Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. METHODS: Five patients with a history of prostate cancer were injected intravenously with 91–148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. RESULTS: Injection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). CONCLUSION: (68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG

Targeted Alpha Radionuclide Therapy of Prostate Cancer Using a Small Molecule Inhibitor of Prostate-specific Membrane Antigen (PSMA)

Objectives: PSMA is a well-recognized target for imaging and therapy of prostate cancer (PCa), as it is expressed in nearly all PCa lesions. Radiolabeled PSMA inhibitors localize rapidly to tumor lesions, including soft-tissue and bone metastases, but also show high uptake in kidneys and salivary glands. The aim of the present study was to evaluate the potential of 213Bi-PSMA I&T a DOTA-chelated urea-based PSMA inhibitor, as therapeutic agent in PSMA-expressing tumor cells in vitro and in vivo. Materials and Methods: PSMA I&T was labeled with 111In for biodistribution studies and with 213Bi for therapeutic studies. The tumor targeting of 111In-PSMA I&T was evaluated in mice with subcutaneous LNCaP tumors and PSMA-transfected LS174T tumors. Biodistribution was determined 2 h after injection of 0.1, 0.3, 1, or 10 nmol of 111In-PSMA I&T. Blocking of PSMA-specific binding to kidneys was investigated by co-injecting 2-(Phosphonomethyl)pentane-1,5-dioic acid (PMPA). Next, the therapeutic efficacy of 213Bi-PSMA I&T was tested in vitro in LNCaP cells and in vivo in mice with LNCaP xenografts. Cells were incubated for 20 min with 213Bi-PSMA I&T, 213Bi-DTPA, or medium, and fixed at 1, 2, 4, 24, and 48 h after treatment. Mice were injected with 213Bi-PSMA I&T (0.2 nmol, 5 MBq) and biodistribution was determined at 1 h after injection. In addition, tumor and kidneys were dissected 1 h and 24 h after injection. Fixed cells and tissues were stained with an anti-53BP1 antibody, an anti-GEMININ antibody and a TUNEL detection kit. Results: 111In-PSMA I&T uptake in LNCaP and LS174T-PSMA tumors, kidneys, spleen, lung and salivary glands was dependent on amount of injected peptide. Optimal doses for tumor targeting were between 0.1 and 0.3 nmol. Co-injection of 10 nmol PMPA resulted in a 2.5-fold decrease in renal uptake, and a 1.2-fold decrease in tumor uptake. Treatment of LNCaP cells with 213Bi-PSMA I&T caused a decrease in cellular proliferation, accumulation of DNA double-strand breaks, and induction of apoptosis. The biodistribution of 213Bi-PSMA I&T and 111In-PSMA I&T were similar. 213Bi-PSMA I&T induced DNA-double strand breaks in LNCaP tumors, from which a significant amount was not repaired at 24 h after injection. Conclusion: PSMA I&T is a promising targeting agent for radionuclide therapy of PCa. In this study we showed that renal accumulation of this tracer can be efficiently reduced by co-injection of PMPA, while tumor uptake was preserved. Our preliminary results reveal a good targeting and therapeutic effect of 213Bi-PSMA I&T in LNCaP cells in vitro and in vivo.JRC.E.5-Nuclear chemistr