{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:36:50Z","timestamp":1790674610209,"version":"4.1.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"13","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100018720","name":"Advanced Accelerator Applications","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018720","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Nucl Med Mol Imaging"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>The radiolabeled gastrin-releasing peptide receptor (GRPR)-targeting antagonist NeoB is a promising radioligand for imaging and therapy of GRPR-expressing malignancies. In the current study, we aimed to discover the target organs of toxicity and the radiotoxic effects to these organs, when repeated dosages of [<jats:sup>177<\/jats:sup>Lu]Lu-NeoB are administered to healthy female and male mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Animals received either 3 injections, with a 7-day interval, of vehicle (control group 1), 1200\u00a0pmol [<jats:sup>175<\/jats:sup>Lu]Lu-NeoB (control group 2) or 40\u00a0MBq\/400\u00a0pmol, 80\u00a0MBq\/800\u00a0pmol, and 120\u00a0MBq\/1200\u00a0pmol [<jats:sup>177<\/jats:sup>Lu]Lu-NeoB (treatment groups 1, 2, and 3, respectively). At week 5, 19, and 43 after the first injection acute, early, and late organ toxicity, respectively, was determined. For this, histopathological and blood analyses were performed. To correlate the observed toxicity to absorbed dose, we also performed extensive biodistribution and dosimetry studies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The biodistribution study showed the highest absorbed doses in GRPR-expressing pancreas, the liver, and the kidneys (the main organs of excretion). Both control groups and almost all animals of treatment group 1 did not show any treatment-related toxicological effects. Despite the high absorbed doses, no clear microscopic signs of toxicity were found in the pancreas and the liver. Histological analysis indicated kidney damage in the form of hydronephrosis and nephropathy in treatment groups 2 and 3 that were sacrificed at the early and late time point. In the same groups, increased blood urea nitrogen levels were found.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In general, repeated administration of [<jats:sup>177<\/jats:sup>Lu]Lu-NeoB was tolerated. The most significant radiotoxic effects were found in the kidneys, similar to other clinically applied radioligands. The results of this study underline the potential of [<jats:sup>177<\/jats:sup>Lu]Lu-NeoB as a promising option for clinical therapy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-022-05926-2","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T06:04:52Z","timestamp":1660197892000},"page":"4440-4451","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Safety of [177Lu]Lu-NeoB treatment: a preclinical study characterizing absorbed dose and acute, early, and late organ toxicity"],"prefix":"10.1007","volume":"49","author":[{"given":"Eline A. M.","family":"Ruigrok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"Verhoeven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Konijnenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"de Blois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrina M. A.","family":"de Ridder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra C.","family":"Stuurman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Bertarione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Rolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6393-6901","authenticated-orcid":false,"given":"Simone U.","family":"Dalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"issue":"7","key":"5926_CR1","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1021\/ar800188e","volume":"42","author":"M de Jong","year":"2009","unstructured":"de Jong M, et al. Tumor imaging and therapy using radiolabeled somatostatin analogues. Acc Chem Res. 2009;42(7):873\u201380.","journal-title":"Acc Chem Res"},{"issue":"9","key":"5926_CR2","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1093\/annonc\/mdm058","volume":"18","author":"DB Cornelio","year":"2007","unstructured":"Cornelio DB, Roesler R, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy. Ann Oncol. 2007;18(9):1457\u201366.","journal-title":"Ann Oncol"},{"issue":"1","key":"5926_CR3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0170536","volume":"12","author":"SU Dalm","year":"2017","unstructured":"Dalm SU, et al. Prospects of targeting the gastrin releasing peptide receptor and somatostatin receptor 2 for nuclear imaging and therapy in metastatic breast cancer. PLoS One. 2017;12(1): e0170536.","journal-title":"PLoS One"},{"issue":"9","key":"5926_CR4","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.2967\/jnumed.116.188011","volume":"58","author":"C Morgat","year":"2017","unstructured":"Morgat C, et al. Expression of gastrin-releasing peptide receptor in breast cancer and its association with pathologic, biologic, and clinical parameters: a study of 1,432 primary tumors. J Nucl Med. 2017;58(9):1401\u20137.","journal-title":"J Nucl Med"},{"issue":"6","key":"5926_CR5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394\u2013424.","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"5926_CR6","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.cpet.2016.12.002","volume":"12","author":"T Maina","year":"2017","unstructured":"Maina T, Nock BA. From bench to bed: new gastrin-releasing peptide receptor-directed radioligands and their use in prostate cancer. PET Clin. 2017;12(2):205\u201317.","journal-title":"PET Clin"},{"key":"5926_CR7","first-page":"S221","volume":"34","author":"L Bodei","year":"2007","unstructured":"Bodei L, et al. Lu-177-AMBA bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations. Eur J Nucl Med Mol Imaging. 