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Omweri JM, Houson HA, Lynch SE, Tekin V, Sorace AG, Lapi SE. PET imaging of 52Mn labeled DOTATATE and DOTAJR11. Sci Rep 2025; 15:2395. [PMID: 39827143 PMCID: PMC11742957 DOI: 10.1038/s41598-025-85143-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 01/01/2025] [Indexed: 01/30/2025] Open
Abstract
Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [68Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [68Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake. The goal of this study was to label both DOTATATE and DOTA-JR11 peptides with 52Mn in high radiochemical yields (RCY) and sufficient specific activity. A comparison of these two compounds was performed in in vitro and in vivo studies in animals with somatostatin receptor-positive xenografts to characterize differences in cell, tumor, and tissue uptake. Radiolabeling of DOTATATE and DOTA-JR11 was carried out by combining varying concentrations of the peptides with [52Mn]MnCl2. In vitro stability of the radiotracers was determined in mouse serum. In vitro cell uptake and internalization assays were performed in SSTR2 + AR42J cells and negative controls. In vivo biodistribution and longitudinal PET imaging was evaluated in mice bearing AR42J tumors. Both [52Mn]Mn-DOTATATE and [52Mn]Mn-DOTA-JR11 showed affinity for SSTR2 in AR42J cells. However, the uptake of [52Mn]Mn-DOTATATE was higher (11.95 ± 0.71%/ mg) compared to [52Mn]Mn-DOTA-JR11 (7.31 ± 0.38%/ mg) after 2 h incubation. After 4 h incubation, 53.13 ± 1.83% of the total accumulated activity of [52Mn]Mn-DOTATATE was internalized, whereas only 20.85 ± 0.59% of the total accumulated activity of [52Mn]Mn-DOTA-JR11 was internalized. The PET images revealed similar biodistribution results, with [52Mn]Mn-DOTATATE showing a significant tumor uptake of 11.16 ± 2.97% ID/g, while [52Mn]Mn-DOTA-JR11 exhibited a lower tumor uptake of 2.11 ± 0.30% ID/g 4 h post-injection. The synthesis of both radiotracers was accomplished with high RCY and purity. The cell uptake and internalization of [52Mn]Mn-DOTATATE showed higher levels compared to [52Mn]Mn-DOTA-JR11. PET images of the radiotracers in AR42J tumor bearing mice demonstrated similar biodistribution in all organs except the tumor, with [52Mn]Mn-DOTATATE showing higher tumor uptake compared to [52Mn]Mn-DOTA-JR11. The variations in the properties of these tracers could be used to guide further imaging and treatment studies.
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Affiliation(s)
- James M Omweri
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA
- Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hailey A Houson
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA
| | - Shannon E Lynch
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA
- Graduate Biomedical Sciences, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Volkan Tekin
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA
| | - Anna G Sorace
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA
- O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Suzanne E Lapi
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, USA.
- Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL, USA.
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA.
- O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
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Gé LG, Danielsen MB, Nielsen AY, Skavenborg ML, Langkjær N, Thisgaard H, McKenzie CJ. Radiocobalt-Labeling of a Polypyridylamine Chelate Conjugated to GE11 for EGFR-Targeted Theranostics. Molecules 2025; 30:212. [PMID: 39860082 PMCID: PMC11767697 DOI: 10.3390/molecules30020212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
The overexpression of the epidermal growth factor receptor (EGFR) in certain types of prostate cancers and glioblastoma makes it a promising target for targeted radioligand therapy. In this context, pairing an EGFR-targeting peptide with the emerging theranostic pair comprising the Auger electron emitter cobalt-58m (58mCo) and the Positron Emission Tomography-isotope cobalt-55 (55Co) would be of great interest for creating novel radiopharmaceuticals for prostate cancer and glioblastoma theranostics. In this study, GE11 (YHWYGYTPQNVI) was investigated for its EGFR-targeting potential when conjugated using click chemistry to N1-((triazol-4-yl)methyl)-N1,N2,N2-tris(pyridin-2-ylmethyl)ethane-1,2-diamine (TZTPEN). This chelator is suitable for binding Co2+ and Co3+. With cobalt-57 (57Co) serving as a surrogate radionuclide for 55/58mCo, the novel GE11-TZTPEN construct was successfully radiolabeled with a high radiochemical yield (99%) and purity (>99%). [57Co]Co-TZTPEN-GE11 showed high stability in PBS (pH 5) and specific uptake in EGFR-positive cell lines. Disappointingly, no tumor uptake was observed in EGFR-positive tumor-bearing mice, with most activity being accumulated predominantly in the liver, gall bladder, kidneys, and spleen. Some bone uptake was also observed, suggesting in vivo dissociation of 57Co from the complex. In conclusion, [57Co]Co-TZTPEN-GE11 shows poor pharmacokinetics in a mouse model and is, therefore, not deemed suitable as a targeting radiopharmaceutical for EGFR.
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Affiliation(s)
- Lorraine Gaenaelle Gé
- Department of Nuclear Medicine, Odense University Hospital, Kloevervaenget 47, 5000 Odense C, Denmark; (L.G.G.); (A.Y.N.); (N.L.)
- Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
| | - Mathias Bogetoft Danielsen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; (M.B.D.); (M.L.S.)
| | - Aaraby Yoheswaran Nielsen
- Department of Nuclear Medicine, Odense University Hospital, Kloevervaenget 47, 5000 Odense C, Denmark; (L.G.G.); (A.Y.N.); (N.L.)
| | - Mathias Lander Skavenborg
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; (M.B.D.); (M.L.S.)
| | - Niels Langkjær
- Department of Nuclear Medicine, Odense University Hospital, Kloevervaenget 47, 5000 Odense C, Denmark; (L.G.G.); (A.Y.N.); (N.L.)
| | - Helge Thisgaard
- Department of Nuclear Medicine, Odense University Hospital, Kloevervaenget 47, 5000 Odense C, Denmark; (L.G.G.); (A.Y.N.); (N.L.)
- Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
| | - Christine J. McKenzie
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; (M.B.D.); (M.L.S.)
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Du Y, Semghouli A, Wang Q, Mei H, Kiss L, Baecker D, Soloshonok VA, Han J. FDA-approved drugs featuring macrocycles or medium-sized rings. Arch Pharm (Weinheim) 2025; 358:e2400890. [PMID: 39865335 PMCID: PMC11771699 DOI: 10.1002/ardp.202400890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 01/28/2025]
Abstract
Macrocycles or medium-sized rings offer diverse functionality and stereochemical complexity in a well-organized ring structure, allowing them to fulfill various biochemical functions, resulting in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular compartments. These features have made macrocycles attractive candidates in organic synthesis and drug discovery. Since the 20th century, more than three-score macrocyclic drugs, including radiopharmaceuticals, have been approved by the US Food and Drug Administration (FDA) for treating bacterial and viral infections, cancer, obesity, immunosuppression, inflammatory, and neurological disorders, managing cardiovascular diseases, diabetes, and more. This review presents 17 FDA-approved macrocyclic drugs during the past 5 years, highlighting their importance and critical role in modern therapeutics, and the innovative synthetic approaches for the construction of these macrocycles.
