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1
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Wenker STM, van Lith SAM, Tamborino G, Konijnenberg MW, Bussink J, Heskamp S. The potential of targeted radionuclide therapy to treat hypoxic tumor cells. Nucl Med Biol 2025; 140-141:108971. [PMID: 39579561 DOI: 10.1016/j.nucmedbio.2024.108971] [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: 08/21/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 11/25/2024]
Abstract
Tumor hypoxia contributes to cancer progression and therapy resistance. Several strategies have been investigated to relieve tumor hypoxia, of which some were successful. However, their clinical application remains challenging and therefore they are not used in daily clinical practice. Here, we review the potential of targeted radionuclide therapy (TRT) to eradicate hypoxic cancer cells. We present an overview of the published TRT strategies using β--particles, α-particles, and Auger electrons. Altogether, we conclude that α-particle emitting radionuclides are most promising since they can cause DNA double strand breaks independent of oxygen levels. Future directions for research are addressed, including more adequate in vitro and in vivo models to proof the potential of TRT to eliminate hypoxic cancer cells. Furthermore, dosimetry and radiobiology are identified as key to better understand the mechanism of action and dose-response relationships in hypoxic tumor areas. Finally, we can conclude that in order to achieve long-term anti-tumor efficacy, TRT combination treatment strategies may be necessary.
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Affiliation(s)
- S T M Wenker
- Department of Medical Imaging, Nuclear Medicine, Radboudumc, Nijmegen, the Netherlands; Department of Radiation Oncology, Radiotherapy & Oncoimmunology laboratory, Radboudumc, Nijmegen, the Netherlands
| | - S A M van Lith
- Department of Medical Imaging, Nuclear Medicine, Radboudumc, Nijmegen, the Netherlands
| | - G Tamborino
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - M W Konijnenberg
- Department of Medical Imaging, Nuclear Medicine, Radboudumc, Nijmegen, the Netherlands; Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - J Bussink
- Department of Radiation Oncology, Radiotherapy & Oncoimmunology laboratory, Radboudumc, Nijmegen, the Netherlands
| | - S Heskamp
- Department of Medical Imaging, Nuclear Medicine, Radboudumc, Nijmegen, the Netherlands.
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2
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Shinada M, Takahashi M, Igarashi C, Matsumoto H, Hihara F, Tachibana T, Oikawa M, Suzuki H, Zhang MR, Higashi T, Kurihara H, Yoshii Y, Doi Y. 64Cu 2+ Complexes of Tripodal Amine Ligands' In Vivo Tumor and Liver Uptakes and Intracellular Cu Distribution in the Extrahepatic Bile Duct Carcinoma Cell Line TFK-1: A Basic Comparative Study. Pharmaceuticals (Basel) 2024; 17:820. [PMID: 39065671 PMCID: PMC11280065 DOI: 10.3390/ph17070820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64Cu2+ is an anticancer radiopharmaceutical that targets the copper requirement of cancer cells. However, intravenously injected 64Cu2+ ions primarily accumulate in the liver. Ligand complexation of 64Cu2+ may be a promising method for increasing tumor delivery by reducing liver uptake. In this study, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64Cu2+ ions and compared their in vivo tumor and liver uptakes using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis of these compounds. 64Cu2+-Tren and 64Cu2+-Dien showed higher tumor uptake than 64Cu2+-TPMA and 64Cu2+ ions in TFK-1 tumors. Among the three 64Cu2+ complexes and 64Cu2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake, and nuclear delivery was the highest for 64Cu2+-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64Cu2+ complexes of tripodal amine ligands and 64Cu2+ ions. These results provide useful information for the future development of anticancer 64Cu radiopharmaceuticals.
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Affiliation(s)
- Mitsuhiro Shinada
- Faculty of Science, Toho University, Funabashi 274-8510, Japan; (M.T.); (T.T.); (Y.D.)
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Masashi Takahashi
- Faculty of Science, Toho University, Funabashi 274-8510, Japan; (M.T.); (T.T.); (Y.D.)
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Chika Igarashi
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Hiroki Matsumoto
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Fukiko Hihara
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Tomoko Tachibana
- Faculty of Science, Toho University, Funabashi 274-8510, Japan; (M.T.); (T.T.); (Y.D.)
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Masakazu Oikawa
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Hisashi Suzuki
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Ming-Rong Zhang
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Tatsuya Higashi
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
| | - Hiroaki Kurihara
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Yukie Yoshii
- Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan; (C.I.); (H.M.); (F.H.); (M.O.); (H.S.); (M.-R.Z.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Yoshihiro Doi
- Faculty of Science, Toho University, Funabashi 274-8510, Japan; (M.T.); (T.T.); (Y.D.)
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3
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Wang Y, Tang T, Yuan Y, Li N, Wang X, Guan J. Copper and Copper Complexes in Tumor Therapy. ChemMedChem 2024; 19:e202400060. [PMID: 38443744 DOI: 10.1002/cmdc.202400060] [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: 01/18/2024] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 03/07/2024]
Abstract
Copper (Cu), a crucial trace element in physiological processes, has garnered significant interest for its involvement in cancer progression and potential therapeutic applications. The regulation of cellular copper levels is essential for maintaining copper homeostasis, as imbalances can lead to toxicity and cell death. The development of drugs that target copper homeostasis has emerged as a promising strategy for anticancer treatment, with a particular focus on copper chelators, copper ionophores, and novel copper complexes. Recent research has also investigated the potential of copper complexes in cancer therapy.
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Affiliation(s)
- Yingqiao Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tingxi Tang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yi Yuan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Nan Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoqing Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Guan
- Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Hierlmeier I, Guillou A, Earley DF, Linden A, Holland JP, Bartholomä MD. HNODThia: A Promising Chelator for the Development of 64Cu Radiopharmaceuticals. Inorg Chem 2023; 62:20677-20687. [PMID: 37487036 DOI: 10.1021/acs.inorgchem.3c01616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (HNODThia and NODThia-AcNHEt). The chelator HNODThia was further derivatized to obtain a novel PSMA-based bioconjugate (NODThia-PSMA) and a bifunctional photoactivatable azamacrocyclic analogue, NODThia-PEG3-ArN3, for the development of copper-64 radiopharmaceuticals. 64Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature. The in vitro stability of NODThia-PSMA in human plasma was assessed by ligand-challenge and copper-exchange experiments. Next, we investigated the viability of the photoactivatable analog (NODThia-PEG3-ArN3) for the light-induced photoradiosynthesis of radiolabeled proteins. One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [64Cu]Cu-7-azepin-HSA and [64Cu]Cu-7-azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable 64Cu-radiopharmaceuticals by using aza-heterocyclic tacn-based chelators, and the method can easily be extended to the development of 67Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.
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Affiliation(s)
- Ina Hierlmeier
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrberger Str. 100, Building 50, 66421 Homburg, Germany
| | - Amaury Guillou
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
- University of Caen, Cyceron, Bd Henri Becquerel, 14000 Caen, France
| | - Daniel F Earley
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Anthony Linden
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Jason P Holland
- University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Mark D Bartholomä
- Department of Nuclear Medicine, Saarland University - Medical Center, Kirrberger Str. 100, Building 50, 66421 Homburg, Germany
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5
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Conforti RA, Delsouc MB, Zorychta E, Telleria CM, Casais M. Copper in Gynecological Diseases. Int J Mol Sci 2023; 24:17578. [PMID: 38139406 PMCID: PMC10743751 DOI: 10.3390/ijms242417578] [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: 11/21/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes' and Wilson's diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal.
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Affiliation(s)
- Rocío A. Conforti
- Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis (UNSL), Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL-CONICET), San Luis CP D5700HHW, Argentina; (R.A.C.); (M.B.D.)
| | - María B. Delsouc
- Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis (UNSL), Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL-CONICET), San Luis CP D5700HHW, Argentina; (R.A.C.); (M.B.D.)
| | - Edith Zorychta
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada;
| | - Carlos M. Telleria
- Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada;
- Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Marilina Casais
- Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis (UNSL), Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL-CONICET), San Luis CP D5700HHW, Argentina; (R.A.C.); (M.B.D.)
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6
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Sharma S, Pandey MK. Radiometals in Imaging and Therapy: Highlighting Two Decades of Research. Pharmaceuticals (Basel) 2023; 16:1460. [PMID: 37895931 PMCID: PMC10610335 DOI: 10.3390/ph16101460] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for imaging and radionuclide therapy, it is included in this review. In regard to radionuclide therapy, both beta-minus (β-) and alpha (α)-emitting radionuclides are discussed by highlighting their production routes, targeted radiopharmaceuticals, and current clinical translation stage.
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Affiliation(s)
| | - Mukesh K. Pandey
- Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA;
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Métivier C, Le Saëc P, Gaschet J, Chauvet C, Marionneau-Lambot S, Hofgaard PO, Bogen B, Pineau J, Le Bris N, Tripier R, Alliot C, Haddad F, Chérel M, Chouin N, Faivre-Chauvet A, Rbah-Vidal L. Preclinical Evaluation of a 64Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma. Pharmaceutics 2023; 15:1817. [PMID: 37514004 PMCID: PMC10385603 DOI: 10.3390/pharmaceutics15071817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/16/2023] [Accepted: 06/16/2023] [Indexed: 07/30/2023] Open
Abstract
Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both β+ and β- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [64Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [64Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [64Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.
