chouin
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
- AMaROC, Oniris, Ecole Nationale Vétérinaire, Agroalimentaire et de l'Alimentation de Nantes-Atlantique, Nantes, France
| | - Raphaël Tripier
- CNRS-UMR6521, University of Bretagne Occidentale, Brest, France
| | - Zakaria Halime
- CNRS-UMR6521, University of Bretagne Occidentale, Brest, France
| | - Ferid Haddad
- Groupement d’Intérêt Public ARRONAX, Saint-Herblain, France
| | - Alain Faivre-Chauvet
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
| | - Françoise Kraeber-Bodéré
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
- Nuclear Medicine Department, ICO-René Gauducheau Cancer Center, Saint-Herblain, France
| | - Michel Chérel
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
- Nuclear Medicine Department, ICO-René Gauducheau Cancer Center, Saint-Herblain, France
- Groupement d’Intérêt Public ARRONAX, Saint-Herblain, France
| | - Caroline Bodet-Milin
- Nuclear Medicine Department, University Hospital, Nantes, France
- Nantes-Angers Cancer Research Center CRCINA, University of Nantes, INSERM UMR1232, CNRS-ERL6001, Nantes, France
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Wiehr S, Warnke P, Rolle AM, Schütz M, Oberhettinger P, Kohlhofer U, Quintanilla-Martinez L, Maurer A, Thornton C, Boschetti F, Reischl G, Autenrieth IB, Pichler BJ, Autenrieth SE. New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection. Oncotarget 2017; 7:10990-1001. [PMID: 26934329 PMCID: PMC4905453 DOI: 10.18632/oncotarget.7770] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 02/20/2016] [Indexed: 01/12/2023] Open
Abstract
The specific and rapid detection of Enterobacteriaceae, the most frequent cause of gram-negative bacterial infections in humans, remains a major challenge. We developed a non-invasive method to rapidly detect systemic Yersinia enterocolitica infections using immunoPET (antibody-targeted positron emission tomography) with [64Cu]NODAGA-labeled Yersinia-specific polyclonal antibodies targeting the outer membrane protein YadA. In contrast to the tracer [18F]FDG, [64Cu]NODAGA-YadA uptake co-localized in a dose dependent manner with bacterial lesions of Yersinia-infected mice, as detected by magnetic resonance (MR) imaging. This was accompanied by elevated uptake of [64Cu]NODAGA-YadA in infected tissues, in ex vivo biodistribution studies, whereas reduced uptake was observed following blocking with unlabeled anti-YadA antibody. We show, for the first time, a bacteria-specific, antibody-based, in vivo imaging method for the diagnosis of a Gram-negative enterobacterial infection as a proof of concept, which may provide new insights into pathogen-host interactions.
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Affiliation(s)
- Stefan Wiehr
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Philipp Warnke
- Institute of Medical Microbiology and Hygiene, Eberhard Karls University, Tübingen, Germany.,Institute of Medical Microbiology, Virology and Hygiene, Rostock University Hospital, Rostock, Germany
| | - Anna-Maria Rolle
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Monika Schütz
- Institute of Medical Microbiology and Hygiene, Eberhard Karls University, Tübingen, Germany
| | - Philipp Oberhettinger
- Institute of Medical Microbiology and Hygiene, Eberhard Karls University, Tübingen, Germany
| | - Ursula Kohlhofer
- Institute of Pathology, Eberhard Karls University Tübingen, Tübingen, Germany
| | | | - Andreas Maurer
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Christopher Thornton
- Biosciences and ISCA Diagnostics Ltd., University of Exeter, Exeter, United Kingdom
| | | | - Gerald Reischl
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Ingo B Autenrieth
- Institute of Medical Microbiology and Hygiene, Eberhard Karls University, Tübingen, Germany
| | - Bernd J Pichler
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Stella E Autenrieth
- Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
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37
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Synthesis and Preliminary Evaluation of68Ga-NOTA-Biphenyl-c(RGDyK) for the Quantification of Integrin αvβ3. B KOREAN CHEM SOC 2017. [DOI: 10.1002/bkcs.11316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Abstract
The development of new methods to image the onset and progression of thrombosis is an unmet need. Non-invasive molecular imaging techniques targeting specific key structures involved in the formation of thrombosis have demonstrated the ability to detect thrombus in different disease state models and in patients. Due to its high concentration in the thrombus and its essential role in thrombus formation, the detection of fibrin is an attractive strategy for identification of thrombosis. Herein we provide an overview of recent and selected fibrin-targeted probes for molecular imaging of thrombosis by magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical techniques. Emphasis is placed on work that our lab has explored over the last 15 years that has resulted in the progression of the fibrin-binding PET probe [64Cu]FBP8 from preclinical studies into human trials.