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Affiliation(s)
- Youlong Du
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Anas Semghouli
- Institute of Organic Chemistry, Stereochemistry Research Group, HUN‐REN Research Centre for Natural SciencesBudapestHungary
| | - Qian Wang
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Haibo Mei
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Loránd Kiss
- Institute of Organic Chemistry, Stereochemistry Research Group, HUN‐REN Research Centre for Natural SciencesBudapestHungary
| | - Daniel Baecker
- Department of Pharmaceutical and Medicinal Chemistry, Institute of PharmacyFreie Universität BerlinBerlinGermany
| | - Vadim A. Soloshonok
- Department of Organic Chemistry I, Faculty of ChemistryUniversity of the Basque Country UPV/EHUSan SebastiánSpain
- IKERBASQUE, Basque Foundation for ScienceBilbaoSpain
| | - Jianlin Han
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
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Baun C, Olsen BB, Alves CML, Ditzel HJ, Terp M, Hildebrandt MG, Poulsen CA, Gé LG, Gammelsrød VS, Orlova A, Dam JH, Thisgaard H. Gastrin-releasing peptide receptor as theranostic target in estrogen-receptor positive breast cancer: A preclinical study of the theranostic pair [ 55Co]Co- and [ 177Lu]Lu-DOTA-RM26. Nucl Med Biol 2024; 138-139:108961. [PMID: 39357076 DOI: 10.1016/j.nucmedbio.2024.108961] [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: 06/11/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Patients with advanced metastatic estrogen receptor-positive breast cancer often develop resistance to standard treatments, leading to uncontrolled progression. Thus, innovative therapies are urgently needed. The gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers, including breast cancer, making it an interesting theranostic target. RM26, a GRPR-targeting antagonist, has demonstrated promising in vivo kinetics in prostate cancer models. This study evaluated the theranostic capabilities of [55Co]Co-/[177Lu]Lu-DOTA-RM26 in vitro in estrogen receptor-positive breast cancer cells and assessed the diagnostic potential of [55Co]Co-DOTA-RM26 in vivo in a breast cancer mouse model. METHODS We analyzed the binding specificity of [57Co]Co-/[177Lu]Lu-DOTA-RM26 in T47D breast cancer cells, using [57Co]Co-DOTA-RM26 as a surrogate for [55Co]Co-DOTA-RM26. The therapeutic efficacy of increasing [177Lu]Lu-DOTA-RM26 concentrations was determined via viability assay in vitro. Ex vivo biodistribution of [57Co]Co-DOTA-RM26 (17.2 ± 2.7 kBq, 33 ± 5.2 pmol/mouse) was investigated in 12 mice (n= 4/group) with orthotopic breast cancer tumors. The mice were sacrificed at 4 and 24 h post-injection (pi), including a blocking group (20 nmol of unlabeled [Tyr4]-Bombesin) at 4 h pi. For imaging, two tumor-bearing mice underwent [55Co]Co-DOTA-RM26 PET/CT, 4 and 24 h pi (2.8 ± 0.2 MBq, 167.5 ± 0.5 pmol/mouse), with or without GRPR blocking. RESULTS In vitro studies revealed high, specific binding of [57Co]Co-DOTA-RM26 (43 ± 1 % of total added activity per 106 cells (%IA/106)) and [177Lu]Lu-DOTA-RM26 (37 ± 4 %IA/106). The activity was predominantly localized at the cell surface: 71 ± 3 % and 80 ± 6 % for [57Co]Co-DOTA-RM26 and [177Lu]Lu-DOTA-RM26, respectively. [177Lu]Lu-DOTA-RM26 significantly reduced cell viability at all activity concentrations >0.625 MBq/mL (p < 0.0001), with cell viability below 1 % at concentrations ≥5 MBq/mL. Biodistribution data (n = 12) indicated a high, specific tumor uptake of [57Co]Co-DOTA-RM26, surpassing all other tissues significantly at both time points, 3.7 ± 0.6 % of the injected activity per gram (%IA/g) 4 h pi and 0.98 ± 0.05 %IA/g 24 h pi. The kidneys showed the second-highest uptake (2.0 ± 0.1 %IA/g 4 h pi), followed by the pancreas (1.4 ± 0.4 %IA/g 4 h pi). PET/CT imaging with [55Co]Co-DOTA-RM26 supported the biodistribution data and, distinctly visualized the tumor 24 h pi and showed an improved tumor-to-background compared to the earlier time points. Effective GRPR blocking significantly reduced tumor uptake in the PET images 24 h pi. CONCLUSION These findings suggest that the theranostic pair [55Co]Co-/[177Lu]Lu-DOTA-RM26 holds significant promise as a theranostic agent for estrogen receptor-positive breast cancer.
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Affiliation(s)
- Christina Baun
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark.
| | - Birgitte Brinkmann Olsen
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Carla Maria Lourenco Alves
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Henrik Jørn Ditzel
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Mikkel Terp
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Malene Grubbe Hildebrandt
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark; Centre for Innovative Medical Technology, Odense University Hospital, Odense, Denmark
| | | | - Lorraine Gaenaelle Gé
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Vigga Sand Gammelsrød
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Anna Orlova
- Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Sweden; Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Sweden
| | - Johan Hygum Dam
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Helge Thisgaard
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Omweri JM, Houson HA, Lynch SE, Tekin V, Sorace AG, Lapi SE. PET imaging of [52 Mn]Mn-DOTATATE and [52 Mn]Mn-DOTA-JR11. RESEARCH SQUARE 2024:rs.3.rs-4684098. [PMID: 39149492 PMCID: PMC11326411 DOI: 10.21203/rs.3.rs-4684098/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [68Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [68Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake. The goal of this study was to label both DOTATATE and DOTA-JR11 peptides with 52Mn in high radiochemical yields (RCY) and sufficient specific activity. A comparison of these two compounds was performed in in vitro and in vivo studies in animals with somatostatin receptor-positive xenografts to characterize differences in cell, tumor, and tissue uptake. Radiolabeling of DOTATATE and DOTA-JR11 was carried out by combining varying concentrations of the peptides with [52Mn]MnCl2. In vitro stability of the radiotracers was determined in mouse serum. In vitro cell uptake and internalization assays were performed in SSTR2 + AR42J cells and negative controls. In vivo biodistribution and longitudinal PET imaging was evaluated in mice bearing AR42J tumors. Both [52Mn]Mn-DOTATATE and [52Mn]Mn-DOTA-JR11showed affinity for SSTR2 in AR42J cells. However, the uptake of [52Mn]Mn-DOTATATE was higher (11.95 ± 0.71%/ mg) compared to [52Mn]Mn-DOTA-JR11 (7.31 ± 0.38%/ mg) after 2 h incubation. After 4 h incubation, 53.13 ± 1.83% of the total activity of [52Mn]Mn-DOTATATE was internalized, whereas only 20.85 ± 0.59% of the total activity of [52Mn]Mn-DOTA-JR11 was internalized. The PET images revealed similar biodistribution results, with [52Mn]Mn-DOTATATE showing a significant tumor uptake of 11.16 ± 2.97% ID/g, while [52Mn]Mn-DOTA-JR11 exhibited a lower tumor uptake of 2.11 ± 0.30% ID/g 4 h post-injection. The synthesis of both radiotracers was accomplished with high RCY and purity. The cell uptake and internalization of [52Mn]Mn-DOTATATE showed higher levels compared to [52Mn]Mn-DOTA-JR11. PET images of the radiotracers in AR42J tumor bearing mice demonstrated similar biodistribution in all organs except the tumor, with [52Mn]Mn-DOTATATE showing higher tumor uptake compared to [52Mn]Mn-DOTA-JR11. The variations in properties of these tracers could be used to guide further imaging and treatment studies.