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Affiliation(s)
- Cassandra Métivier
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
| | - Patricia Le Saëc
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
| | - Joëlle Gaschet
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
| | - Catherine Chauvet
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
| | | | - Peter O Hofgaard
- Department of Immunology, Oslo University Hospital, 04024 Oslo, Norway
| | - Bjarne Bogen
- Department of Immunology, Oslo University Hospital, 04024 Oslo, Norway
| | - Julie Pineau
- Univ. Brest, UMR CNRS 6521 CEMCA, 6 Avenue Victor le Gorgeu, 29200 Brest, France
| | - Nathalie Le Bris
- Univ. Brest, UMR CNRS 6521 CEMCA, 6 Avenue Victor le Gorgeu, 29200 Brest, France
| | - Raphaël Tripier
- Univ. Brest, UMR CNRS 6521 CEMCA, 6 Avenue Victor le Gorgeu, 29200 Brest, France
| | - Cyrille Alliot
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
- GIP ARRONAX, 44800 Saint-Herblain, France
| | - Férid Haddad
- IMT Atlantique, Nantes Université, Subatech, 44307 Nantes, France
- GIP ARRONAX, 44800 Saint-Herblain, France
| | - Michel Chérel
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
- Nuclear Medicine Department, ICO-René Gauducheau Cancer Center, 44800 Saint-Herblain, France
| | - Nicolas Chouin
- Nantes Université, Inserm, CNRS, Université d'Angers, Oniris, CRCI2NA, 44007 Nantes, France
| | - Alain Faivre-Chauvet
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, CHU Nantes, 44007 Nantes, France
| | - Latifa Rbah-Vidal
- Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, 44007 Nantes, France
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8
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Guan D, Zhao L, Shi X, Ma X, Chen Z. Copper in cancer: From pathogenesis to therapy. Biomed Pharmacother 2023; 163:114791. [PMID: 37105071 DOI: 10.1016/j.biopha.2023.114791] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/12/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023] Open
Abstract
One of the basic trace elements for the structure and metabolism of human tissue is copper. However, as a heavy metal, excessive intake or abnormal accumulation of copper in the body can cause inevitable damage to the organism because copper can result in direct injury to various cell components or disruption of the redox balance, eventually leading to cell death. Interestingly, a growing body of research reports that diverse cancers have raised serum and tumor copper levels. Tumor cells depend on more copper for their metabolism than normal cells, and a decrease in copper or copper overload can have a detrimental effect on tumor cells. New modalities for identifying and characterizing copper-dependent signals offer translational opportunities for tumor therapy, but their mechanisms remain unclear. Therefore, this article summarizes what we currently know about the correlation between copper and cancer and describes the characteristics of copper metabolism in tumor cells and the prospective application of copper-derived therapeutics.
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Affiliation(s)
- Defeng Guan
- The First Clinical Medical School of Lanzhou University, Lanzhou, China; The First Hospital of Lanzhou University, Lanzhou, China; Gansu key Laboratory of Reproductive Medicine and Embryology, Lanzhou, China
| | - Lihui Zhao
- The First Clinical Medical School of Lanzhou University, Lanzhou, China; The First Hospital of Lanzhou University, Lanzhou, China; Gansu key Laboratory of Reproductive Medicine and Embryology, Lanzhou, China
| | - Xin Shi
- The First Clinical Medical School of Lanzhou University, Lanzhou, China; The First Hospital of Lanzhou University, Lanzhou, China; Gansu key Laboratory of Reproductive Medicine and Embryology, Lanzhou, China
| | - Xiaoling Ma
- The First Clinical Medical School of Lanzhou University, Lanzhou, China; The First Hospital of Lanzhou University, Lanzhou, China; Gansu key Laboratory of Reproductive Medicine and Embryology, Lanzhou, China.
| | - Zhou Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, China; The First Hospital of Lanzhou University, Lanzhou, China.
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9
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Benfante V, Stefano A, Ali M, Laudicella R, Arancio W, Cucchiara A, Caruso F, Cammarata FP, Coronnello C, Russo G, Miele M, Vieni A, Tuttolomondo A, Yezzi A, Comelli A. An Overview of In Vitro Assays of 64Cu-, 68Ga-, 125I-, and 99mTc-Labelled Radiopharmaceuticals Using Radiometric Counters in the Era of Radiotheranostics. Diagnostics (Basel) 2023; 13:diagnostics13071210. [PMID: 37046428 PMCID: PMC10093267 DOI: 10.3390/diagnostics13071210] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/11/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023] Open
Abstract
Radionuclides are unstable isotopes that mainly emit alpha (α), beta (β) or gamma (γ) radiation through radiation decay. Therefore, they are used in the biomedical field to label biomolecules or drugs for diagnostic imaging applications, such as positron emission tomography (PET) and/or single-photon emission computed tomography (SPECT). A growing field of research is the development of new radiopharmaceuticals for use in cancer treatments. Preclinical studies are the gold standard for translational research. Specifically, in vitro radiopharmaceutical studies are based on the use of radiopharmaceuticals directly on cells. To date, radiometric β- and γ-counters are the only tools able to assess a preclinical in vitro assay with the aim of estimating uptake, retention, and release parameters, including time- and dose-dependent cytotoxicity and kinetic parameters. This review has been designed for researchers, such as biologists and biotechnologists, who would like to approach the radiobiology field and conduct in vitro assays for cellular radioactivity evaluations using radiometric counters. To demonstrate the importance of in vitro radiopharmaceutical assays using radiometric counters with a view to radiogenomics, many studies based on 64Cu-, 68Ga-, 125I-, and 99mTc-labeled radiopharmaceuticals have been revised and summarized in this manuscript.
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Affiliation(s)
- Viviana Benfante
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Alessandro Stefano
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Muhammad Ali
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
| | | | - Walter Arancio
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
| | - Antonino Cucchiara
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Fabio Caruso
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Francesco Paolo Cammarata
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
| | - Claudia Coronnello
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
| | - Giorgio Russo
- Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), 90015 Cefalù, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
| | - Monica Miele
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
| | - Alessandra Vieni
- Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), Via Tricomi 5, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Molecular and Clinical Medicine, University of Palermo, 90127 Palermo, Italy
| | - Anthony Yezzi
- Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Albert Comelli
- Ri.MED Foundation, Via Bandiera 11, 90133 Palermo, Italy
- National Biodiversity Future Center (NBFC), 90133 Palermo, Italy
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10
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Gouel P, Decazes P, Vera P, Gardin I, Thureau S, Bohn P. Advances in PET and MRI imaging of tumor hypoxia. Front Med (Lausanne) 2023; 10:1055062. [PMID: 36844199 PMCID: PMC9947663 DOI: 10.3389/fmed.2023.1055062] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tumor hypoxia is a complex and evolving phenomenon both in time and space. Molecular imaging allows to approach these variations, but the tracers used have their own limitations. PET imaging has the disadvantage of low resolution and must take into account molecular biodistribution, but has the advantage of high targeting accuracy. The relationship between the signal in MRI imaging and oxygen is complex but hopefully it would lead to the detection of truly oxygen-depleted tissue. Different ways of imaging hypoxia are discussed in this review, with nuclear medicine tracers such as [18F]-FMISO, [18F]-FAZA, or [64Cu]-ATSM but also with MRI techniques such as perfusion imaging, diffusion MRI or oxygen-enhanced MRI. Hypoxia is a pejorative factor regarding aggressiveness, tumor dissemination and resistance to treatments. Therefore, having accurate tools is particularly important.
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Affiliation(s)
- Pierrick Gouel
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Pierre Decazes
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Pierre Vera
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Isabelle Gardin
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France
| | - Sébastien Thureau
- QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France,Département de Radiothérapie, Centre Henri Becquerel, Rouen, France
| | - Pierre Bohn
- Département d’Imagerie, Centre Henri Becquerel, Rouen, France,QuantIF-LITIS, EA 4108, IRIB, Université de Rouen, Rouen, France,*Correspondence: Pierre Bohn,
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11
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Milot MC, Bélissant-Benesty O, Dumulon-Perreault V, Ait-Mohand S, Geha S, Richard PO, Rousseau É, Guérin B. Theranostic 64Cu-DOTHA 2-PSMA allows low toxicity radioligand therapy in mice prostate cancer model. Front Oncol 2023; 13:1073491. [PMID: 36741017 PMCID: PMC9889868 DOI: 10.3389/fonc.2023.1073491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Introduction We have previously shown that copper-64 (64Cu)-DOTHA2-PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of 64Cu-DOTHA2-PSMA, the objective of the current study was to evaluate the therapeutic potential of 64Cu-DOTHA2-PSMA in vivo. Methods LNCaP tumor-bearing NOD-Rag1nullIL2rgnull (NRG) mice were treated with an intraveinous single-dose of 64Cu-DOTHA2-PSMA at maximal tolerated injected activity, natCu-DOTHA2-PSMA at equimolar amount (control) or lutetium-177 (177Lu)-PSMA-617 at 120 MBq to assess their impact on survival. Weight, well-being and tumor size were followed until mice reached 62 days post-injection or ethical limits. Toxicity was assessed through weight, red blood cells (RBCs) counts, pathology and dosimetry calculations. Results Survival was longer with 64Cu-DOTHA2-PSMA than with natCu-DOTHA2-PSMA (p < 0.001). Likewise, survival was also longer when compared to 177Lu-PSMA-617, although it did not reach statistical significance (p = 0.09). RBCs counts remained within normal range for the 64Cu-DOTHA2-PSMA group. 64Cu-DOTHA2-PSMA treated mice showed non-pathological fibrosis and no other signs of radiation injury. Human extrapolation of dosimetry yielded an effective dose of 3.14 × 10-2 mSv/MBq, with highest organs doses to gastrointestinal tract and liver. Discussion Collectively, our data showed that 64Cu-DOTHA2-PSMA-directed radioligand therapy was effective for the treatment of LNCaP tumor-bearing NRG mice with acceptable toxicity and dosimetry. The main potential challenge is the hepatic and gastrointestinal irradiation.
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Affiliation(s)
- Marie-Christine Milot
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Ophélie Bélissant-Benesty
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | | | - Samia Ait-Mohand
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sameh Geha
- Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Patrick O. Richard
- Department of Surgery, Division of urology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Étienne Rousseau
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada,Sherbrooke Molecular Imaging Center (CIMS), Centre de recherche du CHUS, Sherbrooke, QC, Canada
| | - Brigitte Guérin
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada,Sherbrooke Molecular Imaging Center (CIMS), Centre de recherche du CHUS, Sherbrooke, QC, Canada,*Correspondence: Brigitte Guérin,
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12
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Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther 2022; 7:378. [PMID: 36414625 PMCID: PMC9681860 DOI: 10.1038/s41392-022-01229-y] [Citation(s) in RCA: 595] [Impact Index Per Article: 198.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/19/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022] Open
Abstract
As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson's disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.