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Affiliation(s)
- Bruno L Oliveira
- Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
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39
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Kopka K, Benešová M, Bařinka C, Haberkorn U, Babich J. Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers. J Nucl Med 2017; 58:17S-26S. [PMID: 28864607 DOI: 10.2967/jnumed.116.186775] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 03/27/2017] [Indexed: 01/19/2023] Open
Abstract
In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21st century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of 18F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC. For the continuing clinical development and long-term success of theranostic agents, designing modern prospective clinical trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-molecule PSMA inhibitors showed highly sensitive imaging of PSMA-positive PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clinical trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1-carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clinical trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the number of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examination of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clinical demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed? Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clinical demands been reached? Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches?
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Affiliation(s)
- Klaus Kopka
- Division of Radiopharmaceutical Chemistry, German Cancer Research Center, INF 280, Heidelberg, Germany .,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Martina Benešová
- Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.,Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen, Switzerland
| | - Cyril Bařinka
- Laboratory of Structural Biology, Institute of Biotechnology CAS, Prumyslova, Vestec, Czech Republic
| | - Uwe Haberkorn
- Department of Nuclear Medicine, University of Heidelberg, INF 400, Heidelberg, Germany.,Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, INF 280, Heidelberg, Germany; and
| | - John Babich
- Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York
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40
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Ghosh SC, Rodriguez M, Carmon KS, Voss J, Wilganowski NL, Schonbrunn A, Azhdarinia A. A Modular Dual-Labeling Scaffold That Retains Agonistic Properties for Somatostatin Receptor Targeting. J Nucl Med 2017; 58:1858-1864. [PMID: 28572490 DOI: 10.2967/jnumed.116.187971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 05/26/2017] [Indexed: 12/20/2022] Open
Abstract
Fluorescence-guided surgery is an emerging imaging technique that can enhance the ability of surgeons to detect tumors when compared with visual observation. To facilitate characterization, fluorescently labeled probes have been dual-labeled with a radionuclide to enable cross-validation with nuclear imaging. In this study, we selected the somatostatin receptor imaging agent DOTATOC as the foundation for developing a dual-labeled analog. We hypothesized that a customized dual-labeling approach with a multimodality chelation (MMC) scaffold would minimize steric effects of dye conjugation and retain agonist properties. Methods: An MMC conjugate (MMC-TOC) was synthesized on solid-phase and compared with an analog prepared using conventional methods (DA-TOC). Both analogs were conjugated to IRDye 800 using copper-free click chemistry. The resulting compounds, MMC(IR800)-TOC and DA(IR800)-TOC, were labeled with Cu and 64Cu and tested in vitro in somatostatin receptor subtype 2-overexpressing HEK-293 cells to assess agonist properties, and in AR42J rat pancreatic cancer cells to determine receptor binding characteristics. Multimodality imaging was performed in AR42J xenografts. Results: Cu-MMC(IR800)-TOC demonstrated higher potency for cyclic adenosine monophosphate inhibition (half maximal effective concentration [EC50]: 0.21 ± 0.18 vs. 1.38 ± 0.54 nM) and receptor internalization (EC50: 41.9 ± 29.8 vs. 455 ± 299 nM) than Cu-DA(IR800)-TOC. Radioactive uptake studies showed that blocking with octreotide caused a dose-dependent reduction in 64Cu-MMC(IR800)-TOC uptake whereas 64Cu-DA(IR800)-TOC was not affected. In vivo studies revealed higher tumor uptake for 64Cu-MMC(IR800)-TOC than 64Cu-DA(IR800)-TOC (5.2 ± 0.2 vs. 3.6 ± 0.4 percentage injected dose per gram). In vivo blocking studies with octreotide reduced tumor uptake of 64Cu-MMC(IR800)-TOC by 66%. Excretion of 64Cu-MMC(IR800)-TOC was primarily through the liver and spleen whereas 64Cu-DA(IR800)-TOC was cleared through the kidneys. Ex vivo analysis at 24 h confirmed PET/CT data by showing near-infrared fluorescence signal in tumors and a tumor-to-muscle ratio of 5.3 ± 0.8 as determined by γ-counting. Conclusion: The findings demonstrate that drug design affected receptor pharmacology and suggest that the MMC scaffold is a useful tool for the development of dual-labeled imaging agents.