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Lin W, Fonseca Cabrera GO, Aluicio-Sarduy E, Barnhart TE, Mixdorf JC, Li Z, Wu Z, Engle JW. Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [ 55Co]Co-NT-Sarcage as a Proof of Concept in a Murine Xenograft Model. Bioconjug Chem 2024; 35:412-418. [PMID: 38411531 PMCID: PMC10954389 DOI: 10.1021/acs.bioconjchem.4c00043] [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] [Indexed: 02/28/2024]
Abstract
Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added 55Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with 55Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [55Co]CoCl2 to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [55Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice. The [55Co]Co-DSar complex can be formed at 37 °C with purity and stability suitable for preclinical in vivo radiopharmaceutical applications, and [55Co]Co-NT-Sarcage demonstrated prominent tumor uptake with a low background signal. In a direct comparison with [64Cu]Cu-NT-Sarcage, [55Co]Co-NT-Sarcage achieved a higher tumor-to-liver ratio but with overall similar biodistribution profile. These results demonstrate that Sar would be a promising chelator for constructing Co-based radiopharmaceuticals including 55Co for PET and 58mCo for therapeutic applications.
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Affiliation(s)
- Wilson Lin
- Department of Medical Physics, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, United States
| | - German Oscar Fonseca Cabrera
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, NC 27599, United States
| | - Eduardo Aluicio-Sarduy
- Department of Medical Physics, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, United States
| | - Todd E. Barnhart
- Department of Medical Physics, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, United States
| | - Jason C. Mixdorf
- Department of Medical Physics, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, United States
| | - Zibo Li
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, NC 27599, United States
| | - Zhanhong Wu
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, NC 27599, United States
| | - Jonathan W. Engle
- Department of Medical Physics, University of Wisconsin, 1111 Highland Ave., Madison, WI 53705, United States
- Department of Radiology, University of Wisconsin, 600 Highland Ave., Madison, WI, 53792, United States
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Baun C, Dam JH, Hildebrandt MG, Ewald JD, Kristensen BW, Gammelsrød VS, Olsen BB, Thisgaard H. Preclinical evaluation of [ 58mCo]Co-DOTA-PSMA-617 for Auger electron therapy of prostate cancer. Sci Rep 2023; 13:18837. [PMID: 37914790 PMCID: PMC10620164 DOI: 10.1038/s41598-023-43429-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/23/2023] [Indexed: 11/03/2023] Open
Abstract
Prostate-specific membrane antigen (PSMA), highly expressed in prostate cancer, is a promising target for radionuclide therapy. Auger electron-emitting radionuclides are well suited for targeted radionuclide therapy if they can be delivered close to the DNA of the targeted cells. This preclinical study evaluated the theranostic pair [55/58mCo]Co-DOTA-PSMA-617 for PET imaging and Auger electron therapy of prostate cancer. [58mCo]Co-DOTA-PSMA-617 was successfully prepared with > 99% radiochemical yield and purity. In vitro, uptake and subcellular distribution assays in PSMA-positive prostate cancer cells showed PSMA-specific uptake with high cell-associated activity in the nucleus. Incubation with [58mCo]Co-DOTA-PSMA-617 reduced cell viability and clonogenic survival in a significant dose-dependent manner (p < 0.05). Biodistribution of xenografted mice showed high specific tumor uptake of the cobalt-labeled PSMA ligand for all time points with rapid clearance from normal tissues, which PET imaging confirmed. In vivo, therapy with [58mCo]Co-DOTA-PSMA-617 in tumor-bearing mice demonstrated significantly increased median survival for treated mice compared to control animals (p = 0.0014). In conclusion, [55/58mCo]Co-DOTA-PSMA-617 displayed excellent in vitro and in vivo properties, offering significant survival benefits in mice with no observed toxicities.
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Affiliation(s)
- Christina Baun
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Center for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark
| | - Johan Hygum Dam
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Malene Grubbe Hildebrandt
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Center for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark
- Centre for Innovative Medical Technology, Odense University Hospital, Odense, Denmark
| | - Jesper Dupont Ewald
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Bjarne Winther Kristensen
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Vigga Sand Gammelsrød
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Birgitte Brinkmann Olsen
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Helge Thisgaard
- Department of Nuclear Medicine, Odense University Hospital, Kløvervænget 47, 5000, Odense C, Denmark.
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Kozlovskaya V, Ducharme M, Dolmat M, Omweri JM, Tekin V, Lapi SE, Kharlampieva E. Direct Radiolabeling of Trastuzumab-Targeting Triblock Copolymer Vesicles with 89Zr for Positron Emission Tomography Imaging. Biomacromolecules 2023; 24:1784-1797. [PMID: 36926842 DOI: 10.1021/acs.biomac.2c01539] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Radiolabeled drug nanocarriers that can be easily imaged via positron emission tomography (PET) are highly significant as their in vivo outcome can be quantitatively PET-traced with high sensitivity. However, typical radiolabeling of most PET-guided theranostic vehicles utilizes modification with chelator ligands, which presents various challenges. In addition, unlike passive tumor targeting, specific targeting of drug delivery vehicles via binding affinity to overexpressed cancer cell receptors is crucial to improve the theranostic delivery to tumors. Herein, we developed 89Zr-labeled triblock copolymer polymersomes of 60 nm size through chelator-free radiolabeling. The polymersomes are assembled from poly(N-vinylpyrrolidone)5-b-poly(dimethylsiloxane)30-b-poly(N-vinylpyrrolidone)5 (PVPON5-PDMS30-PVPON5) triblock copolymers followed by adsorption of a degradable tannin, tannic acid (TA), on the polymersome surface through hydrogen bonding. TA serves as an anchoring layer for both 89Zr radionuclide and targeting recombinant humanized monoclonal antibody, trastuzumab (Tmab). Unlike bare PVPON5-PDMS30-PVPON5 polymersomes, TA- and Tmab-modified polymersomes demonstrated a high radiochemical yield of more than 95%. Excellent retention of 89Zr by the vesicle membrane for up to 7 days was confirmed by PET in vivo imaging. Animal biodistribution using healthy BALB/c mice confirmed the clearance of 89Zr-labeled polymersomes through the spleen and liver without their accumulation in bone, unlike the free nonbound 89Zr radiotracer. The 89Zr-radiolabeled polymersomes were found to specifically target BT474 HER2-positive breast cancer cells via the Tmab-TA complex on the vesicle surface. The noncovalent Tmab anchoring to the polymersome membrane can be highly advantageous for nanoparticle modification compared to currently developed covalent methods, as it allows easy and quick integration of a broad range of targeting proteins. Given the ability of these polymersomes to encapsulate and release anticancer therapeutics, they can be further expanded as precision-targeted therapeutic carriers for advancing human health through highly effective drug delivery strategies.
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Affiliation(s)
- Veronika Kozlovskaya
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Maxwell Ducharme
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Maksim Dolmat
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - James M Omweri
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Volkan Tekin
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Suzanne E Lapi
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Eugenia Kharlampieva
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- Center for Nanomaterials and Biointegration, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
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9
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Chakraborty K, Mondal J, An JM, Park J, Lee YK. Advances in Radionuclides and Radiolabelled Peptides for Cancer Therapeutics. Pharmaceutics 2023; 15:pharmaceutics15030971. [PMID: 36986832 PMCID: PMC10054444 DOI: 10.3390/pharmaceutics15030971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/13/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Radiopharmaceutical therapy, which can detect and treat tumours simultaneously, was introduced more than 80 years ago, and it has changed medical strategies with respect to cancer. Many radioactive radionuclides have been developed, and functional, molecularly modified radiolabelled peptides have been used to produce biomolecules and therapeutics that are vastly utilised in the field of radio medicine. Since the 1990s, they have smoothly transitioned into clinical application, and as of today, a wide variety of radiolabelled radionuclide derivatives have been examined and evaluated in various studies. Advanced technologies, such as conjugation of functional peptides or incorporation of radionuclides into chelating ligands, have been developed for advanced radiopharmaceutical cancer therapy. New radiolabelled conjugates for targeted radiotherapy have been designed to deliver radiation directly to cancer cells with improved specificity and minimal damage to the surrounding normal tissue. The development of new theragnostic radionuclides, which can be used for both imaging and therapy purposes, allows for more precise targeting and monitoring of the treatment response. The increased use of peptide receptor radionuclide therapy (PRRT) is also important in the targeting of specific receptors which are overexpressed in cancer cells. In this review, we provide insights into the development of radionuclides and functional radiolabelled peptides, give a brief background, and describe their transition into clinical application.
