Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy

• DOI: 10.1007/s00259-020-05057-6
• Publication Date: 2020-10-22T22:02:54Z
• Authors: Eline A. M. Ruigrok; Nicole van Vliet; Simone U. Dalm; Erik de Blois; Dik C. van Gent; Joost Haeck; Corrina de Ridder; Debra Stuurman; Mark W. Konijnenberg; Wytske M. van Wee...; Marion de Jong; Julie Nonnekens
• Keywords: Biodistribution; Radionuclide therapy; DOTA; Lutetium; Glutamate carboxypeptidase II

Abstract 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, DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern PSMA-targeting is the toxicity other PSMA-expressing organs, such as salivary glands, thus demanding careful evaluation most optimal safest radiotracer. In this extensive preclinical study, we evaluated small molecule inhibitors DOTA-PSMA-617 (PSMA-617) DOTAGA-PSMA-I&T (PSMA-I&T) nanobody DOTA-JVZ-007 (JVZ-007) using cell lines, a unique set PCa patient-derived xenografts (PDX) healthy human tissues. Methods results vitro displacement studies on cells cryosections PSMA-positive PDX revealed high specific affinity all three labeled with lutetium-177 IC 50 values nanomolar range. Interestingly, [ 177 Lu]Lu-JVZ-007 could be displaced by PSMA-617 or PSMA-I&T, suggesting that tracer targets an alternative site. Autoradiography assays renal tissues Lu]Lu-PSMA-617 to lowest organs Lu]Lu-PSMA-I&T. vivo biodistribution confirmed comparable tumor uptake Lu]Lu-PSMA-I&T at timepoints, resulting induction similar levels DNA double-strand breaks tumors. However, demonstrated approximately 40× higher 4 8 h post injection unfavorable tumor-to-kidney ratio. Conclusion has favorable mice well more characteristics kidney gland specimens Lu]Lu-JVZ-007. Based our evaluation, best performing taken further into clinical PSMA-targeted radiotherapeutic development although organs.