The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model
| العنوان: | The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model |
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| المؤلفون: | Melpomeni Fani, Svetlana N. Rylova, Keelara Abiraj, C. Stoykow, Maria Luisa Tamma, Luigi Del Pozzo, Yvonne Kiefer, Helmut R. Maecke |
| المصدر: | PLoS ONE, Vol 13, Iss 4, p e0195802 (2018) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Physiology, Peptide Hormones, lcsh:Medicine, Pharmacology, Acetates, Biochemistry, 030218 nuclear medicine & medical imaging, Diagnostic Radiology, Mice, 0302 clinical medicine, Neoplasms, Medicine and Health Sciences, Somatostatin receptor 2, Tissue Distribution, Receptors, Somatostatin, Internalization, lcsh:Science, Tomography, media_common, Multidisciplinary, Radiochemistry, Molecular Structure, Chemistry, Radiology and Imaging, Physics, Animal Models, Molecular Imaging, Body Fluids, Somatostatin, Blood, Radioactivity, Liver, Experimental Organism Systems, 030220 oncology & carcinogenesis, Physical Sciences, Heterografts, Anatomy, Research Article, Agonist, Biodistribution, medicine.drug_class, Imaging Techniques, media_common.quotation_subject, Neuroimaging, Mouse Models, Research and Analysis Methods, 03 medical and health sciences, Heterocyclic Compounds, 1-Ring, Model Organisms, Pharmacokinetics, In vivo, Diagnostic Medicine, medicine, Animals, Humans, Nuclear Physics, lcsh:R, Antagonist, Biology and Life Sciences, Kidneys, Renal System, Hormones, Disease Models, Animal, HEK293 Cells, Copper Radioisotopes, Positron-Emission Tomography, lcsh:Q, Radiopharmaceuticals, Positron Emission Tomography, Neuroscience |
| الوصف: | Copper-64 is an attractive radionuclide for PET imaging and is frequently used in clinical applications. The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7-acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clinically used sst2 agonist 64Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. Cell uptake studies showed the expected differences between agonists and antagonists. Whereas 64Cu-DOTA-TATE (the agonist) showed very effective internalization in the cell culture assay (with 50% internalized at 4 hours post-peptide addition under the given experimental conditions), 64Cu-NODAGA-JR11 (the antagonist) showed little internalization but strong receptor-mediated uptake at the cell membrane. Biodistribution studies of 64Cu-NODAGA-JR11 showed rapid blood clearance and tumor uptake with increasing tumor-to-relevant organ ratios within the first 4 hours and in some cases, 24 hours, respectively. The tumor washout was slow or non-existent in the first 4 hours, whereas the kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Specificity of tumor uptake was proven by co-injection of high excess of non-radiolabeled peptide, which led to >80% tumor blocking. 64Cu-DOTA-TATE showed less favorable pharmacokinetics, with the exception of lower kidney uptake. Blood clearance was distinctly slower and persistent higher blood values were found at 24 hours. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGA-JR11 at 1 h, but release from the tumor was very fast, particularly between 4 and 24 hours. Tumor-to-normal organ ratios were distinctly lower after 1 hour. This is indicative of insufficient in vivo stability. PET studies of 64Cu-NODAGA-JR11 reflected the biodistribution data with nicely delineated tumor and low background. 64Cu-NODAGA-JR11 shows promising pharmacokinetic properties for further translation into the clinic. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72604dbfb7c5c809e2da71f55aaa9593 http://europepmc.org/articles/PMC5906006?pdf=render |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....72604dbfb7c5c809e2da71f55aaa9593 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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