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Affiliation(s)
- Kushal Chakraborty
- Department of IT and Energy Convergence (BK21 FOUR), Korea National University of Transportation, Chungju 27469, Republic of Korea
| | - Jagannath Mondal
- Department of Green Bio Engineering, Graduate School, Korea National University of Transportation, Chungju 27469, Republic of Korea
- 4D Convergence Technology Institute, Korea National University of Transportation, Jeungpyeong 27909, Republic of Korea
| | - Jeong Man An
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Jooho Park
- Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Republic of Korea
- Research Institute for Biomedical & Health Science, Konkuk University, Chungju 27478, Republic of Korea
- Correspondence: (J.P.); (Y.-K.L.); Tel.: +82-43-841-5224 (Y.-K.L.)
| | - Yong-Kyu Lee
- Department of Green Bio Engineering, Graduate School, Korea National University of Transportation, Chungju 27469, Republic of Korea
- 4D Convergence Technology Institute, Korea National University of Transportation, Jeungpyeong 27909, Republic of Korea
- Correspondence: (J.P.); (Y.-K.L.); Tel.: +82-43-841-5224 (Y.-K.L.)
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10
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Brown AM, Butman JL, Lengacher R, Vargo NP, Martin KE, Koller A, Śmiłowicz D, Boros E, Robinson JR. N, N-Alkylation Clarifies the Role of N- and O-Protonated Intermediates in Cyclen-Based 64Cu Radiopharmaceuticals. Inorg Chem 2023; 62:1362-1376. [PMID: 36490364 DOI: 10.1021/acs.inorgchem.2c02907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Radioisotopes of Cu, such as 64Cu and 67Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications. Cyclen-based macrocyclic polyaminocarboxylates are one of the most frequently examined bifunctional chelators in vitro and in vivo, including the FDA-approved 64Cu radiopharmaceutical, Cu(DOTATATE) (Detectnet); however, connections between the structure of plausible reactive intermediates and their stability under physiologically relevant conditions remain to be established. In this study, we share the synthesis of a cyclen-based, N,N-alkylated spirocyclic chelate, H2DO3AC4H8, which serves as a model for N-protonation. Our combined experimental (in vitro and in vivo) and computational studies unravel complex pH-dependent speciation and enable side-by-side comparison of N- and O-protonated species of relevant 64Cu radiopharmaceuticals. Our studies suggest that N-protonated species are not inherently unstable species under physiological conditions and demonstrate the potential of N,N-alkylation as a tool for the rational design of future radiopharmaceuticals.
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Affiliation(s)
- Alexander M Brown
- Department of Chemistry, Brown University, Providence, Rhode Island02912, United States
| | - Jana L Butman
- Department of Chemistry, Brown University, Providence, Rhode Island02912, United States
| | - Raphael Lengacher
- Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York11794, United States
| | - Natasha P Vargo
- Department of Chemistry, Brown University, Providence, Rhode Island02912, United States
| | - Kirsten E Martin
- Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York11794, United States
| | - Angus Koller
- Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York11794, United States
| | - Dariusz Śmiłowicz
- Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York11794, United States
| | - Eszter Boros
- Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York11794, United States
| | - Jerome R Robinson
- Department of Chemistry, Brown University, Providence, Rhode Island02912, United States
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11
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Houson HA, Tekin V, Lin W, Aluicio-Sarduy E, Engle JW, Lapi SE. PET Imaging of the Neurotensin Targeting Peptide NOTA-NT-20.3 Using Cobalt-55, Copper-64 and Gallium-68. Pharmaceutics 2022; 14:pharmaceutics14122724. [PMID: 36559218 PMCID: PMC9781609 DOI: 10.3390/pharmaceutics14122724] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/18/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work focuses on a the neurotensin peptide analogue NT-20.3 conjugated to the chelator NOTA for radiolabeling for use in noninvasive positron emission tomography (PET). NOTA-NT-20.3 was radiolabeled with gallium-68, copper-64, and cobalt-55 to determine the effect that modification of the radiometal has on imaging and potential therapeutic properties of NOTA-NT-20.3. Methods: In vitro assays investigating cell uptake and subcellular localization of the radiolabeled peptides were performed using human colorectal adenocarcinoma HT29 cells. In vivo PET/CT imaging was used to determine the distribution and clearance of the peptide in mice bearing NTSR1 expressing HT29 tumors. Results: Cell uptake studies showed that the highest uptake was obtained with [55Co] Co-NOTA-NT-20.3 (18.70 ± 1.30%ID/mg), followed by [64Cu] Cu-NOTA-NT-20.3 (15.46 ± 0.91%ID/mg), and lastly [68Ga] Ga-NOTA-NT-20.3 (10.94 ± 0.46%ID/mg) (p < 0.001). Subcellular distribution was similar across the three constructs, with the membranous fraction containing the highest amount of radioactivity. In vivo PET/CT imaging of the three constructs revealed similar distribution and tumor uptake at the 1 h imaging timepoint. Tumor uptake was receptor-specific and blockable by co-injection of non-radiolabeled NOTA-NT-20.3. SUV ratios of tumor to heart at the 24 h imaging timepoint show that [55Co] Co-NOTA-NT-20.3 (20.28 ± 3.04) outperformed [64Cu] Cu-NOTA-NT-20.3 (6.52 ± 1.97). In conclusion, our studies show that enhanced cell uptake and increasing tumor to blood ratios over time displayed the superiority of [55Co] Co-NOTA-NT-20.3 over [68Ga] Ga-NOTA-NT-20.3 and [64Cu] Cu-NOTA-NT-20.3 for the targeting of NTSR1.
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Affiliation(s)
- Hailey A. Houson
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Volkan Tekin
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Wilson Lin
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Eduardo Aluicio-Sarduy
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Jonathan W. Engle
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53705, USA
- Department of Radiology, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Suzanne E. Lapi
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence:
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12
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Pacak K, Taieb D, Jha A. Functional Imaging of Neuroendocrine Tumors: Stacking the Odds in a Patient's Favor. J Clin Endocrinol Metab 2022; 107:e3953-e3954. [PMID: 35536703 PMCID: PMC9387716 DOI: 10.1210/clinem/dgac298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Karel Pacak
- Correspondence: Karel Pacak, MD, PhD, DSc, Section on Medical Neuroendocrinology & Head, Developmental Endocrinology, Metabolism, Genetics and Endocrine Oncology Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Bldg 10, CRC, Rm 1E-3140, 10 Center Dr, MSC-1109, Bethesda, MD 20892-1109, USA.