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Affiliation(s)
- Liyun Chen
- grid.13402.340000 0004 1759 700XThe Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China ,grid.412017.10000 0001 0266 8918The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Junxia Min
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. .,The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
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13
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Chhabra A, Thakur ML. Theragnostic Radionuclide Pairs for Prostate Cancer Management: 64Cu/ 67Cu, Can Be a Budding Hot Duo. Biomedicines 2022; 10:2787. [PMID: 36359312 PMCID: PMC9687163 DOI: 10.3390/biomedicines10112787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/26/2022] [Accepted: 10/30/2022] [Indexed: 08/26/2023] Open
Abstract
Prostate cancer (PCa) is one of the preeminent causes of mortality in men worldwide. Theragnostic, a combination of therapy and diagnostic, using radionuclide pairs to diagnose and treat disease, has been shown to be a promising approach for combating PCa. In PCa patients, bone is one of the most common sites of metastases, and about 90% of patients develop bone metastases. This review focuses on (i) clinically translated theragnostic radionuclide pairs for the management of PCa, (ii) radionuclide therapy of bone metastases in PCa, and (iii) a special emphasis on emerging theragnostic radionuclide pair, Copper-64/Copper-67 (64Cu/67Cu) for managing the disease.
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Affiliation(s)
- Anupriya Chhabra
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Mathew L. Thakur
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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14
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Wen X, Zeng X, Liu J, Zhang Y, Shi C, Wu X, Zhuang R, Chen X, Zhang X, Guo Z. Synergism of 64Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect. Bioconjug Chem 2022; 33:2170-2179. [PMID: 36256849 DOI: 10.1021/acs.bioconjchem.2c00408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We put forward a novel targeting-triggering-therapy (TTT) scheme that combines 64Cu-based targeted radionuclide therapy (TRT) with programmed death-ligand 1 (PD-L1)-based immunotherapy for enhancing therapeutic efficacy. The αvβ3 integrin-targeted 64Cu-DOTA-EB-cRGDfK (64Cu-DER) was synthesized. Flow cytometry, immunofluorescence staining, and RT-qPCR were performed to verify PD-L1 upregulation after irradiation with 64Cu-DER. Positron emission tomography imaging was performed to investigate the prominent tumor retention property of 64Cu-DER. In the MC38 tumor model, anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner after 64Cu-DER was injected, followed by the testing of changes in tumor microenvironment (TME). PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 64Cu-DER. The combination of 64Cu-DER TRT (925 MBq/kg) and αPD-L1 mAb (10 mg/kg) resulted in significant delay in tumor growth and protected against tumor rechallenge. Blockade of PD-L1 at 4 h after 64Cu-DER TRT (64Cu-DER + αPD-L1 mAb @ 4 h combination group) was able to achieve 100% survival rate, prevent tumor relapse, and evidently prolong the survival of mice. In summary, the combination of 64Cu-DER and αPD-L1 mAb in a time-dependent manner could be a promising approach to improve therapeutic efficacy. Understandably, this strategy has the potential to extend the scope of 64Cu-based TTT and merits translation into clinical practice for the better management of immune checkpoint blockade immunotherapy.
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Affiliation(s)
- Xuejun Wen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Xinying Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Jia Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Yiren Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Changrong Shi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Xiaoming Wu
- Yantai Dongcheng Biochemicals Co., Ltd., Yantai 264006, China
| | - Rongqiang Zhuang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology and Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.,Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.,Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.,Departments of Chemical and Biomolecular Engineering, and Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore 119074, Singapore
| | - Xianzhong Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
| | - Zhide Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China
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15
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Xie F, Wei W. [ 64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation. Eur J Nucl Med Mol Imaging 2022; 49:3964-3972. [PMID: 35918492 DOI: 10.1007/s00259-022-05887-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Fang Xie
- PET Center, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, 200127, China.
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16
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Hihara F, Matsumoto H, Yoshimoto M, Masuko T, Endo Y, Igarashi C, Tachibana T, Shinada M, Zhang MR, Kurosawa G, Sugyo A, Tsuji AB, Higashi T, Kurihara H, Ueno M, Yoshii Y. In Vitro Tumor Cell-Binding Assay to Select High-Binding Antibody and Predict Therapy Response for Personalized 64Cu-Intraperitoneal Radioimmunotherapy against Peritoneal Dissemination of Pancreatic Cancer: A Feasibility Study. Int J Mol Sci 2022; 23:5807. [PMID: 35628616 PMCID: PMC9146758 DOI: 10.3390/ijms23105807] [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: 04/20/2022] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 02/01/2023] Open
Abstract
Peritoneal dissemination of pancreatic cancer has a poor prognosis. We have reported that intraperitoneal radioimmunotherapy using a 64Cu-labeled antibody (64Cu-ipRIT) is a promising adjuvant therapy option to prevent this complication. To achieve personalized 64Cu-ipRIT, we developed a new in vitro tumor cell-binding assay (64Cu-TuBA) system with a panel containing nine candidate 64Cu-labeled antibodies targeting seven antigens (EGFR, HER2, HER3, TfR, EpCAM, LAT1, and CD98), which are reportedly overexpressed in patients with pancreatic cancer. We investigated the feasibility of 64Cu-TuBA to select the highest-binding antibody for individual cancer cell lines and predict the treatment response in vivo for 64Cu-ipRIT. 64Cu-TuBA was performed using six human pancreatic cancer cell lines. For three cell lines, an in vivo treatment study was performed with 64Cu-ipRIT using high-, middle-, or low-binding antibodies in each peritoneal dissemination mouse model. The high-binding antibodies significantly prolonged survival in each mouse model, while low-and middle-binding antibodies were ineffective. There was a correlation between in vitro cell binding and in vivo therapeutic efficacy. Our findings suggest that 64Cu-TuBA can be used for patient selection to enable personalized 64Cu-ipRIT. Tumor cells isolated from surgically resected tumor tissues would be suitable for analysis with the 64Cu-TuBA system in future clinical studies.
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Affiliation(s)
- Fukiko Hihara
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Hiroki Matsumoto
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Mitsuyoshi Yoshimoto
- Division of Functional Imaging, National Cancer Center Hospital East, Chiba 277-8577, Japan;
| | - Takashi Masuko
- School of Pharmacy, Kindai University, Osaka 577-8502, Japan; (T.M.); (Y.E.)
| | - Yuichi Endo
- School of Pharmacy, Kindai University, Osaka 577-8502, Japan; (T.M.); (Y.E.)
| | - Chika Igarashi
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Tomoko Tachibana
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Mitsuhiro Shinada
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
- Faculty of Science, Toho University, Chiba 274-8510, Japan
| | - Ming-Rong Zhang
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Gene Kurosawa
- International Center for Cell and Gene Therapy, Fujita Health University, Aichi 470-1192, Japan;
| | - Aya Sugyo
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Atsushi B. Tsuji
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
| | - Hiroaki Kurihara
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
| | - Yukie Yoshii
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan;
(F.H.); (H.M.); (C.I.); (T.T.); (M.S.); (M.-R.Z.); (A.S.); (A.B.T.); (T.H.)
- Department of Diagnostic Radiology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan;
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17
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Parrilha GL, dos Santos RG, Beraldo H. Applications of radiocomplexes with thiosemicarbazones and bis(thiosemicarbazones) in diagnostic and therapeutic nuclear medicine. Coord Chem Rev 2022. [DOI: 10.1016/j.ccr.2022.214418] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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18
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Roy I, Krishnan S, Kabashin AV, Zavestovskaya IN, Prasad PN. Transforming Nuclear Medicine with Nanoradiopharmaceuticals. ACS NANO 2022; 16:5036-5061. [PMID: 35294165 DOI: 10.1021/acsnano.1c10550] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Nuclear medicine is expected to make major advances in cancer diagnosis and therapy; tumor-targeted radiopharmaceuticals preferentially eradicate tumors while causing minimal damage to healthy tissues. The current scope of nuclear medicine can be significantly expanded by integration with nanomedicine, which utilizes nanoparticles for cancer diagnosis and therapy by capitalizing on the increased surface area-to-volume ratio, the passive/active targeting ability and high loading capacity, the greater interaction cross section with biological tissues, the rich surface properties of nanomaterials, the facile decoration of nanomaterials with a plethora of functionalities, and the potential for multiplexing several functionalities within one construct. This review provides a comprehensive discussion of nuclear nanomedicine using tumor-targeted nanoparticles for cancer radiation therapy with either pre-embedded radionuclides or nonradioactive materials which can be extrinsically triggered using various external nuclear particle sources to produce in situ radioactivity. In addition, it describes the prospect of combining nuclear nanomedicine with other modalities to enable synergistically enhanced combination therapies. The review also discusses advances in the fabrication of radionuclides as well as describes laser ablation technologies for producing nanoradiopharmaceuticals, which combine the ease of production with exceptional purity and rapid biodegradability, along with additional imaging or therapeutic functionalities. From a practical standpoint, these attributes of nanoradiopharmaceuticals may provide distinct advantages in diagnostic/therapeutic sensitivity and specificity, imaging resolution, and scalability of turnkey platforms. Coupling image-guided targeted radiation therapy with the possibility of in situ activation of nanomaterials as well as combining with other therapeutic modalities using a multifunctional nanoplatform could herald an era of exciting technological and therapeutic advances to radically transform the landscape of nuclear medicine. The review concludes with a discussion of current challenges and presents the authors' views on future opportunities to stimulate further research in this rewarding field of high societal impact.