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Affiliation(s)
- Sukhen C Ghosh
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Melissa Rodriguez
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Kendra S Carmon
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Julie Voss
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Nathaniel L Wilganowski
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Agnes Schonbrunn
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Ali Azhdarinia
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas; and
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Fani M, Peitl PK, Velikyan I. Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms. Pharmaceuticals (Basel) 2017; 10:E30. [PMID: 28295000 PMCID: PMC5374434 DOI: 10.3390/ph10010030] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/08/2017] [Accepted: 03/09/2017] [Indexed: 02/06/2023] Open
Abstract
Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
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Affiliation(s)
- Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, University Hospital of Basel, 4031 Basel, Switzerland.
| | - Petra Kolenc Peitl
- Department of Nuclear Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
| | - Irina Velikyan
- Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
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Moscaroli A, Jones G, Lühmann T, Meinel L, Wälti S, Blanc A, Fischer E, Hilbert M, Schibli R, Béhé M. Radiolabeled 111In-FGF-2 Is Suitable for In Vitro/Ex Vivo Evaluations and In Vivo Imaging. Mol Pharm 2017; 14:639-648. [PMID: 28221043 DOI: 10.1021/acs.molpharmaceut.6b00913] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Fibroblast growth factor-2 (FGF-2) is a potent modulator of cell growth and regulation, with improper FGF-2 signaling being involved in impaired responses to injury or even cancer. Therefore, the exploitation of FGF-2 as a therapeutic drives the prerequisite for effective insight into drug disposition kinetics. In this article, we present an 111In-radiolabeled FGF-2 derivative for noninvasive imaging in small animals deploying single photon emission tomography (SPECT). 111In-FGF-2 is equally well suitable for in vitro and ex vivo investigations as 125I-FGF-2. Furthermore, 111In-FGF-2 permits the performance of in vivo imaging, for example for the analysis of FGF-2 containing pharmaceutical formulations in developmental or preclinical stages. 111In-FGF-2 had affinity for the low-molecular-weight heparin enoxaparin identical to that of unlabeled FGF-2 (Kd: 0.6 ± 0.07 μM and 0.33 ± 0.03 μM, respectively) as assessed by isothermal titration calorimetry. The binding of 111In-FGF-2 to heparan sulfate proteoglycans (HPSGs) and the biological activity were comparable to those of unlabeled FGF-2, with EC50 values of 12 ± 2 pM and 25 ± 6 pM, respectively. In vivo biodistribution in healthy nude mice indicated a predominant accumulation of 111In-FGF-2 in filtering organs and minor uptake in the retina and the salivary and pituitary glands, which was confirmed by SPECT imaging. Therefore, 111In-FGF-2 is a valid tracer for future noninvasive animal imaging of FGF-2 in pharmaceutical development.