| | - David Taieb
- Department of Nuclear Medicine, La Timone University Hospital, European Center for Research in Medical Imaging, Aix-Marseille University, 13385 Marseille, France
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1109, USA
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13
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Desai P, Rimal R, Sahnoun SEM, Mottaghy FM, Möller M, Morgenroth A, Singh S. Radiolabeled Nanocarriers as Theranostics-Advancement from Peptides to Nanocarriers. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2200673. [PMID: 35527333 DOI: 10.1002/smll.202200673] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/15/2022] [Indexed: 06/14/2023]
Abstract
Endogenous targeted radiotherapy is emerging as an integral modality to treat a variety of cancer entities. Nevertheless, despite the positive clinical outcome of the treatment using radiolabeled peptides, small molecules, antibodies, and nanobodies, a high degree of hepatotoxicity and nephrotoxicity still persist. This limits the amount of dose that can be injected. In an attempt to mitigate these side effects, the use of nanocarriers such as nanoparticles (NPs), dendrimers, micelles, liposomes, and nanogels (NGs) is currently being explored. Nanocarriers can prolong circulation time and tumor retention, maximize radiation dosage, and offer multifunctionality for different targeting strategies. In this review, the authors first provide a summary of radiation therapy and imaging and discuss the new radiotracers that are used preclinically and clinically. They then highlight and identify the advantages of radio-nanomedicine and its potential in overcoming the limitations of endogenous radiotherapy. Finally, the review points to the ongoing efforts to maximize the use of radio-nanomedicine for efficient clinical translation.
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Affiliation(s)
- Prachi Desai
- DWI Leibniz Institute for Interactive Materials e.V, RWTH Aachen University, Forckenbeckstrasse 50, 52074, Aachen, Germany
| | - Rahul Rimal
- DWI Leibniz Institute for Interactive Materials e.V, RWTH Aachen University, Forckenbeckstrasse 50, 52074, Aachen, Germany
| | - Sabri E M Sahnoun
- Department of Nuclear Medicine, University hospital RWTH Aachen, Pauwelstraße 30, 52074, Aachen, Germany
| | - Felix M Mottaghy
- Department of Nuclear Medicine, University hospital RWTH Aachen, Pauwelstraße 30, 52074, Aachen, Germany
- Department of Radiology and Nuclear Medicine, School for Cardiovascular Diseases (CARIM) and School of oncology (GROW), Maastricht University, Maastricht, 6229 HX, The Netherlands
| | - Martin Möller
- DWI Leibniz Institute for Interactive Materials e.V, RWTH Aachen University, Forckenbeckstrasse 50, 52074, Aachen, Germany
| | - Agnieszka Morgenroth
- Department of Nuclear Medicine, University hospital RWTH Aachen, Pauwelstraße 30, 52074, Aachen, Germany
| | - Smriti Singh
- DWI Leibniz Institute for Interactive Materials e.V, RWTH Aachen University, Forckenbeckstrasse 50, 52074, Aachen, Germany
- Max-Planck-Institute for Medical Research (MPImF), Jahnstrasse 29, 69120, Heidelberg, Germany
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14
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Grey N, Silosky M, Lieu CH, Chin BB. Current status and future of targeted peptide receptor radionuclide positron emission tomography imaging and therapy of gastroenteropancreatic-neuroendocrine tumors. World J Gastroenterol 2022; 28:1768-1780. [PMID: 35633909 PMCID: PMC9099199 DOI: 10.3748/wjg.v28.i17.1768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/07/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Theranostics is the highly targeted molecular imaging and therapy of tumors. Targeted peptide receptor radionuclide therapy has taken the lead in demonstrating the safety and effectiveness of this molecular approach to treating cancers. Metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors may be most effectively imaged and treated with DOTATATE ligands. We review the current practice, safety, advantages, and limitations of DOTATATE based theranostics. Finally, we briefly describe the exciting new areas of development and future directions of gastroenteropancreatic neuroendocrine tumor theranostics.
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Affiliation(s)
- Neil Grey
- Radiology-Nuclear Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Michael Silosky
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Christopher H Lieu
- Medical Oncology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Bennett B Chin
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
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15
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Toner YC, Ghotbi AA, Naidu S, Sakurai K, van Leent MMT, Jordan S, Ordikhani F, Amadori L, Sofias AM, Fisher EL, Maier A, Sullivan N, Munitz J, Senders ML, Mason C, Reiner T, Soultanidis G, Tarkin JM, Rudd JHF, Giannarelli C, Ochando J, Pérez-Medina C, Kjaer A, Mulder WJM, Fayad ZA, Calcagno C. Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation. Sci Rep 2022; 12:6185. [PMID: 35418569 PMCID: PMC9007951 DOI: 10.1038/s41598-022-09590-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/22/2022] [Indexed: 02/08/2023] Open
Abstract
In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [18F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [64Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [68Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [64Cu]Cu-DOTATATE and [18F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [64Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUVmax 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUVmax 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUVmax 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [18F]F-FDG PET. In atherosclerotic mice, [64Cu]Cu-DOTATATE PET aortic signal, but not [18F]F-FDG PET, was higher compared to controls (SUVmax 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [64Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [18F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [68Ga]Ga-DOTATATE and [18F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [68Ga]Ga-DOTATATE and [18F]F-FDG in atherosclerotic (SUVmax 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUVmax 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [18F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [18F]F-FDG.
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Affiliation(s)
- Yohana C Toner
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Adam A Ghotbi
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | - Sonum Naidu
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ken Sakurai
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mandy M T van Leent
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stefan Jordan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Institute of Microbiology, Infectious Diseases and Immunology, Berlin, Germany
| | - Farideh Ordikhani
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Letizia Amadori
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- New York University Cardiovascular Research Center, Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, New York University Langone Health, New York, NY, USA
| | - Alexandros Marios Sofias
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Elizabeth L Fisher
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexander Maier
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Cardiology and Angiology I, Faculty of Medicine, Heart Center Freiburg University, University of Freiburg, Freiburg, Germany
| | - Nathaniel Sullivan
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jazz Munitz
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Max L Senders
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
| | - Christian Mason
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Thomas Reiner
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Department of Radiology and Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, Weill Cornell Medical College, New York, NY, USA
| | - Georgios Soultanidis
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jason M Tarkin
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - James H F Rudd
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Chiara Giannarelli
- Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- New York University Cardiovascular Research Center, Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, New York University Langone Health, New York, NY, USA
- Cardiovascular Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Transplant Immunology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Pérez-Medina
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | - Willem J M Mulder
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
- Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Zahi A Fayad
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Claudia Calcagno
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, PO Box: 1234, New York, NY, 10029, USA.
- Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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16
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Yields of Photo-Proton Reactions on Nuclei of Nickel and Separation of Cobalt Isotopes from Irradiated Targets. Molecules 2022; 27:molecules27051524. [PMID: 35268626 PMCID: PMC8911929 DOI: 10.3390/molecules27051524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 11/16/2022] Open
Abstract
Nowadays, cobalt isotopes 55Co, 57Co, and 58mCo are considered to be promising radionuclides in nuclear medicine, with 55Co receiving the most attention as an isotope for diagnostics by positron emission tomography. One of the current research directions is dedicated to its production using electron accelerators (via photonuclear method). In our work, the yields of nuclear reactions occurring during the irradiation of natNi and 60Ni by bremsstrahlung photons with energy up to 55 MeV were determined. A method of fast and simple cobalt isotopes separation from irradiated targets using extraction chromatography was developed.