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Affiliation(s)
- Indrajit Roy
- Department of Chemistry, University of Delhi, Delhi 110007, India
| | - Sunil Krishnan
- Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, Florida 32224, United States
| | - Andrei V Kabashin
- Aix Marseille University, CNRS, LP3, Campus de Luminy - Case 917, 13288 Marseille, France
- MEPhI, Institute of Engineering Physics for Biomedicine (PhysBio), 115409 Moscow, Russia
| | - Irina N Zavestovskaya
- MEPhI, Institute of Engineering Physics for Biomedicine (PhysBio), 115409 Moscow, Russia
- Nuclear Physics and Astrophysics Department, LPI of RAS, 119991 Moscow, Russia
| | - Paras N Prasad
- MEPhI, Institute of Engineering Physics for Biomedicine (PhysBio), 115409 Moscow, Russia
- Department of Chemistry and Institute for Lasers, Photonics, and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
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19
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Benešová M, Reischl G. Production of radionuclides: Cyclotrons and reactors. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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20
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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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21
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Igarashi C, Yoshii Y, Tashima H, Iwao Y, Sakurai K, Hihara F, Tachibana T, Yoshida E, Wakizaka H, Akamatsu G, Yamaya T, Yoshimoto M, Matsumoto H, Zhang MR, Nagatsu K, Sugyo A, Tsuji AB, Higashi T. Usefulness of PET-guided surgery with 64Cu-labeled cetuximab for resection of intrapancreatic residual tumors in a xenograft mouse model of resectable pancreatic cancer. Nucl Med Commun 2021; 42:1112-1121. [PMID: 34100794 DOI: 10.1097/mnm.0000000000001442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND In pancreatic cancer surgery, accurate identification and resection of intrapancreatic residual tumors are quite difficult. We have developed a novel open-typed PET system (called 'OpenPET'), which enables high-resolution PET-guided surgery in real time, and demonstrated that OpenPET-guided surgery with intraperitoneally administered 64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab is useful to detect and resect primary pancreatic cancer. Here, we investigated applicability of OpenPET-guided surgery for unexpected residual intrapancreatic tumors and examined its survival benefit over conventional surgery. METHODS A mouse model with large (>1 cm) resectable pancreatic cancer of xPA-1-DC cells expressing red fluorescent protein was used. OpenPET-guided surgery was conducted 24 h after intraperitoneal administration of 64Cu-labeled cetuximab (7.4 MBq/mouse). For comparison, similar surgical procedures were conducted, and conventional tumor resection was attempted using only the naked eye (control). Survival rate after OpenPET-guided surgery was compared to that after control operations. RESULTS Intraoperative OpenPET guidance enabled detection and resection of small residual tumors. Ten residual tumor specimens (3-10 mm in diameter) were intraoperatively isolated with OpenPET guidance (n = 7 mice). All isolated specimens showed tumor RFP signals. No resection of tumor tissue was performed in control group because the tumor could not be clearly detected with the naked eye alone. Mice after OpenPET-guided surgery showed significantly longer survival rates than those in control group. CONCLUSIONS OpenPET-guided surgery with 64Cu-labeled-cetuximab enabled intraoperative identification and resection of intrapancreatic small residual tumors. This technology could be useful to prevent tumor residuals during surgery and improve pancreatic cancer survival.
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Affiliation(s)
| | - Yukie Yoshii
- Department of Molecular Imaging and Theranostics
| | - Hideaki Tashima
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Yuma Iwao
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | | | | | | | - Eiji Yoshida
- Department of Molecular Imaging and Theranostics
| | - Hidekatsu Wakizaka
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Go Akamatsu
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Taiga Yamaya
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Mitsuyoshi Yoshimoto
- Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | | | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Kotaro Nagatsu
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba
| | - Aya Sugyo
- Department of Molecular Imaging and Theranostics
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22
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Huang Y, Fan J, Li Y, Fu S, Chen Y, Wu J. Imaging of Tumor Hypoxia With Radionuclide-Labeled Tracers for PET. Front Oncol 2021; 11:731503. [PMID: 34557414 PMCID: PMC8454408 DOI: 10.3389/fonc.2021.731503] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/19/2021] [Indexed: 01/27/2023] Open
Abstract
The hypoxic state in a solid tumor refers to the internal hypoxic environment that appears as the tumor volume increases (the maximum radius exceeds 180-200 microns). This state can promote angiogenesis, destroy the balance of the cell’s internal environment, and lead to resistance to radiotherapy and chemotherapy, as well as poor prognostic factors such as metastasis and recurrence. Therefore, accurate quantification, mapping, and monitoring of hypoxia, targeted therapy, and improvement of tumor hypoxia are of great significance for tumor treatment and improving patient survival. Despite many years of development, PET-based hypoxia imaging is still the most widely used evaluation method. This article provides a comprehensive overview of tumor hypoxia imaging using radionuclide-labeled PET tracers. We introduced the mechanism of tumor hypoxia and the reasons leading to the poor prognosis, and more comprehensively included the past, recent and ongoing studies of PET radiotracers for tumor hypoxia imaging. At the same time, the advantages and disadvantages of mainstream methods for detecting tumor hypoxia are summarized.
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Affiliation(s)
- Yuan Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Junying Fan
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shaozhi Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China
| | - Yue Chen
- Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China.,Nuclear Medicine and Molecular Imaging key Laboratory of Sichuan Province, Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Academician (Expert) Workstation of Sichuan Province, Luzhou, China
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23
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Lavanya M, Haribabu J, Ramaiah K, Suresh Yadav C, Kumar Chitumalla R, Jang J, Karvembu R, Varada Reddy A, Jagadeesh M. 2′-Thiophenecarboxaldehyde derived thiosemicarbazone metal complexes of copper(II), palladium(II) and zinc(II) ions: Synthesis, spectroscopic characterization, anticancer activity and DNA binding studies. Inorganica Chim Acta 2021. [DOI: 10.1016/j.ica.2021.120440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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24
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Herrero Álvarez N, Bauer D, Hernández-Gil J, Lewis JS. Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer. ChemMedChem 2021; 16:2909-2941. [PMID: 33792195 DOI: 10.1002/cmdc.202100135] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Indexed: 12/14/2022]
Abstract
Nuclear medicine is defined as the use of radionuclides for diagnostic and therapeutic applications. The imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on γ-emissions of specific energies. The therapeutic technologies are based on β- -particle-, α-particle-, and Auger electron emitters. In oncology, PET and SPECT are used to detect cancer lesions, to determine dosimetry, and to monitor therapy effectiveness. In contrast, radiotherapy is designed to irreparably damage tumor cells in order to eradicate or control the disease's progression. Radiometals are being explored for the development of diagnostic and therapeutic radiopharmaceuticals. Strategies that combine both modalities (diagnostic and therapeutic), referred to as theranostics, are promising candidates for clinical applications. This review provides an overview of the basic concepts behind therapeutic and diagnostic radiopharmaceuticals and their significance in contemporary oncology. Select radiometals that significantly impact current and upcoming cancer treatment strategies are grouped as clinically suitable theranostics pairs. The most important physical and chemical properties are discussed. Standard production methods and current radionuclide availability are provided to indicate whether a cost-efficient use in a clinical routine is feasible. Recent preclinical and clinical developments and outline perspectives for the radiometals are highlighted in each section.
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Affiliation(s)
- Natalia Herrero Álvarez
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - David Bauer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Javier Hernández-Gil
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.,Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Katholieke Universiteit, Herestraat 49, 3000, Leuven, Belgium
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.,Department of Radiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.,Department of Pharmacology, Weill-Cornell Medical College, New York, NY, 10065, USA
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25
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PET Radiochemistry. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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26
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Cheng MHY, Mo Y, Zheng G. Nano versus Molecular: Optical Imaging Approaches to Detect and Monitor Tumor Hypoxia. Adv Healthc Mater 2021; 10:e2001549. [PMID: 33241672 DOI: 10.1002/adhm.202001549] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/21/2020] [Indexed: 12/18/2022]
Abstract
Hypoxia is a ubiquitous feature of solid tumors, which plays a key role in tumor angiogenesis and resistance development. Conventional hypoxia detection methods lack continuous functional detection and are generally less suitable for dynamic hypoxia measurement. Optical sensors hereby provide a unique opportunity to noninvasively image hypoxia with high spatiotemporal resolution and enable real-time detection. Therefore, these approaches can provide a valuable tool for personalized treatment planning against this hallmark of aggressive cancers. Many small optical molecular probes can enable analyte triggered response and their photophysical properties can also be fine-tuned through structural modification. On the other hand, optical nanoprobes can acquire unique intrinsic optical properties through nanoconfinement as well as enable simultaneous multimodal imaging and drug delivery. Furthermore, nanoprobes provide biological advantages such as improving bioavailability and systemic delivery of the sensor to enhance bioavailability. This review provides a comprehensive overview of the physical, chemical, and biological analytes for cancer hypoxia detection and focuses on discussing the latest nano- and molecular developments in various optical imaging approaches (fluorescence, phosphorescence, and photoacoustic) in vivo. Finally, this review concludes with a perspective toward the potentials of these optical imaging approaches in hypoxia detection and the challenges with molecular and nanotechnology design strategies.
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Affiliation(s)
- Miffy Hok Yan Cheng
- Princess Margaret Cancer Centre University Health Network 101 College Street, PMCRT 5–354 Toronto Ontario M5G 1L7 Canada
| | - Yulin Mo
- Princess Margaret Cancer Centre University Health Network 101 College Street, PMCRT 5–354 Toronto Ontario M5G 1L7 Canada
- Institute of Medical Science University of Toronto 101 College Street Toronto Ontario M5G 1L7 Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre University Health Network 101 College Street, PMCRT 5–354 Toronto Ontario M5G 1L7 Canada
- Institute of Medical Science University of Toronto 101 College Street Toronto Ontario M5G 1L7 Canada
- Department of Medical Biophysics University of Toronto 101 College Street Toronto Ontario M5G 1L7 Canada
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27
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Lelièvre P, Sancey L, Coll JL, Deniaud A, Busser B. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers (Basel) 2020; 12:E3594. [PMID: 33271772 PMCID: PMC7760327 DOI: 10.3390/cancers12123594] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open
Abstract
In the human body, copper (Cu) is a major and essential player in a large number of cellular mechanisms and signaling pathways. The involvement of Cu in oxidation-reduction reactions requires close regulation of copper metabolism in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concentrations of intratumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness or may even confer resistance to treatments. Once characterized, the dysregulated Cu metabolism is pinpointing several promising biomarkers for clinical use with prognostic or predictive capabilities. The altered Cu metabolism in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete, or increase Cu levels in tumors. The metallic nature of Cu as a chemical element is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclinical setting, and others are already in the clinic.
