1. Academic Validation
  2. Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

  • Theranostics. 2016 Apr 12;6(6):849-61. doi: 10.7150/thno.14744.
Kristell L S Chatalic 1 Sandra Heskamp 2 Mark Konijnenberg 3 Janneke D M Molkenboer-Kuenen 2 Gerben M Franssen 2 Marian C Clahsen-van Groningen 4 Margret Schottelius 5 Hans-Jürgen Wester 5 Wytske M van Weerden 6 Otto C Boerman 2 Marion de Jong 7
Affiliations

Affiliations

  • 1 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;
  • 2 4. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
  • 3 1. Department of Nuclear Medicine, Erasmus MC Rotterdam, The Netherlands;
  • 4 5. Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
  • 5 6. Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
  • 6 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands;
  • 7 1. Department of Nuclear Medicine, Erasmus MC Rotterdam, The Netherlands;; 2. Department of Radiology, Erasmus MC Rotterdam, The Netherlands;
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.

Keywords

2-PMPA.; CRPC; PSMA; SPECT; imaging; prostate cancer; radionuclide therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148761
    99.67%, PSMA抑制剂