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Hansen SB, Bender D. Advancement in production of radiotracers. Semin Nucl Med 2021; 52:266-275. [PMID: 34836618 DOI: 10.1053/j.semnuclmed.2021.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/19/2021] [Indexed: 11/11/2022]
Abstract
After introduction of the first commercial combined PET and/or CT technology in 2001, this diagnostic tool quickly became a clinical success and was considered the fastest growing diagnostic imaging technology ever. However, this technique is very dependent on the availability of positron emitting isotopes and radiochemistry to incorporate the radioactive isotopes into larger molecules of physiological interest. Within this review article a historical overview starting with the first applications of positron emitting isotopes in the 1930's is presented. Afterwards a more detailed presentation summarizing the physical basis and advancements in cyclotron technology is given. Radiochemical and/or pharmaceutical advancements are presented systematically for the most significant isotopes like 15O, 13N, 11C, 18F and 68Ga Besides these major PET isotopes, advancements of other radio-metals and future perspectives regarding application of new radionuclides will be discussed. Finally, very interesting new and compact accelerator technology and microfluidic chemical reaction approaches will be discussed. Especially, new compact accelerator technology might be new quantum leap within this radiodiagnostic technology and might result in even further prevalence, ultimately envisioned by the dose-on-demand concept that will be briefly discussed.
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Affiliation(s)
- Søren Baarsgaard Hansen
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Dirk Bender
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Liu A, Han J, Nakano A, Konno H, Moriwaki H, Abe H, Izawa K, Soloshonok VA. New pharmaceuticals approved by FDA in 2020: Small-molecule drugs derived from amino acids and related compounds. Chirality 2021; 34:86-103. [PMID: 34713503 DOI: 10.1002/chir.23376] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/09/2021] [Accepted: 09/26/2021] [Indexed: 12/24/2022]
Abstract
Amino acids (AAs) play an important role in the modern health industry as key synthetic precursors for pharmaceuticals, biomaterials, biosensors, and drug delivery systems. Currently, over 30% of small-molecule drugs contain residues of tailor-made AAs or derived from them amino-alcohols and di-amines. In this review article, we profile 12 AA-derived new pharmaceuticals approved by the FDA in 2020. These newly introduced drugs include Tazverik (epithelioid sarcoma), Gemtesa (overactive bladder), Zeposia (multiple sclerosis), Byfavo (induction and maintenance of procedural sedation), Cu 64 dotatate, and Gallium 68 PSMA-11 (both PET imaging), Rimegepant (acute migraine), Zepzelca (lung cancer), Remdesivir (COVID-19), Amisulpride (nausea and vomiting), Setmelanotide (obesity), and Lonafarnib (progeria syndrome). For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.
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Affiliation(s)
- Aiyao Liu
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, China
| | - Jianlin Han
- Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, China
| | - Arina Nakano
- Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Japan
| | - Hiroyuki Konno
- Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Japan
| | | | | | | | - Vadim A Soloshonok
- Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, San Sebastián, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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Deyev SM, Xu T, Liu Y, Schulga A, Konovalova E, Garousi J, Rinne SS, Larkina M, Ding H, Gräslund T, Orlova A, Tolmachev V, Vorobyeva A. Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1. Cancers (Basel) 2021; 13:cancers13143589. [PMID: 34298801 PMCID: PMC8304184 DOI: 10.3390/cancers13143589] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Metastasis-targeting therapy might improve outcomes in oligometastatic prostate cancer. Epithelial cell adhesion molecule (EpCAM) is overexpressed in 40–60% of prostate cancer cases and might be used as a target for specific delivery of toxins and drugs. Radionuclide molecular imaging could enable non-invasive detection of EpCAM and stratification of patients for targeted therapy. Designed ankyrin repeat proteins (DARPins) are scaffold proteins, which can be selected for specific binding to different targets. The DARPin Ec1 binds strongly to EpCAM. To determine an optimal design of Ec1-based probes, we labeled Ec1 at two different positions with four different nuclides (68Ga, 111In, 57Co and 125I) and investigated the impact on Ec1 biodistribution. We found that the C-terminus is the best position for labeling and that 111In and 125I provide the best imaging contrast. This study might be helpful for scientists developing imaging probes based on scaffold proteins. Abstract The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing [125I]I-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1.
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Affiliation(s)
- Sergey M. Deyev
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
- Bio-Nanophotonic Lab., Institute of Engineering Physics for Biomedicine (PhysBio), National Research Nuclear University “MEPhI”, 115409 Moscow, Russia
| | - Tianqi Xu
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; (T.X.); (Y.L.); (J.G.)
| | - Yongsheng Liu
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; (T.X.); (Y.L.); (J.G.)
| | - Alexey Schulga
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
| | - Elena Konovalova
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
| | - Javad Garousi
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; (T.X.); (Y.L.); (J.G.)
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 114 17 Stockholm, Sweden; (H.D.); (T.G.)
| | - Sara S. Rinne
- Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden;
| | - Maria Larkina
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Department of Pharmaceutical Analysis, Siberian State Medical University (SSMU), 2, Moscow Trakt, 634050 Tomsk, Russia
| | - Haozhong Ding
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 114 17 Stockholm, Sweden; (H.D.); (T.G.)
| | - Torbjörn Gräslund
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 114 17 Stockholm, Sweden; (H.D.); (T.G.)
| | - Anna Orlova
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden;
- Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden
| | - Vladimir Tolmachev
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; (T.X.); (Y.L.); (J.G.)
- Correspondence:
| | - Anzhelika Vorobyeva
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; (S.M.D.); (A.S.); (M.L.); (A.O.); (A.V.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; (T.X.); (Y.L.); (J.G.)
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Di Stasio GD, Buonomano P, Travaini LL, Grana CM, Mansi L. From the Magic Bullet to Theragnostics: Certitudes and Hypotheses, Trying to Optimize the Somatostatin Model. Cancers (Basel) 2021; 13:cancers13143474. [PMID: 34298688 PMCID: PMC8305798 DOI: 10.3390/cancers13143474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 01/21/2023] Open
Abstract
Simple Summary In oncology, the hypothetical “perfect magic bullet” should have a specific target on tumor cells which allows one to target only the tumor, in the absence of uptake in normal and/or non-neoplastic cells. Theragnostics is a strategy that strictly combines diagnosis and therapy, which creates the conditions for an “a priori” definition of an effective therapeutic effect. The most complete theragnostic and “magic bullet” experiences in clinical practice are those associated with radioiodine and somatostatin model. In this paper, we analyze whether it could be possible to improve present clinical results, further extending the survival of a wider number of patients, expanding the recruitment criteria to other types of pathology, and improving the quality of life. The ultimate goal is to transform the theragnostic strategy based on the somatostatin model into a curative therapy in the highest possible number of patients. Abstract The first “theragnostic model”, that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the “DOTA-Ga-68/Lu-177”, used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted.
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Affiliation(s)
| | - Pasqualina Buonomano
- Nuclear Medicine Service, Ios and Coleman Medicina Futura Medical Center, 80011 Acerra, Italy;
| | - Laura Lavinia Travaini
- Nuclear Medicine Division, European Institute of Oncology—IRCCS, 20141 Milano, Italy; (L.L.T.); (C.M.G.)
| | - Chiara Maria Grana
- Nuclear Medicine Division, European Institute of Oncology—IRCCS, 20141 Milano, Italy; (L.L.T.); (C.M.G.)
| | - Luigi Mansi
- Section Health and Development, Interuniversity Research Center for Sustainability (CIRPS), 00038 Rome, Italy
- Correspondence: ; Tel.: +39-3280024554
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Barrett KE, Houson HA, Lin W, Lapi SE, Engle JW. Production, Purification, and Applications of a Potential Theranostic Pair: Cobalt-55 and Cobalt-58m. Diagnostics (Basel) 2021; 11:diagnostics11071235. [PMID: 34359318 PMCID: PMC8306844 DOI: 10.3390/diagnostics11071235] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 11/16/2022] Open
Abstract
The emerging success of [68Ga/177Lu]Ga/Lu-DOTATATE as a theranostic pair has spurred interest in other isotopes as potential theranostic combinations. Here, we review cobalt-55 and cobalt-58m as a potential theranostic pair. Radionuclidically pure cobalt-55 and cobalt-58m have been produced on small cyclotrons with high molar activity. In vitro, DOTATOC labeled with cobalt has shown greater affinity for SSTR2 than DOTATOC labeled with gallium and yttrium. Similarly, [58mCo]Co-DOTATATE has shown improved cell-killing capabilities as compared to DOTATATE labeled with either indium-111 or lutetium-177. Finally, PET imaging with an isotope such as cobalt-55 allows for image acquisition at much later timepoints than gallium, allowing for an increased degree of biological clearance of non-bound radiotracer. We discuss the accelerator targetry and radiochemistry used to produce cobalt-55,58m, emphasizing the implications of these techniques to downstream radiotracers being developed for imaging and therapy.