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Affiliation(s)
- Pierre Lelièvre
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Lucie Sancey
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Jean-Luc Coll
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
| | - Aurélien Deniaud
- Univ. Grenoble Alpes, CNRS, CEA, IRIG, Laboratoire de Chimie et Biologie des Métaux, 38000 Grenoble, France
| | - Benoit Busser
- Institute for Advanced Biosciences, UGA INSERM U1209 CNRS UMR5309, 38700 La Tronche, France; (P.L.); (L.S.); (J.-L.C.)
- Department of Clinical Biochemistry, Grenoble Alpes University Hospital, 38043 Grenoble, France
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28
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Svedjehed J, Kutyreff CJ, Engle JW, Gagnon K. Automated, cassette-based isolation and formulation of high-purity [ 61Cu]CuCl 2 from solid Ni targets. EJNMMI Radiopharm Chem 2020; 5:21. [PMID: 33151400 PMCID: PMC7644601 DOI: 10.1186/s41181-020-00108-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/19/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND A need for improved, cassette-based automation of 61Cu separation from irradiated Ni targets was identified given the growing interest in theranostics, and generally lengthy separation chemistries for 64Cu/64Ni, upon which 61Cu chemistry is often based. METHODS A method for separating 61Cu from irradiated natNi targets was therefore developed, with provision for target recycling. Following deuteron irradiation, electroplated natNi targets were remotely transferred from the cyclotron and dissolved in acid. The dissolved target solution was then transferred to an automated FASTlab chemistry module, where sequential TBP and TK201 (Triskem) resins isolated the [61Cu]CuCl2, removed Ni, Co, and Fe, and concentrated the product into a formulation suitable for anticipated radiolabelling reactions. RESULTS 61Cu saturation yields of 190 ± 33 MBq/μA from energetically thick natNi targets were measured. The average, decay-corrected, activity-based dissolution efficiency was 97.5 ± 1.4% with an average radiochemical yield of 90.4 ± 3.2% (N = 5). The isolated activity was collected approximately 65 min post end of bombardment in ~ 2 mL of 0.06 M HCl (HCl concentration was verified by titration). Quality control of the isolated [61Cu]CuCl2 (N = 5) measured 58Co content of (8.3 ± 0.6) × 10- 5% vs. 61Cu by activity, Ni separation factors ≥ (2.2 ± 1.8) × 106, EoB molar activities 85 ± 23 GBq/μmol and NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for the 30 min and 3.3 h (N = 1) irradiations, respectively. CONCLUSION High purity 61Cu was produced with the developed automated method using a single-use, cassette-based approach. It was also applicable for 64Cu, as demonstrated with a single proof-of-concept 64Ni target production run.
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Affiliation(s)
- Johan Svedjehed
- Cyclotrons and TRACERcenter, GE Healthcare, GEMS PET Systems AB, Uppsala, Sweden
| | - Christopher J Kutyreff
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Jonathan W Engle
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.,Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Katherine Gagnon
- Cyclotrons and TRACERcenter, GE Healthcare, GEMS PET Systems AB, Uppsala, Sweden.
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29
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Pasquali M, Martini P, Shahi A, Jalilian AR, Osso JA, Boschi A. Copper-64 based radiopharmaceuticals for brain tumors and hypoxia imaging. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF RADIOPHARMACEUTICAL CHEMISTRY AND BIOLOGY 2020; 64:371-381. [PMID: 33026209 DOI: 10.23736/s1824-4785.20.03285-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The most common and aggressive primary malignancy of the central nervous system is Glioblastoma that, as a wide range of malignant solid tumor, is characterized by extensive hypoxic regions. A great number of PET radiopharmaceuticals have been developed for the identification of hypoxia in solid tumors, among these, we find copper-based tracers. The aim of the current review paper was to provide an overview of radiocopper compounds applied for preclinical and clinical research in brain tumors and hypoxia imaging or therapy. EVIDENCE ACQUISITION Copper offers a wide variety of isotopes, useful for nuclear medicine applications, but only 64Cu and 67Cu are under the spotlight of the scientific community since being good candidates for theranostic applications. Between the two, 64Cu availability and production cost have attracted more interest of the scientific community. EVIDENCE SYNTHESIS In order to better understand the application of copper-bis thiosemicarbazones in hypoxia imaging, an overview of the role of hypoxia in cancer, existing non-imaging and imaging techniques for hypoxia identification and promising future avenues regarding hypoxia is necessary. Different proposed uptake mechanisms of [64Cu][Cu(ATSM)] inside the cell will be discussed and other 64Cu-based tracers for brain tumors described. CONCLUSIONS Among radio copper compounds [64Cu][Cu(ATSM)] is the most studied radiopharmaceutical for imaging and treatment of brain tumors. Experimental evidence suggested that [64Cu][Cu(ATSM)] could be more appropriately considered as a marker of over-reduced intracellular state rather than a pure hypoxia agent. Moreover, preliminary clinical data suggested that [64Cu]CuCl<inf>2</inf> can be a potentially useful diagnostic agent for malignancies of the central nervous system (CNS).
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Affiliation(s)
- Micol Pasquali
- National Institute of Nuclear Physics, National Laboratories of Legnaro, Padua, Italy
| | - Petra Martini
- National Institute of Nuclear Physics, National Laboratories of Legnaro, Padua, Italy.,Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Arman Shahi
- Faculty of Science, McMaster University, Hamilton, Canada
| | - Amir R Jalilian
- Department of Nuclear Science and Applications, International Atomic Energy Agency (IAEA), Vienna, Austria
| | - Joao A Osso
- Department of Nuclear Science and Applications, International Atomic Energy Agency (IAEA), Vienna, Austria
| | - Alessandra Boschi
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy -
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30
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Singh NK, Kumbhar AA, Pokharel YR, Yadav PN. Anticancer potency of copper(II) complexes of thiosemicarbazones. J Inorg Biochem 2020; 210:111134. [DOI: 10.1016/j.jinorgbio.2020.111134] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/31/2020] [Accepted: 06/06/2020] [Indexed: 12/20/2022]
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31
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Martinez S, Brandl A, Leary D. Monte Carlo Evaluation of Dose Enhancement Due to CuATSM or GNP Uptake in Hypoxic Environments with External Beam Radiation. Int J Nanomedicine 2020; 15:3719-3727. [PMID: 32547024 PMCID: PMC7261688 DOI: 10.2147/ijn.s241756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Most solid tumors contain areas of chronic hypoxia. Gold nanoparticles (GNP) have been extensively explored as enhancers of external beam radiation; however, GNP have lower cellular uptake in hypoxic conditions than under normoxic conditions. Conversely, the chelator diacetyl-bis (N(4)-methylthiosemicarbazonato) copper II (CuATSM) deposits copper in hypoxic regions, allowing for dose enhancement in previously inaccessible regions. Methods External beam sources with different spectra were modeled using a Monte Carlo code (EGSnrc) to evaluate radioenhancement in a layered model with metal solutions. Also considered was a simple concentric layered tumor model containing a hypoxic core with each layer varying in concentrations of either copper or gold according to hypoxic conditions. Low energy external photon beams were then projected onto the tumor to determine the regional dose enhancement dependent on hypoxic conditions. Results Dose enhancement was more pronounced for beam spectra with low energy photons (225 kVp) and was highly dependent on metal concentrations from 0.1 g/kg to 100 g/kg. Increasing the depth of the metallic solution layer from 1 cm to 6 cm decreased dose enhancement. A small increase in the dose enhancement factor (DEF) of 1.01 was predicted in the hypoxic regions of the tumor model with commonly used diagnostic concentrations of CuATSM. At threshold concentrations of toxic subcutaneous injection levels, the DEF increases to 1.02, and in simulation of a high concentration of CuATSM, the DEF increased to 1.07. High concentration treatments are also considered, as well as synergistic combinations of GNP/CuATSM treatments. Conclusion The research presented is novel utilization of CuATSM to target hypoxic regions and act as a radiosensitizer by the nature of its ability to deposit copper metal in reduced tissue. We demonstrate CuATSM at high concentrations with low energy photons can increase dose deposition in hypoxic tumor regions.
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Affiliation(s)
- Stephen Martinez
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Alexander Brandl
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Del Leary
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
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32
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Liu T, Karlsen M, Karlberg AM, Redalen KR. Hypoxia imaging and theranostic potential of [ 64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms. EJNMMI Res 2020; 10:33. [PMID: 32274601 PMCID: PMC7145880 DOI: 10.1186/s13550-020-00621-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Tumor hypoxia (low tissue oxygenation) is an adverse condition of the solid tumor environment, associated with malignant progression, radiotherapy resistance, and poor prognosis. One method to detect tumor hypoxia is by positron emission tomography (PET) with the tracer [64Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] ([64Cu][Cu(ATSM)]), as demonstrated in both preclinical and clinical studies. In addition, emerging studies suggest using [64Cu][Cu(ATSM)] for molecular radiotherapy, mainly due to the release of therapeutic Auger electrons from copper-64, making [64Cu][Cu(ATSM)] a “theranostic” agent. However, the radiocopper retention based on a metal-ligand dissociation mechanism under hypoxia has long been controversial. Recent studies using ionic Cu(II) salts as tracers have raised further questions on the original mechanism and proposed a potential role of copper itself in the tracer uptake. We have reviewed the evidence of using the copper radiopharmaceuticals [60/61/62/64Cu][Cu(ATSM)]/ionic copper salts for PET imaging of tumor hypoxia, their possible therapeutic applications, issues related to the metal-ligand dissociation mechanism, and possible explanations of copper trapping based on studies of the copper metabolism under hypoxia. Results We found that hypoxia selectivity of [64Cu][Cu(ATSM)] has been clearly demonstrated in both preclinical and clinical studies. Preclinical therapeutic studies in mice have also demonstrated promising results, recently reporting significant tumor volume reductions and improved survival in a dose-dependent manner. Cu(II)-[Cu(ATSM)] appears to be accumulated in regions with substantially higher CD133+ expression, a marker for cancer stem cells. This, combined with the reported requirement of copper for activation of the hypoxia inducible factor 1 (HIF-1), provides a possible explanation for the therapeutic effects of [64Cu][Cu(ATSM)]. Comparisons between [64Cu][Cu(ATSM)] and ionic Cu(II) salts have showed similar results in both imaging and therapeutic studies, supporting the argument for the central role of copper itself in the retention mechanism. Conclusions We found promising evidence of using copper-64 radiopharmaceuticals for both PET imaging and treatment of hypoxic tumors. The Cu(II)-[Cu(ATSM)] retention mechanism remains controversial and future mechanistic studies should be focused on understanding the role of copper itself in the hypoxic tumor metabolism.