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Affiliation(s)
- Alessandra Moscaroli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland
| | - Gabriel Jones
- Institute for Pharmacy and Food Chemistry, University of Wurzburg , 97074 Wurzburg, Germany
| | - Tessa Lühmann
- Institute for Pharmacy and Food Chemistry, University of Wurzburg , 97074 Wurzburg, Germany
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Wurzburg , 97074 Wurzburg, Germany
| | - Stephanie Wälti
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich , 8092 Zurich, Switzerland
| | - Alain Blanc
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland
| | - Eliane Fischer
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland
| | - Manuel Hilbert
- Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland.,Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich , 8092 Zurich, Switzerland
| | - Martin Béhé
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute , 5232 Villigen PSI, Switzerland
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Ito T, Jensen RT. Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management. Curr Opin Endocrinol Diabetes Obes 2017; 24:15-24. [PMID: 27875420 PMCID: PMC5195891 DOI: 10.1097/med.0000000000000300] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The purpose is to review recent advances in molecular imaging of neuroendocrine tumors (NETs), discuss unresolved issues, and review how these advances are affecting clinical management. RECENT FINDINGS Molecular imaging of NETs underwent a number of important changes in the last few years, leading to some controversies, unresolved issues, and significant changes in clinical management. The most recent changes are reviewed in this article. Particularly important is the rapid replacement in somatostatin receptor scintigraphy of In-diethylenetriamine penta-acetic acid-single-photon emission computed tomography/computed tomography (CT) by Ga-fluorodopa(F-D)PA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide-PET/CT imaging, which is now approved in many countries including the USA. Numerous studies in many different types of NETs demonstrate the greater sensitivity of Ga-DOTA-peptide PET/CT, its high specificity, and its impact on management. Other important developments in somatostatin receptor scintigraphy/molecular imaging include demonstrating the prognostic value of both Ga-DOTA-peptide PET/CT and F-fluoro-deoxyglucose PET/CT; how their use can be complementary; comparing the sensitivities and usefulness of Ga-DOTA-peptide PET/CT and F-FDOPA PET/CT; introducing new linkers and radiolabeled ligands such as Cu-DOTA-peptides with a long half-life, enhancing utility; and the introduction of somatostatin receptor antagonists which show enhanced uptake by NETs. In addition, novel ligands which interact with other receptors (GLP-1, bombesin, cholecystokinin, gastric inhibitory polpeptide, integrin, chemokines) are described, which show promise in the imaging of both NETs and other tumors. SUMMARY Molecular imaging is now required for all aspects of the management of patients with NETs. Its results are essential not only for the proper diagnostic management of the patient, but also for assessing whether the patient is a candidate for peptide receptor radionuclide therapy with Lu and also for providing prognostic value.
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Affiliation(s)
- Tetsuhide Ito
- aDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan bDigestive Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
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44
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Frindel M, Le Saëc P, Beyler M, Navarro AS, Saï-Maurel C, Alliot C, Chérel M, Gestin JF, Faivre-Chauvet A, Tripier R. Cyclam te1pa for64Cu PET imaging. Bioconjugation to antibody, radiolabeling and preclinical application in xenografted colorectal cancer. RSC Adv 2017. [DOI: 10.1039/c6ra26003a] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
te1pa conjugated to an F6 antibody was confirmed to be an interesting alternative to dota for64Cuin vivoPET imaging.
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Affiliation(s)
- Mathieu Frindel
- Université de Brest
- UMR-CNRS 6521/SFR148 ScInBioS
- UFR Sciences et Techniques
- 29238 Brest
- France
| | - Patricia Le Saëc
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
| | - Maryline Beyler
- Université de Brest
- UMR-CNRS 6521/SFR148 ScInBioS
- UFR Sciences et Techniques
- 29238 Brest
- France
| | - Anne-Sophie Navarro
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
| | - Catherine Saï-Maurel
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
| | | | - Michel Chérel
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
- Institut de Cancérologie de l'Ouest
| | - Jean-François Gestin
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
| | - Alain Faivre-Chauvet
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA)
- Unité INSERM 892 – CNRS 6299
- 44007 NANTES Cedex
- France
| | - Raphaël Tripier
- Université de Brest
- UMR-CNRS 6521/SFR148 ScInBioS
- UFR Sciences et Techniques
- 29238 Brest
- France
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45
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Moreau M, Poty S, Vrigneaud JM, Walker P, Guillemin M, Raguin O, Oudot A, Bernhard C, Goze C, Boschetti F, Collin B, Brunotte F, Denat F. MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET. Dalton Trans 2017; 46:14659-14668. [DOI: 10.1039/c7dt01772c] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A comparison of four bifunctional chelating agents showed superior behaviour of a new NOTA derivative for 64Cu labelling of antibody fragments.