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Affiliation(s)
- Kendall E. Barrett
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53711, USA; (K.E.B.); (W.L.)
| | - Hailey A. Houson
- Department of Radiology, University of Alabama at Birmingham, 619 19th Street, Birmingham, AL 35294, USA; (H.A.H.); (S.E.L.)
| | - Wilson Lin
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53711, USA; (K.E.B.); (W.L.)
| | - Suzanne E. Lapi
- Department of Radiology, University of Alabama at Birmingham, 619 19th Street, Birmingham, AL 35294, USA; (H.A.H.); (S.E.L.)
| | - Jonathan W. Engle
- Department of Medical Physics, University of Wisconsin, 1111 Highland Avenue, Madison, WI 53711, USA; (K.E.B.); (W.L.)
- Department of Radiology, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA
- Correspondence:
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Radzik M, Pijarowska-Kruszyna J, Jaroń A, Maurin M, Decristoforo C, Mikołajczak R, Garnuszek P. Development and validation of the HPLC method for quality control of radiolabelled DOTA-TATE and DOTA-TOC preparations. Nucl Med Biol 2021; 93:63-73. [PMID: 33360498 DOI: 10.1016/j.nucmedbio.2020.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/30/2020] [Accepted: 11/15/2020] [Indexed: 11/29/2022]
Abstract
INTRODUCTION The information on the presence of cold metal complexes in radiolabeled DOTA-TATE or DOTA-TOC is important in assessing the cause of the radiolabeling failure, poor radiolabeling yield and/or low effective molar activity. DOTA-peptide complexes are detectable using UV-Vis detector. The main limitation in the quantitative analysis is the limited availability of standard substances and the lack of data on their molar absorption coefficients. The aim of our study was development and validation of HPLC method enabling RCP analysis and identification and quantification of metal complexes impurities in the radiopharmaceutical preparations of DOTA-chelated peptides. METHODS Complexes of DOTA-TATE and DOTA-TOC with several metals, were prepared. Their molar absorption coefficients at 220 nm were determined. The developed HPLC method has been validated in terms of quantitative determination of non-complexed DOTA-TATE and DOTA-TOC and their respective complexes with metallic individuals. RESULTS Good chromatographic separation of the individual metal-DOTA-peptide complexes was achieved. The resolution between peaks of interest in radioactive preparations (complexes with: yttrium-90, lutetium-177, gallium-68) and metallic impurities was well above 1.5 (except gallium-68 DOTA-TOC preparations). Limits of detection and quantification were determined based on the parameters of the calibration curves. Based on the spectrophotometric and HPLC-DAD studies and statistical analysis of the results obtained, the average molar absorption coefficient was determined for studied DOTA-TATE and DOTA-TOC complexes, εHPLC-DAD = 48 × 103M-1 cm-1. With the use of the determined molar absorption coefficient the method enabled quantitative determination of non-labelled peptide in the radioactive preparation in the linearity range of 0.5-100 μg/mL for DOTA-TATE(net) and 0.5-100 μg/mL for DOTA-TOC(net). CONCLUSION The developed HPLC method is suitable for RCP determination of radiolabelled DOTA-TATE and DOTA-TOC preparations. Determination of the average molar absorption coefficient for DOTA-TATE and DOTA-TOC complexes allows assessment of the total content of the peptide in radiopharmaceutical preparation regardless of its chemical form (free ligand, associated with radionuclide, in the form of a complex with metal ions being the impurity) using the HPLC method with UV detection.
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Affiliation(s)
- Marcin Radzik
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland
| | - Justyna Pijarowska-Kruszyna
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland
| | - Antoni Jaroń
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland
| | - Michał Maurin
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland
| | - Clemens Decristoforo
- Department of Nuclear Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria
| | - Renata Mikołajczak
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland
| | - Piotr Garnuszek
- National Centre for Nuclear Research Radioisotope Centre POLATOM, 7 A. Soltana Street, 05-400 Otwock, Poland.
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Kozlovskaya V, Alford A, Dolmat M, Ducharme M, Caviedes R, Radford L, Lapi SE, Kharlampieva E. Multilayer Microcapsules with Shell-Chelated 89Zr for PET Imaging and Controlled Delivery. ACS APPLIED MATERIALS & INTERFACES 2020; 12:56792-56804. [PMID: 33306342 DOI: 10.1021/acsami.0c17456] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Radionuclide-functionalized drug delivery vehicles capable of being imaged via positron emission tomography (PET) are of increasing interest in the biomedical field as they can reveal the in vivo behavior of encapsulated therapeutics with high sensitivity. However, the majority of current PET-guided theranostic agents suffer from poor retention of radiometal over time, low drug loading capacities, and time-limited PET imaging capability. To overcome these challenges, we have developed hollow microcapsules with a thin (<100 nm) multilayer shell as advanced theranostic delivery systems for multiday PET tracking in vivo. The 3 μm capsules were fabricated via the aqueous multilayer assembly of a natural antioxidant, tannic acid (TA), and a poly(N-vinylpyrrolidone) (PVPON) copolymer containing monomer units functionalized with deferoxamine (DFO) to chelate the 89Zr radionuclide, which has a half-life of 3.3 days. We have found using radiochromatography that (TA/PVPON-DFO)6 capsules retained on average 17% more 89Zr than their (TA/PVPON)6 counterparts, which suggests that the covalent attachment of the DFO to PVPON provides stable 89Zr chelation. In vivo PET imaging studies performed in mice demonstrated that excellent stability and imaging contrast were still present 7 days postinjection. Animal biodistribution analyses showed that capsules primarily accumulated in the spleen, liver, and lungs with negligible accumulation in the femur, with the latter confirming the stable binding of the radiotracer to the capsule walls. The application of therapeutic ultrasound (US) (60 s of 20 kHz US at 120 W cm-2) to Zr-functionalized capsules could release the hydrophilic anticancer drug doxorubicin from the capsules in the therapeutic amounts. Polymeric capsules with the capability of extended in vivo PET-based tracking and US-induced drug release provide an advanced platform for development of precision-targeted therapeutic carriers and could aid in the development of more effective drug delivery systems.