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Affiliation(s)
- Tengzhi Liu
- Department of Physics, Norwegian University of Science and Technology, Høgskoleringen 5, 7491, Trondheim, Norway.,Department of Radiology and Nuclear Medicine, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway
| | - Morten Karlsen
- Department of Radiology and Nuclear Medicine, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway
| | - Anna Maria Karlberg
- Department of Radiology and Nuclear Medicine, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kathrine Røe Redalen
- Department of Physics, Norwegian University of Science and Technology, Høgskoleringen 5, 7491, Trondheim, Norway.
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33
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Liu K, Liu K, Liu J, Ren Q, Zhao Z, Wu X, Li D, Yuan F, Ye K, Li B. Copper chalcogenide materials as photothermal agents for cancer treatment. NANOSCALE 2020; 12:2902-2913. [PMID: 31967164 DOI: 10.1039/c9nr08737k] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Copper-based chalcogenide nanomaterials have made tremendous progress for cancer theranostics due to their simple preparation, low cost, stable performance, and easy functionalization. But a systematic review and analysis about them does not exist. Therefore, we offer an account, mainly focusing on the design and functionalization of the copper-based chalcogenide nanomaterials for cancer theranostics, aiming to briefly demonstrate the design and concepts, summarize some of the past studies and analyze the development trends in the copper-based chalcogenide nanomaterials for clinical application.
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Affiliation(s)
- Kun Liu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Kai Liu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. and Department of vascular surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qindao 266000, Shandong, China
| | - Junchao Liu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Qilong Ren
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China
| | - Zhen Zhao
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Xiaoyu Wu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Dalin Li
- Department of vascular surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qindao 266000, Shandong, China
| | - Fukang Yuan
- Department of General Surgery of XuZhou Central Hospital, XuZhou 221009, Jiangsu, China. and XuZhou Clinical School of Xuzhou Medical University, XuZhou 221009, Jiangsu, China
| | - Kaichuang Ye
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Bo Li
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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Yoshii Y, Matsumoto H, Yoshimoto M, Oe Y, Zhang MR, Nagatsu K, Sugyo A, Tsuji AB, Higashi T. 64Cu-Intraperitoneal Radioimmunotherapy: A Novel Approach for Adjuvant Treatment in a Clinically Relevant Preclinical Model of Pancreatic Cancer. J Nucl Med 2019; 60:1437-1443. [PMID: 30850497 PMCID: PMC6785796 DOI: 10.2967/jnumed.118.225045] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 02/20/2019] [Indexed: 01/11/2023] Open
Abstract
Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of 64Cu-intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. Methods: The efficacy of adjuvant 64Cu-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of 64Cu-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant 64Cu-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of 64Cu-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. Results: The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant 64Cu-ipRIT with 64Cu-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant 64Cu-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Conclusion:64Cu-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.
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Affiliation(s)
- Yukie Yoshii
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | | | - Mitsuyoshi Yoshimoto
- Division of Functional Imaging, National Cancer Center Hospital East, Chiba, Japan
| | - Yoko Oe
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Ming-Rong Zhang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Kotaro Nagatsu
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Aya Sugyo
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Atsushi B Tsuji
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tatsuya Higashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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Matsumoto H, Igarashi C, Kaneko E, Hashimoto H, Suzuki H, Kawamura K, Zhang MR, Higashi T, Yoshii Y. Process development of [64Cu]Cu-ATSM: efficient stabilization and sterilization for therapeutic applications. J Radioanal Nucl Chem 2019. [DOI: 10.1007/s10967-019-06738-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Zhang H, Xie F, Cheng M, Peng F. Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma. J Med Chem 2019; 62:6985-6991. [PMID: 31283215 DOI: 10.1021/acs.jmedchem.9b00386] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Haiyuan Zhang
- Carman & Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, Michigan 48201, United States
| | - Fang Xie
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 735390, United States
| | - Muhua Cheng
- Department of Nuclear Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P. R. China
| | - Fangyu Peng
- Carman & Ann Adams Department of Pediatrics, School of Medicine, Wayne State University, Detroit, Michigan 48201, United States
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 735390, United States
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
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Matsumoto H, Yoshii Y, Baden A, Kaneko E, Hashimoto H, Suzuki H, Kawamura K, Zhang MR, Higashi T, Kurihara H. Preclinical Pharmacokinetic and Safety Studies of Copper-Diacetyl-Bis(N 4-Methylthiosemicarbazone) (Cu-ATSM): Translational Studies for Internal Radiotherapy. Transl Oncol 2019; 12:1206-1212. [PMID: 31252311 PMCID: PMC6600784 DOI: 10.1016/j.tranon.2019.05.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 11/25/2022] Open
Abstract
Hypoxia plays important roles in the prognosis of malignant brain tumors such as glioblastoma because it causes drug delivery deficiencies and the induction of hypoxia-inducible factor-1α in tumor cells. Extensive hypoxic areas are associated with poor prognosis of these fatal diseases. We previously reported that multiple administrations of the hypoxia-targeted internal radiotherapy agent 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), four times at intervals of 1 or 2 weeks, show antitumor effects in glioblastoma without treatment-related adverse events. Before initiating clinical trials, preclinical safety studies using Cu-ATSM composed of stable isotopes and its precursor ATSM were required to understand the potential risks of systemic and repeated chemical exposure of our investigational drug. In this study, the concentrations of Cu-ATSM and ATSM in mouse plasma after intravenous administration were determined by liquid chromatography–tandem mass spectrometry, and the half-lives were estimated to be 21.5 and 22.4 minutes for Cu-ATSM and ATSM, respectively. Based on this result, approach 2 of the current ICH M3 [R2] guideline was adopted, and a 7-day intravenous toxicity study was conducted in mice. Cu-ATSM and ATSM in a ratio of 2:25 mimicking our current investigational drug was used, and no adverse effects were observed when Cu-ATSM and ATSM were administered at 81 μg/kg. These results and those of previous studies suggest that our current investigational drug formulation containing Cu-ATSM and ATSM at a dose of 15 μg can be safely administered to patients once per week for 4 weeks for treatment with 64Cu-ATSM.
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Affiliation(s)
- Hiroki Matsumoto
- Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura 299-0266, Japan
| | - Yukie Yoshii
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
| | - Atsumi Baden
- Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura 299-0266, Japan
| | - Emi Kaneko
- Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura 299-0266, Japan
| | - Hiroki Hashimoto
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Hisashi Suzuki
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Kazunori Kawamura
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Ming-Rong Zhang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Tatsuya Higashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Hiroaki Kurihara
- Department of Diagnostic Radiology, National Cancer Center Hospital, 104-0045, Tokyo, Japan
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Zhou Y, Li J, Xu X, Zhao M, Zhang B, Deng S, Wu Y. 64Cu-based Radiopharmaceuticals in Molecular Imaging. Technol Cancer Res Treat 2019; 18:1533033819830758. [PMID: 30764737 PMCID: PMC6378420 DOI: 10.1177/1533033819830758] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Copper-64 (T1/2 = 12.7 hours; β+: 19%, β-: 38%) has a unique decay profile and can be used for positron emission tomography imaging and radionuclide therapy. The well-established coordination chemistry of copper allows for its reaction with different types of chelator systems. It can be linked to antibodies, proteins, peptides, and other biologically relevant small molecules. Two potential ways to produce copper-64 radioisotopes concern the use of the cyclotron or the reactor. This review summarized several commonly used biomarkers of copper-64 radionuclide.
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Affiliation(s)
- Yeye Zhou
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jihui Li
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Xu
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Man Zhao
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bin Zhang
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengming Deng
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yiwei Wu
- 1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
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Paterson BM, Cullinane C, Crouch PJ, White AR, Barnham KJ, Roselt PD, Noonan W, Binns D, Hicks RJ, Donnelly PS. Modification of Biodistribution and Brain Uptake of Copper Bis(thiosemicarbazonato) Complexes by the Incorporation of Amine and Polyamine Functional Groups. Inorg Chem 2019; 58:4540-4552. [PMID: 30869878 DOI: 10.1021/acs.inorgchem.9b00117] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The synthesis of new bis(thiosemicarbazonato)copper(II) complexes featuring polyamine substituents via selective transamination reactions is presented. Polyamines of different lengths, with different ionizable substituent groups, were used to modify and adjust the hydrophilic/lipophilic balance of the copper complexes. The new analogues were radiolabeled with copper-64 and their lipophilicities estimated using distribution coefficients. The cell uptake of the new polyamine complexes was investigated with preliminary in vitro biological studies using a neuroblastoma cancer cell line. The in vivo biodistribution of three of the new analogues was investigated in vivo in mice using positron-emission tomography imaging, and one of the new complexes was compared to [64Cu]Cu(atsm) in an A431 squamous cell carcinoma xenograft model. Modification of the copper complexes with various amine-containing functional groups alters the biodistribution of the complexes in mice. One complex, with a pendent ( N, N-dimethylamino)ethane functional group, displayed tumor uptake similar to that of [64Cu]Cu(atsm) but higher brain uptake, suggesting that this compound has the potential to be of use in the diagnostic brain imaging of tumors and neurodegenerative diseases.