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46
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Kaloudi A, Nock BA, Lymperis E, Krenning EP, de Jong M, Maina T. Improving the In Vivo Profile of Minigastrin Radiotracers: A Comparative Study Involving the Neutral Endopeptidase Inhibitor Phosphoramidon. Cancer Biother Radiopharm 2016; 31:20-8. [PMID: 26844849 DOI: 10.1089/cbr.2015.1935] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Minigastrin radiotracers, such as [(111)In-DOTA]MG0 ([(111)In-DOTA-DGlu(1)]minigastrin), have been considered for diagnostic imaging and radionuclide therapy of CCK2R-positive human tumors, such as medullary thyroid carcinoma. However, the high kidney retention assigned to the pentaGlu(2-6) repeat in the peptide sequence has compromised their clinical applicability. On the other hand, truncated des(Glu)(2-6)-analogs, such as [(111)In-DOTA]MG11 ([(111)In-DOTA-DGlu(10),desGlu(2-6)]minigastrin), despite their low renal uptake, show poor bioavailability and tumor targeting. [(111)In]CP04 ([(111)In-DOTA-DGlu(1-6)]minigastrin) acquired by Glu(2-6)/DGlu(2-6) substitution showed promising tumor-to-kidney ratios in rodents. In the present study, we compare the biological profiles of [(111)In]CP04, [(111)In-DOTA]MG11, and [(111)In-DOTA]MG0 during in situ neutral endopeptidase (NEP) inhibition, recently shown to improve the bioavailability of several peptide radiotracers. After coinjection of the NEP inhibitor, phosphoramidon (PA), the stability of [(111)In]CP04 and [(111)In-DOTA]MG0 in peripheral mouse blood increased, with an exceptional >14-fold improvement monitored for [(111)In-DOTA]MG11. In line with these findings, PA treatment increased the uptake of [(111)In]CP04 (8.5 ± 0.4%ID/g to 16.0 ± 2.3%ID/g) and [(111)In-DOTA]MG0 (11.9 ± 2.2%ID/g to 17.2 ± 0.9%ID/g) in A431-CCK2R(+) tumors at 4 hours postinjection, whereas the respective increase for [(111)In-DOTA]MG11 was >6-fold (2.5 ± 0.9%ID/g to 15.1 ± 1.7%ID/g). Interestingly, kidney uptake remained lowest for [(111)In-DOTA]MG11, but unfavorably increased by PA treatment for [(111)In-DOTA]MG0. Thus, overall, the most favorable in vivo profile was displayed by [(111)In-DOTA]MG11 during NEP inhibition, highlighting the need to validate this promising concept in the clinic.
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Affiliation(s)
- Aikaterini Kaloudi
- 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece
| | - Berthold A Nock
- 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece
| | - Emmanouil Lymperis
- 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece
| | - Eric P Krenning
- 2 Department of Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands
| | - Marion de Jong
- 2 Department of Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .,3 Department of Radiology, Erasmus MC , Rotterdam, The Netherlands
| | - Theodosia Maina
- 1 Molecular Radiopharmacy, INRASTES, National Center for Scientific Research "Demokritos ," Athens, Greece
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47
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Lee JW, Lee YJ, Shin UC, Kim SW, Kim BI, Lee KC, Kim JY, Park JA. Improved Pharmacokinetics Following PEGylation and Dimerization of a c(RGD-ACH-K) Conjugate Used for Tumor Positron Emission Tomography Imaging. Cancer Biother Radiopharm 2016; 31:295-301. [PMID: 27754748 DOI: 10.1089/cbr.2016.2036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Improving the in vivo pharmacokinetics (PK) of positron emission tomography (PET) radiotracers is of critical importance to tumor diagnosis and therapy. In the case of peptide-based radiotracers, the modification and addition of a linker or spacer functional group often offer faster in vivo pharmacokinetic behavior. In this study, the authors introduced two new PEGlyated dimeric c(RGD-ACH-K) conjugates, in which an aminocyclohexane carboxylic acid (ACH) is inserted into the ring chain of the cyclic RGD peptides, with a common bifunctional chelator (DOTA or NOTA) used for labeling with radiometals (including 68Ga and 64Cu). The addition of polyethylene glycol (PEG) and dimerization of c(RGD-ACH-K) affected the PK of the renal system and the tumor-targeting ability, relative to unmodified molecule. As a result, both 64Cu-DOTA-E[c(RGD-ACH-K)]2 (complex 1) and 64Cu-NOTA-E[c(RGD-ACH-K)]2 (complex 2) exhibited specific tumor-targeting properties relative to tumor-blocking control group, most likely resulting from improved in vivo tumor imaging. The in vivo tumor-to-blood ratio of the 64Cu(NOTA) complex shows better PET imaging than that of the 64Cu(DOTA) complex, which should lead to improved dosimetry and increased suitability for noninvasive monitoring of tumor growth or tumor-targeted radionuclide therapy.
