Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy.
Purpose: Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been comp...
| Publicado en: | European Journal of Nuclear Medicine & Molecular Imaging Vol. 48; no. 5; pp. 1339 - 1351 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
May2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=150259763&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 150259763 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 16197070 NPC jtl: European Journal of Nuclear Medicine & Molecular Imaging issn: 16197070 maglogo: N pubinfo: dt: May2021 vid: 48 iid: 5 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 150259763 146691579 10.1007/s00259-020-05057-6 150259763 ppf: 1339 ppct: 12 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy. aug: au: Ruigrok, Eline A. M. van Vliet, Nicole Dalm, Simone U. de Blois, Erik van Gent, Dik C. Haeck, Joost de Ridder, Corrina Stuurman, Debra Konijnenberg, Mark W. van Weerden, Wytske M. de Jong, Marion Nonnekens, Julie affil: Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands sug: ab: Purpose: Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results: In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion: [177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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