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Affiliation(s)
| | - Carleen Cullinane
- The Centre for Molecular Imaging and Translational Research Laboratory , The Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia
| | | | | | | | - Peter D Roselt
- The Centre for Molecular Imaging and Translational Research Laboratory , The Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia
| | - Wayne Noonan
- The Centre for Molecular Imaging and Translational Research Laboratory , The Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia
| | - David Binns
- The Centre for Molecular Imaging and Translational Research Laboratory , The Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia
| | - Rodney J Hicks
- The Centre for Molecular Imaging and Translational Research Laboratory , The Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia
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40
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Merlot AM, Kalinowski DS, Kovacevic Z, Jansson PJ, Sahni S, Huang MLH, Lane DJ, Lok H, Richardson DR. Exploiting Cancer Metal Metabolism using Anti-Cancer Metal- Binding Agents. Curr Med Chem 2019; 26:302-322. [DOI: 10.2174/0929867324666170705120809] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/09/2017] [Accepted: 06/09/2017] [Indexed: 02/07/2023]
Abstract
Metals are vital cellular elements necessary for multiple indispensable biological processes of living organisms, including energy transduction and cell proliferation. Interestingly, alterations in metal levels and also changes in the expression of proteins involved in metal metabolism have been demonstrated in a variety of cancers. Considering this and the important role of metals for cell growth, the development of drugs that sequester metals has become an attractive target for the development of novel anti-cancer agents. Interest in this field has surged with the design and development of new generations of chelators of the thiosemicarbazone class. These ligands have shown potent anticancer and anti-metastatic activity in vitro and in vivo. Due to their efficacy and safe toxicological assessment, some of these agents have recently entered multi-center clinical trials as therapeutics for advanced and resistant tumors. This review highlights the role and changes in homeostasis of metals in cancer and emphasizes the pre-clinical development and clinical assessment of metal ion-binding agents, namely, thiosemicarbazones, as antitumor agents.
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Affiliation(s)
- Angelica M. Merlot
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Danuta S. Kalinowski
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Patric J. Jansson
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Sumit Sahni
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Michael L.-H. Huang
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Darius J.R. Lane
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Hiu Lok
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
| | - Des R. Richardson
- Molecular Pharmacology and Pathology Program, The University of Sydney, Department of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine, Sydney, NSW, 2006, Australia
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Yadav V, Roy S, Singh P, Khan Z, Jaiswal A. 2D MoS 2 -Based Nanomaterials for Therapeutic, Bioimaging, and Biosensing Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1803706. [PMID: 30565842 DOI: 10.1002/smll.201803706] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 10/18/2018] [Indexed: 05/26/2023]
Abstract
Molybdenum disulfide (MoS2 ), a typical layered 2D transition metal dichalcogenide, has received colossal interest in the past few years due to its unique structural, physicochemical, optical, and biological properties. While MoS2 is mostly applied in traditional industries such as dry lubricants, intercalation agents, and negative electrode material in lithium-ion batteries, its 2D and 0D forms have led to diverse applications in sensing, catalysis, therapy, and imaging. Herein, a systematic overview of the progress that is made in the field of MoS2 research with an emphasis on its different biomedical applications is presented. This article provides a general discussion on the basic structure and property of MoS2 and gives a detailed description of its different morphologies that are synthesized so far, namely, nanosheets, nanotubes, and quantum dots along with synthesis strategies. The biomedical applications of MoS2 -based nanocomposites are also described in detail and categorically, such as in varied therapeutic and diagnostic modalities like drug delivery, gene delivery, phototherapy, combined therapy, bioimaging, theranostics, and biosensing. Finally, a brief commentary on the current challenges and limitations being faced is provided, along with a discussion of some future perspectives for the overall improvement of MoS2 -based nanocomposites as a potential nanomedicine.
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Affiliation(s)
- Varnika Yadav
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Mandi, 175005, Himachal Pradesh, India
| | - Shounak Roy
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Mandi, 175005, Himachal Pradesh, India
| | - Prem Singh
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Mandi, 175005, Himachal Pradesh, India
| | - Ziyauddin Khan
- Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, SE-60174, Norrköping, Sweden
| | - Amit Jaiswal
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Mandi, 175005, Himachal Pradesh, India
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Wehbe M, Leung AWY, Abrams MJ, Orvig C, Bally MB. A Perspective - can copper complexes be developed as a novel class of therapeutics? Dalton Trans 2018; 46:10758-10773. [PMID: 28702645 DOI: 10.1039/c7dt01955f] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(ii) coordination compounds referred to as casiopeínas these compounds have yet to reach the clinic for human use. The pharmaceutical challenges associated with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chemistry, computer-aided drug design, and nanotechnology to address the development of this important class of drug candidates.
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Affiliation(s)
- Mohamed Wehbe
- Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
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Kurihara H. Integrated 64Cu therapy for the peritoneal dissemination of gastrointestinal cancer. Oncotarget 2018; 9:31165-31166. [PMID: 30131842 PMCID: PMC6101283 DOI: 10.18632/oncotarget.25840] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 07/17/2018] [Indexed: 11/25/2022] Open
Affiliation(s)
- Hiroaki Kurihara
- Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan
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Yoshii Y, Yoshimoto M, Matsumoto H, Tashima H, Iwao Y, Takuwa H, Yoshida E, Wakizaka H, Yamaya T, Zhang MR, Sugyo A, Hanadate S, Tsuji AB, Higashi T. Integrated treatment using intraperitoneal radioimmunotherapy and positron emission tomography-guided surgery with 64Cu-labeled cetuximab to treat early- and late-phase peritoneal dissemination in human gastrointestinal cancer xenografts. Oncotarget 2018; 9:28935-28950. [PMID: 29989003 PMCID: PMC6034757 DOI: 10.18632/oncotarget.25649] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/03/2018] [Indexed: 02/03/2023] Open
Abstract
Peritoneal dissemination is a common cause of death from gastrointestinal cancers and is difficult to treat using current therapeutic options, particularly late-phase disease. Here, we investigated the feasibility of integrated therapy using 64Cu-intraperitoneal radioimmunotherapy (ipRIT), alone or in combination with positron emission tomography (PET)-guided surgery using a theranostic agent (64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab) to treat early- and late-phase peritoneal dissemination in mouse models. In this study, we utilized the OpenPET system, which has open space for conducting surgery while monitoring objects at high resolution in real time, as a novel approach to make PET-guided surgery feasible. 64Cu-ipRIT with cetuximab inhibited tumor growth and prolonged survival with little toxicity in mice with early-phase peritoneal dissemination of small lesions. For late-phase peritoneal dissemination, a combination of 64Cu-ipRIT for down-staging and subsequent OpenPET-guided surgery for resecting large tumor masses effectively prolonged survival. OpenPET clearly detected tumors (≥3 mm in size) behind other organs in the peritoneal cavity and was useful for confirming the presence or absence of residual tumors during an operation. These findings suggest that integrated 64Cu therapy can serve as a novel treatment strategy for peritoneal dissemination.
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Affiliation(s)
- Yukie Yoshii
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Mitsuyoshi Yoshimoto
- Division of Functional Imaging, National Cancer Center Hospital East, Chiba, Japan
| | | | - Hideaki Tashima
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Yuma Iwao
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Hiroyuki Takuwa
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Eiji Yoshida
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Hidekatsu Wakizaka
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Taiga Yamaya
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Ming-Rong Zhang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Aya Sugyo
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Sayaka Hanadate
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Atsushi B Tsuji
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
| | - Tatsuya Higashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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Jin ZH, Tsuji AB, Degardin M, Sugyo A, Yoshii Y, Nagatsu K, Zhang MR, Fujibayashi Y, Dumy P, Boturyn D, Higashi T. Uniform intratumoral distribution of radioactivity produced using two different radioagents, 64Cu-cyclam-RAFT-c(-RGDfK-) 4 and 64Cu-ATSM, improves therapeutic efficacy in a small animal tumor model. EJNMMI Res 2018; 8:54. [PMID: 29923139 PMCID: PMC6008272 DOI: 10.1186/s13550-018-0407-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 06/05/2018] [Indexed: 12/15/2022] Open
Abstract
Background The present study proposed a new concept for targeted radionuclide therapy (TRT) to improve the intratumoral distribution of radioactivity using two different radiopharmaceuticals. We examined the efficacy of a combination of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide-based radiopharmaceutical, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD, an αVβ3 integrin [αVβ3] tracer), and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM, a supposed tracer for hypoxic metabolism) in a small animal tumor model. Results Mice with subcutaneous αVβ3-positive U87MG glioblastoma xenografts were used. The intratumoral distribution of a near-infrared dye, Cy5.5-labeled RAFT-c(-RGDfK-)4 (Cy5.5-RaftRGD), 64Cu-RaftRGD, and 64Cu-ATSM was visualized by fluorescence imaging and autoradiography of the co-injected Cy5.5-RaftRGD with 64Cu-RaftRGD or 64Cu-ATSM at 3 h postinjection. Mice were treated with a single intravenous dose of the vehicle solution (control), 18.5 or 37 MBq of 64Cu-RaftRGD or 64Cu-ATSM, or a combination (18.5 MBq of each agent). The tumor volume, tumor cell proliferation, body weight, survival, and tumor and organ uptake of radiopharmaceuticals were assessed. It was shown that Cy5.5-RaftRGD colocalized with 64Cu-RaftRGD and could be used as a surrogate for the radioactive agent. The intratumoral distribution of Cy5.5-RaftRGD and 64Cu-ATSM was discordant and nearly complementary, indicating a more uniform distribution of radioactivity achievable with the combined use of 64Cu-RaftRGD and 64Cu-ATSM. Neither 64Cu-RaftRGD nor 64Cu-ATSM showed significant effects on tumor growth at 18.5 MBq. The combination of both (18.5 MBq each) showed sustained inhibitory effects against tumor growth and tumor cell proliferation and prolonged the survival of the mice, compared to that by either single agent at 37 MBq. Interestingly, the uptake of the combination by the tumor was higher than that of 64Cu-RaftRGD alone, but lower than that of 64Cu-ATSM alone. The kidneys showed the highest uptake of 64Cu-RaftRGD, whereas the liver exhibited the highest uptake of 64Cu-ATSM. No obvious adverse effects were observed in all treated mice. Conclusions The combination of 64Cu-RaftRGD and 64Cu-ATSM achieved an improved antitumor effect owing to the more uniform intratumoral distribution of radioactivity. Thus, combining different radiopharmaceuticals to improve the intratumoral distribution would be a promising concept for more effective and safer TRT. Electronic supplementary material The online version of this article (10.1186/s13550-018-0407-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhao-Hui Jin
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan.