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Affiliation(s)
- Ji Woong Lee
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea.,2 Department of Integrated Biomedical and Life Science, Korea University , Seoul, Republic of Korea
| | - Yong Jin Lee
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea
| | - Un Chol Shin
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea
| | - Suhng Wook Kim
- 2 Department of Integrated Biomedical and Life Science, Korea University , Seoul, Republic of Korea
| | - Byung Il Kim
- 3 Department of Nuclear Medicine, Korea Cancer Center Hospital , Seoul, Republic of Korea
| | - Kyo Chul Lee
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea
| | - Jung Young Kim
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea
| | - Ji-Ae Park
- 1 Molecular Imaging Research Center, Korea Institute of Radiological & Medical Sciences , Seoul, Republic of Korea
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48
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Same S, Aghanejad A, Akbari Nakhjavani S, Barar J, Omidi Y. Radiolabeled theranostics: magnetic and gold nanoparticles. BIOIMPACTS 2016; 6:169-181. [PMID: 27853680 PMCID: PMC5108989 DOI: 10.15171/bi.2016.23] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 09/21/2016] [Accepted: 09/27/2016] [Indexed: 01/08/2023]
Abstract
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Introduction: Growing advances in nanotechnology have facilitated the applications of newly emerged nanomaterials in the field of biomedical/pharmaceutical sciences. Following this trend, the multifunctional nanoparticles (NPs) play a significant role in development of advanced drug delivery systems (DDSs) such as diapeutics/theranostics used for simultaneous diagnosis and therapy. Multifunctional radiolabeled NPs with capability of detecting, visualizing and destroying diseased cells with least side effects have been considered as an emerging filed in presentation of the best choice in solving the therapeutic problems. Functionalized magnetic and gold NPs (MNPs and GNPs, respectively) have produced the potential of nanoparticles as sensitive multifunctional probes for molecular imaging, photothermal therapy and drug delivery and targeting.
Methods: In this study, we review the most recent works on the improvement of various techniques for development of radiolabeled magnetic and gold nanoprobes, and discuss the methods for targeted imaging and therapies.
Results: The receptor-specific radiopharmaceuticals have been developed to localized radiotherapy in disease sites. Application of advanced multimodal imaging methods and related modality imaging agents labeled with various radioisotopes (e.g., 125I, 111In, 64Cu, 68Ga, 99mTc) and MNPs/GNPs have significant effects on treatment and prognosis of cancer therapy. In addition, the surface modification with biocompatible polymer such as polyethylene glycol (PEG) have resulted in development of stealth NPs that can evade the opsonization and immune clearance. These long-circulating agents can be decorated with homing agents as well as radioisotopes for targeted imaging and therapy purposes.
Conclusion: The modified MNPs or GNPs have wide applications in concurrent diagnosis and therapy of various malignancies. Once armed with radioisotopes, these nanosystems (NSs) can be exploited for combined multimodality imaging with photothermal/photodynamic therapy while delivering the loaded drugs or genes to the targeted cells/tissues. These NSs will be a game changer in combating various cancers.
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Affiliation(s)
- Saeideh Same
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayuob Aghanejad
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sattar Akbari Nakhjavani
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran ; Department of Molecular Medicine, School of Advanced Technologies in Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
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Spang P, Herrmann C, Roesch F. Bifunctional Gallium-68 Chelators: Past, Present, and Future. Semin Nucl Med 2016; 46:373-94. [DOI: 10.1053/j.semnuclmed.2016.04.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Sullivan MT, Senaratne NK, Eichhorn DM. Synthesis and X-ray crystallographic characterization of [In(tsalen)(OAc)] (tsalen = N,N′-ethylenebis(thiosalicylideneimine)). Polyhedron 2016. [DOI: 10.1016/j.poly.2015.11.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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