2007;34:S221\u2013S221.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"2","key":"5926_CR8","doi-asserted-by":"publisher","first-page":"318","DOI":"10.2967\/jnumed.107.045054","volume":"49","author":"R Cescato","year":"2008","unstructured":"Cescato R, et al. Bombesin receptor antagonists may be preferable to agonists for tumor targeting. J Nucl Med. 2008;49(2):318\u201326.","journal-title":"J Nucl Med"},{"key":"5926_CR9","doi-asserted-by":"publisher","first-page":"1750","DOI":"10.2741\/4569","volume":"22","author":"F Gallivanone","year":"2017","unstructured":"Gallivanone F, et al. Targeted radionuclide therapy: frontiers in theranostics. Front Biosci (Landmark Ed). 2017;22:1750\u20139.","journal-title":"Front Biosci (Landmark Ed)"},{"issue":"12","key":"5926_CR10","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.2967\/jnumed.119.238808","volume":"61","author":"L Gruber","year":"2020","unstructured":"Gruber L, et al. MITIGATE-NeoBOMB1, a phase I\/IIa study to evaluate safety, pharmacokinetics, and preliminary imaging of (68)Ga-NeoBOMB1, a gastrin-releasing peptide receptor antagonist. GIST patients J Nucl Med. 2020;61(12):1749\u201355.","journal-title":"GIST patients J Nucl Med"},{"key":"5926_CR11","doi-asserted-by":"crossref","unstructured":"Kaloudi A, et al.\u00a02017 NeoBOMB1 a GRPR-antagonist for breast cancer theragnostics: first results of a preclinical study with [(67)Ga]NeoBOMB1 in T-47D cells and tumor-bearing mice. Molecules. 22(11).","DOI":"10.3390\/molecules22111950"},{"issue":"2","key":"5926_CR12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.2967\/jnumed.116.176636","volume":"58","author":"SU Dalm","year":"2017","unstructured":"Dalm SU, et al. 68Ga\/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J Nucl Med. 2017;58(2):293\u20139.","journal-title":"J Nucl Med"},{"issue":"1","key":"5926_CR13","doi-asserted-by":"publisher","first-page":"75","DOI":"10.2967\/jnumed.116.178889","volume":"58","author":"BA Nock","year":"2017","unstructured":"Nock BA, et al. Theranostic perspectives in prostate cancer with the gastrin-releasing peptide receptor antagonist NeoBOMB1: preclinical and first clinical results. J Nucl Med. 2017;58(1):75\u201380.","journal-title":"J Nucl Med"},{"issue":"1","key":"5926_CR14","first-page":"1","volume":"45","author":"SU Dalm","year":"2018","unstructured":"Dalm SU. Efficacy and toxicity of 177Lu-NeoBOMB1 for prostate cancer treatment - a preclinical study October 13\u201317, 2018 Germany. Ann Cong of the Eur Assoc of Nucl Med. 2018;45(1):1\u2013844.","journal-title":"Ann Cong of the Eur Assoc of Nucl Med"},{"key":"5926_CR15","unstructured":"Advanced Accelerator A. 177Lu -NeoB in Patients With Advanced Solid Tumors and With 68Ga -NeoB Lesion Uptake. 2023 August 31; Available from: https:\/\/ClinicalTrials.gov\/show\/NCT03872778."},{"issue":"3","key":"5926_CR16","doi-asserted-by":"publisher","first-page":"477","DOI":"10.2967\/jnumed.108.056036","volume":"50","author":"WE Bolch","year":"2009","unstructured":"Bolch WE, et al. MIRD pamphlet No. 21 a generalized schema for radiopharmaceutical dosimetry\u2013standardization of nomenclature. J Nucl Med. 2009;50(3):477\u201384.","journal-title":"J Nucl Med"},{"issue":"3","key":"5926_CR17","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1089\/cbr.2006.320","volume":"22","author":"E Larsson","year":"2007","unstructured":"Larsson E, et al. Mouse S-factors based on Monte Carlo simulations in the anatomical realistic Moby phantom for internal dosimetry. Cancer Biother Radiopharm. 2007;22(3):438\u201342.","journal-title":"Cancer Biother Radiopharm"},{"issue":"3","key":"5926_CR18","doi-asserted-by":"publisher","first-page":"471","DOI":"10.2967\/jnumed.109.070532","volume":"51","author":"MA Keenan","year":"2010","unstructured":"Keenan MA, et al. RADAR realistic animal model series for dose assessment. J Nucl Med. 2010;51(3):471\u20136.","journal-title":"J Nucl Med"},{"issue":"1","key":"5926_CR19","first-page":"149","volume":"41","author":"MG Stabin","year":"2000","unstructured":"Stabin MG, Konijnenberg MW. Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes. J Nucl Med. 2000;41(1):149\u201360.","journal-title":"J Nucl Med"},{"issue":"1","key":"5926_CR20","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s00259-019-04504-3","volume":"47","author":"J Kurth","year":"2020","unstructured":"Kurth J, et al. First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [(177)Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2020;47(1):123\u201335.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"3","key":"5926_CR21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s00259-015-3193-4","volume":"43","author":"H Bergsma","year":"2016","unstructured":"Bergsma H, et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging. 2016;43(3):453\u201363.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"5","key":"5926_CR22","doi-asserted-by":"publisher","first-page":"762","DOI":"10.2967\/jnumed.112.112169","volume":"54","author":"RA Dumont","year":"2013","unstructured":"Dumont RA, et al. Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin. J Nucl Med. 2013;54(5):762\u20139.","journal-title":"J Nucl Med"},{"issue":"18","key":"5926_CR23","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1016\/j.clinbiochem.2017.07.003","volume":"50","author":"OZ Ismail","year":"2017","unstructured":"Ismail OZ, Bhayana V. Lipase or amylase for the diagnosis of acute pancreatitis? Clin Biochem. 2017;50(18):1275\u201380.","journal-title":"Clin Biochem"},{"key":"5926_CR24","doi-asserted-by":"crossref","unstructured":"Montemagno C, et al. In vivo biodistribution and efficacy evaluation of neob, a radiotracer targeted to GRPR, in mice bearing gastrointestinal stromal tumor. Cancers (Basel).\u00a0\u00a02021;13(5).","DOI":"10.3390\/cancers13051051"},{"issue":"1","key":"5926_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.12968\/hmed.2019.0274","volume":"81","author":"K Patel","year":"2020","unstructured":"Patel K, Batura D. An overview of hydronephrosis in adults. Br J Hosp Med (Lond). 2020;81(1):1\u20138.","journal-title":"Br J Hosp Med (Lond)"},{"issue":"5","key":"5926_CR26","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/S0270-9295(03)00093-7","volume":"23","author":"EP Cohen","year":"2003","unstructured":"Cohen EP, Robbins MEC. Radiation nephropathy. Semin Nephrol. 2003;23(5):486\u201399.","journal-title":"Semin Nephrol"},{"key":"5926_CR27","doi-asserted-by":"crossref","unstructured":"Quimby FW, Luong RH. Chapter 6 - clinical chemistry of the laboratory mouse, in The Mouse in Biomedical Research (Second Edition), J.G. Fox, et al., Editors, Academic Press: Burlington. p. 171\u2013216.\u00a02007.","DOI":"10.1016\/B978-012369454-6\/50060-1"},{"issue":"1","key":"5926_CR28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.semnephrol.2008.10.003","volume":"29","author":"C Chazot","year":"2009","unstructured":"Chazot C. Why are chronic kidney disease patients anorexic and what can be done about it? Semin Nephrol. 2009;29(1):15\u201323.","journal-title":"Semin Nephrol"},{"issue":"10","key":"5926_CR29","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1007\/s00259-016-3382-9","volume":"43","author":"H Bergsma","year":"2016","unstructured":"Bergsma H, et al. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging. 2016;43(10):1802\u201311.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"7","key":"5926_CR30","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1097\/MNM.0000000000000685","volume":"38","author":"D Pencharz","year":"2017","unstructured":"Pencharz D, et al. Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET. Nucl Med Commun. 2017;38(7):593\u2013600.","journal-title":"Nucl Med Commun"},{"issue":"9","key":"5926_CR31","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1089\/cbr.2012.1195","volume":"27","author":"SK Gupta","year":"2012","unstructured":"Gupta SK, Singla S, Bal C. Renal and hematological toxicity in patients of neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-DOTATATE. Cancer Biother Radiopharm. 2012;27(9):593\u20139.","journal-title":"Cancer Biother Radiopharm"},{"issue":"7","key":"5926_CR32","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1007\/s00259-009-1072-6","volume":"36","author":"F Forrer","year":"2009","unstructured":"Forrer F, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0), Tyr(3)]octreotate. Eur J Nucl Med Mol Imaging. 2009;36(7):1138\u201346.","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"2","key":"5926_CR33","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.fertnstert.2003.06.031","volume":"81","author":"T Falcone","year":"2004","unstructured":"Falcone T, et al. Ovarian function preservation in the cancer patient. Fertil Steril. 2004;81(2):243\u201357.","journal-title":"Fertil Steril"},{"issue":"4","key":"5926_CR34","first-page":"375","volume":"55","author":"GP Otto","year":"2016","unstructured":"Otto GP, et al. Clinical chemistry reference intervals for C57BL\/6J, C57BL\/6N, and C3HeB\/FeJ mice (Mus musculus). J Am Assoc Lab Anim Sci. 2016;55(4):375\u201386.","journal-title":"J Am Assoc Lab Anim Sci"}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-022-05926-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-022-05926-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-022-05926-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T04:15:36Z","timestamp":1666757736000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-022-05926-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":34,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["5926"],"URL":"https:\/\/doi.org\/10.1007\/s00259-022-05926-2","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]},"assertion":[{"value":"6 May 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Financial interests: L.B. and K.R. are employed by Advanced Accelerators Applications, a Novartis Company. The other authors have no relevant financial or non-financial interests to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The datasets generated during and\/or analyzed during the current study are available from the corresponding author on reasonable request.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"All conducted animal experiments were approved by the Erasmus MC Animal Welfare Committee and were in accordance to the European law.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}