| | - Atsushi B Tsuji
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Mélissa Degardin
- Département de Chimie Moléculaire-UMR CNRS 5250, Université Grenoble Alpes, 38041, Grenoble Cedex 9, France
| | - Aya Sugyo
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Yukie Yoshii
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Kotaro Nagatsu
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Ming-Rong Zhang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Yasuhisa Fujibayashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
| | - Pascal Dumy
- IBMM, UMR-5247, Université de Montpellier, CNRS, École Nationale Supérieure de Chimie de Montpellier, 34296, Montpellier Cedex 5, France
| | - Didier Boturyn
- Département de Chimie Moléculaire-UMR CNRS 5250, Université Grenoble Alpes, 38041, Grenoble Cedex 9, France
| | - Tatsuya Higashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba, 263-8555, Japan
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46
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Comba P, Starke M, Wadepohl H. Optimization of Hexadentate Bispidine Ligands as Chelators for 64
CuII
PET Imaging. Chempluschem 2018; 83:597-604. [DOI: 10.1002/cplu.201800110] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 03/29/2018] [Indexed: 11/06/2022]
Affiliation(s)
- Peter Comba
- Universität Heidelberg; Anorganisch-Chemisches Institut; and Interdisciplinary Center for Scientific Computing INF 270; 69120 Heidelberg Germany
| | - Miriam Starke
- Universität Heidelberg; Anorganisch-Chemisches Institut; and Interdisciplinary Center for Scientific Computing INF 270; 69120 Heidelberg Germany
| | - Hubert Wadepohl
- Universität Heidelberg; Anorganisch-Chemisches Institut; and Interdisciplinary Center for Scientific Computing INF 270; 69120 Heidelberg Germany
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47
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Righi S, Ugolini M, Bottoni G, Puntoni M, Iacozzi M, Paparo F, Cabria M, Ceriani L, Gambaro M, Giovanella L, Piccardo A. Biokinetic and dosimetric aspects of 64CuCl 2 in human prostate cancer: possible theranostic implications. EJNMMI Res 2018; 8:18. [PMID: 29492782 PMCID: PMC5833894 DOI: 10.1186/s13550-018-0373-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 02/20/2018] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND The aim of the present study is to evaluate the kinetics and dosimetry of 64CuCl2 in human prostate cancer (PCa) lesions. We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external beam radiation therapy. All patients underwent 64CuCl2-PET/CT to detect PCa recurrence/metastases. Volumes of interest were manually drawn for each 64CuCl2 avid PCa lesion with a diameter > 1 cm on mpMRI in each patient. Time-activity curves for all lesions were obtained. The effective and biological half-life and the standard uptake values (SUVs) were calculated. Tumour/background ratio (TBR) curves as a function of time were considered. Finally, the absorbed dose per lesion was estimated. RESULTS The mean effective half-life of 64CuCl2 calculated in the lymph nodes (10.2 ± 1.7 h) was significantly higher than in local relapses (8.8 ± 1.1 h) and similar to that seen in bone metastases (9.0 ± 0.4 h). The mean 64CuCl2 SUVmax calculated 1 h after tracer injection was significantly higher in the lymph nodes (6.8 ± 4.3) and bone metastases (6.8 ± 2.9) than in local relapses (4.7 ± 2.4). TBR mean curve of 64CuCl2 revealed that the calculated TBRmax value was 5.0, 7.0, and 6.2 in local relapse and lymph node and bone metastases, respectively, and it was achieved about 1 h after 64CuCl2 injection. The mean absorbed dose of the PCa lesions per administrated activity was 6.00E-2 ± 4.74E-2mGy/MBq. Indeed, for an administered activity of 3.7 GBq, the mean dose absorbed by the lesion would be 0.22 Gy. CONCLUSIONS Dosimetry showed that the dose absorbed by PCa recurrences/metastases per administrated activity was low. The dosimetric study performed does not take into account the possible therapeutic effect of the Auger electrons. Clinical trials are needed to evaluate 64Cu internalization in the cell nucleus that seems related to the therapeutic effectiveness reported in preclinical studies.
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Affiliation(s)
- Sergio Righi
- Medical Physics Department, E.O. Galliera Hospital, Genoa, Italy
| | - Martina Ugolini
- Medical Physics Department, E.O. Galliera Hospital, Genoa, Italy
| | - Gianluca Bottoni
- Department of Nuclear Medicine, Galliera Hospital, Mura delle Cappuccine 14, 16128, Genoa, Italy
| | - Matteo Puntoni
- Clinical Trial Unit, Office of the Scientific Director, Galliera Hospital, Genoa, Italy
| | - Massimiliano Iacozzi
- Department of Nuclear Medicine, Galliera Hospital, Mura delle Cappuccine 14, 16128, Genoa, Italy
| | | | - Manlio Cabria
- Department of Nuclear Medicine, Galliera Hospital, Mura delle Cappuccine 14, 16128, Genoa, Italy
| | - Luca Ceriani
- Department of Nuclear Medicine, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Monica Gambaro
- Medical Physics Department, E.O. Galliera Hospital, Genoa, Italy
| | - Luca Giovanella
- Department of Nuclear Medicine, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Arnoldo Piccardo
- Department of Nuclear Medicine, Galliera Hospital, Mura delle Cappuccine 14, 16128, Genoa, Italy.
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48
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Liang L, Gao P. Lead-Free Hybrid Perovskite Absorbers for Viable Application: Can We Eat the Cake and Have It too? ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2018; 5:1700331. [PMID: 29610719 PMCID: PMC5827473 DOI: 10.1002/advs.201700331] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 08/24/2017] [Indexed: 05/02/2023]
Abstract
Many years since the booming of research on perovskite solar cells (PSCs), the hybrid perovskite materials developed for photovoltaic application form three main categories since 2009: (i) high-performance unstable lead-containing perovskites, (ii) low-performance lead-free perovskites, and (iii) moderate performance and stable lead-containing perovskites. The search for alternative materials to replace lead leads to the second group of perovskite materials. To date, a number of these compounds have been synthesized and applied in photovoltaic devices. Here, lead-free hybrid light absorbers used in PV devices are focused and their recent developments in related solar cell applications are reviewed comprehensively. In the first part, group 14 metals (Sn and Ge)-based perovskites are introduced with more emphasis on the optimization of Sn-based PSCs. Then concerns on halide hybrids of group 15 metals (Bi and Sb) are raised, which are mainly perovskite derivatives. At the same time, transition metal Cu-based perovskites are also referred. In the end, an outlook is given on the design strategy of lead-free halide hybrid absorbers for photovoltaic applications. It is believed that this timely review can represent our unique view of the field and shed some light on the direction of development of such promising materials.
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Affiliation(s)
- Lusheng Liang
- CAS Key Laboratory of Design and Assembly of Functional Nanostructuresand Fujian Provincial Key Laboratory of NanomaterialsFujian Institute of Research on the Structure of MatterChinese Academy of SciencesFuzhou350002China
- Laboratory of Advanced Functional MaterialsXiamen Institute of Rare Earth MaterialsHaixi InstituteChinese Academy of SciencesXiamen361021China
| | - Peng Gao
- CAS Key Laboratory of Design and Assembly of Functional Nanostructuresand Fujian Provincial Key Laboratory of NanomaterialsFujian Institute of Research on the Structure of MatterChinese Academy of SciencesFuzhou350002China
- Laboratory of Advanced Functional MaterialsXiamen Institute of Rare Earth MaterialsHaixi InstituteChinese Academy of SciencesXiamen361021China
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49
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Abstract
Radiometal based radiopharmaceuticals for imaging and therapy require selective ligands (bifunctional chelators, BFCs) that form metal complexes, which are inert against trans-chelation under physiological conditions, linked to a biological vector, directing them to the targeted tissue. Bispidine ligands with a very rigid backbone and widely variable donor sets are reviewed as an ideal class of BFCs, and recent applications are discussed.
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Affiliation(s)
- Peter Comba
- Ruprecht-Karls Universität Heidelberg
- Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing (IWR)
- 69120 Heidelberg
- Germany
| | - Marion Kerscher
- Ruprecht-Karls Universität Heidelberg
- Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing (IWR)
- 69120 Heidelberg
- Germany
| | - Katharina Rück
- Ruprecht-Karls Universität Heidelberg
- Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing (IWR)
- 69120 Heidelberg
- Germany
| | - Miriam Starke
- Ruprecht-Karls Universität Heidelberg
- Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing (IWR)
- 69120 Heidelberg
- Germany
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50
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Yoshii Y, Matsumoto H, Yoshimoto M, Zhang MR, Oe Y, Kurihara H, Narita Y, Jin ZH, Tsuji AB, Yoshinaga K, Fujibayashi Y, Higashi T. Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts. Transl Oncol 2017; 11:24-30. [PMID: 29154146 PMCID: PMC5697999 DOI: 10.1016/j.tranon.2017.10.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 10/23/2017] [Accepted: 10/23/2017] [Indexed: 01/07/2023] Open
Abstract
Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease.
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Affiliation(s)
- Yukie Yoshii
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
| | - Hiroki Matsumoto
- Research Centre, Nihon Medi-Physics Co., Ltd., Sodegaura 299-0266, Japan
| | - Mitsuyoshi Yoshimoto
- Division of Functional Imaging, National Cancer Center Hospital East, 277-8577, Kashiwa, Japan
| | - Ming-Rong Zhang
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Yoko Oe
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Hiroaki Kurihara
- Department of Diagnostic Radiology, National Cancer Center Hospital, 104-0045, Tokyo, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 104-0045, Tokyo, Japan
| | - Zhao-Hui Jin
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Atsushi B Tsuji
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Keiichiro Yoshinaga
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Yasuhisa Fujibayashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Tatsuya Higashi
- National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
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