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Affiliation(s)
- Veronika Kozlovskaya
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- Center for Nanomaterials and Biointegration, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Aaron Alford
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Maksim Dolmat
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Maxwell Ducharme
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Racquel Caviedes
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Lauren Radford
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Suzanne E Lapi
- Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
| | - Eugenia Kharlampieva
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
- Center for Nanomaterials and Biointegration, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
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Preclinical Evaluation of the Copper-64 Labeled GRPR-Antagonist RM26 in Comparison with the Cobalt-55 Labeled Counterpart for PET-Imaging of Prostate Cancer. Molecules 2020; 25:molecules25245993. [PMID: 33352838 PMCID: PMC7766840 DOI: 10.3390/molecules25245993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 01/21/2023] Open
Abstract
Gastrin-releasing peptide receptor (GRPR) is overexpressed in the majority of prostate cancers. This study aimed to investigate the potential of 64Cu (radionuclide for late time-point PET-imaging) for imaging of GRPR expression using NOTA-PEG2-RM26 and NODAGA-PEG2-RM26. Methods: NOTA/NODAGA-PEG2-RM26 were labeled with 64Cu and evaluated in GRPR-expressing PC-3 cells. Biodistribution of [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was studied in PC-3 xenografted mice and compared to the biodistribution of [57Co]Co-NOTA/NODAGA-PEG2-RM26 at 3 and 24 h p.i. Preclinical PET/CT imaging was performed in tumor-bearing mice. NOTA/NODAGA-PEG2-RM26 were stably labeled with 64Cu with quantitative yields. In vitro, binding of [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was rapid and GRPR-specific with slow internalization. In vivo, [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 bound specifically to GRPR-expressing tumors with fast clearance from blood and normal organs and displayed generally comparable biodistribution profiles to [57Co]Co-NOTA/NODAGA-PEG2-RM26; tumor uptake exceeded normal tissue uptake 3 h p.i.. Tumor-to-organ ratios did not increase significantly with time. [64Cu]Cu-NOTA-PEG2-RM26 had a significantly higher liver and pancreas uptake compared to other agents. 57Co-labeled radioconjugates showed overall higher tumor-to-non-tumor ratios, compared to the 64Cu-labeled counterparts. [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was able to visualize GRPR-expression in a murine PC model using PET. However, [55/57Co]Co-NOTA/NODAGA-PEG2-RM26 provided better in vivo stability and overall higher tumor-to-non-tumor ratios compared with the 64Cu-labeled conjugates.
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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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Eychenne R, Bouvry C, Bourgeois M, Loyer P, Benoist E, Lepareur N. Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy. Molecules 2020; 25:4012. [PMID: 32887456 PMCID: PMC7504749 DOI: 10.3390/molecules25174012] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/28/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.
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Affiliation(s)
- Romain Eychenne
- UPS, CNRS, SPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique)—UMR 5068, Université de Toulouse, F-31062 Toulouse, France; (R.E.); (E.B.)
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint Herblain, France;
- CNRS, CRCINA (Centre de Recherche en Cancérologie et Immunologie Nantes—Angers)—UMR 1232, ERL 6001, Inserm, Université de Nantes, F-44000 Nantes, France
| | - Christelle Bouvry
- Comprehensive Cancer Center Eugène Marquis, Rennes, F-35000, France;
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Univ Rennes, F-35000 Rennes, France
| | - Mickael Bourgeois
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint Herblain, France;
- CNRS, CRCINA (Centre de Recherche en Cancérologie et Immunologie Nantes—Angers)—UMR 1232, ERL 6001, Inserm, Université de Nantes, F-44000 Nantes, France
| | - Pascal Loyer
- INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer)—UMR_A 1341, UMR_S 1241, Inserm, Univ Rennes, F-35000 Rennes, France;
| | - Eric Benoist
- UPS, CNRS, SPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique)—UMR 5068, Université de Toulouse, F-31062 Toulouse, France; (R.E.); (E.B.)
| | - Nicolas Lepareur
- Comprehensive Cancer Center Eugène Marquis, Rennes, F-35000, France;
- INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer)—UMR_A 1341, UMR_S 1241, Inserm, Univ Rennes, F-35000 Rennes, France;
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Rinne SS, Dahlsson Leitao C, Saleh-Nihad Z, Mitran B, Tolmachev V, Ståhl S, Löfblom J, Orlova A. Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules. Int J Mol Sci 2020; 21:ijms21061972. [PMID: 32183096 PMCID: PMC7139902 DOI: 10.3390/ijms21061972] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
HER3-binding affibody molecules are a promising format for visualization of HER3 expression. Cobalt-55, a positron-emitting isotope, with a half-life of 17.5 h, allows for next-day imaging. We investigated the influence of the charge of the radiocobalt–chelator complex on the biodistribution of anti-HER3 affibody molecule (HE)3-ZHER3 and compared the best radiocobalt-labeled variant with a recently optimized gallium-labeled variant. Affibody conjugates (HE)3-ZHER3-X (X = NOTA, NODAGA, DOTA, DOTAGA) were labeled with [57Co]Co (surrogate for 55Co). Affinity measurements, binding specificity and cellular processing were studied in two HER3-expressing cancer cell lines. Biodistribution was studied 3 and 24 h post-injection (pi) in mice with HER3-expressing BxPC-3 xenografts and compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA. Micro-single-photon emission tomography/computed tomography (microSPECT/CT) and micro-positron emission tomography/computed tomography (microPET/CT) imaging was performed 3 and 24 h pi. Stably labeled conjugates bound to HER3 with subnanomolar affinity. [57Co]Co-(HE)3-ZHER3-DOTA had the best tumor retention and a significantly lower concentration in blood than other conjugates, leading to superior tumor-to-blood and tumor-to-liver ratios 24 h pi. Compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA 3 h pi, [57Co]Co-(HE)3-ZHER3-DOTA provided superior imaging contrast in liver 24 h pi. Concluding, the composition and charge of the [57Co]Co–chelator complex influenced the uptake in tumors and normal tissue. [57Co]Co-(HE)3-ZHER3-DOTA provided the best imaging properties among the cobalt-labeled conjugates. Delayed imaging of HER3 expression with [57Co]Co-(HE)3-ZHER3-DOTA improved imaging contrast compared to early-time-point imaging with [68Ga]Ga-(HE)3-ZHER3-NODAGA.
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Affiliation(s)
- Sara S Rinne
- Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
| | - Charles Dahlsson Leitao
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden
| | - Zahra Saleh-Nihad
- Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
| | - Bogdan Mitran
- Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
| | - Stefan Ståhl
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden
| | - John Löfblom
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden
| | - Anna Orlova
- Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
- Science for Life Laboratory, Uppsala University, 752 37 Uppsala, Sweden
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Radford LL, Fernandez S, Beacham R, El Sayed R, Farkas R, Benešová M, Müller C, Lapi SE. New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging. Pharmaceuticals (Basel) 2019; 12:ph12040166. [PMID: 31717279 PMCID: PMC6958329 DOI: 10.3390/ph12040166] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/02/2019] [Accepted: 11/04/2019] [Indexed: 01/23/2023] Open
Abstract
Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.
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Affiliation(s)
- Lauren L. Radford
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (L.L.R.); (S.F.); (R.B.); (R.E.S.)
| | - Solana Fernandez
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (L.L.R.); (S.F.); (R.B.); (R.E.S.)
| | - Rebecca Beacham
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (L.L.R.); (S.F.); (R.B.); (R.E.S.)
| | - Retta El Sayed
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (L.L.R.); (S.F.); (R.B.); (R.E.S.)
| | - Renata Farkas
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland; (R.F.); (M.B.); (C.M.)
| | - Martina Benešová
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland; (R.F.); (M.B.); (C.M.)
- Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Cristina Müller
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland; (R.F.); (M.B.); (C.M.)
- Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Suzanne E. Lapi
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (L.L.R.); (S.F.); (R.B.); (R.E.S.)
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35205, USA
- Correspondence:
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