title: Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent.
abstract: Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics-they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. (111)In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of (111)In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during (177)Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with (177)Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with (177)Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA.
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC Rotterdam, The Netherlands;; 2. Department of Radiology, Erasmus MC Rotterdam, The Netherlands;; 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands;
authors.forename: Kristell L S
authors.initials: KL
authors.lastname: Chatalic
authors.affiliation: 4. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC Rotterdam, The Netherlands;
authors.forename: Mark
authors.initials: M
authors.lastname: Konijnenberg
authors.affiliation: 4. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Janneke D M
authors.initials: JD
authors.lastname: Molkenboer-Kuenen
authors.affiliation: 4. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.affiliation: 5. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.affiliation: 6. Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.affiliation: 6. Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands;
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.affiliation: 4. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC Rotterdam, The Netherlands;; 2. Department of Radiology, Erasmus MC Rotterdam, The Netherlands;
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D000954:Antigens, Surface; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D057285:Precision Medicine / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000628:therapy*; D011868:Radioisotopes / Q000008:administration & dosage / Q000009:adverse effects; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods*; D000072098:Single Photon Emission Computed Tomography Computed Tomography / Q000379:methods*; D000068936:Theranostic Nanomedicine / Q000379:methods*
chemical_list: D000954:Antigens, Surface; D011868:Radioisotopes; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 2-PMPA.; CRPC; PSMA; SPECT; imaging; prostate cancer; radionuclide therapy