Abstract
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Objectives Tracers targeting prostate-specific membrane antigen (PSMA) have attracted considerable attention for radionuclide imaging and therapy of prostate cancer (PCa). The theranostic agent PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, has shown impressive results in preliminary clinical studies. Although not confirmed in first therapy studies, high tracer uptake in kidneys and salivary glands may limit the application of PSMA inhibitors. Here, we present optimization of SPECT/CT imaging and radionuclide therapy with PSMA I&T and 2-PMPA to reduce renal uptake.
Methods Biodistribution of 111In-PSMA I&T (0.1-10 nmol) was evaluated in mice bearing subcutaneous (sc) PSMA-transfected LS174T-tumors. PSMA-specific uptake of 111In-PSMA I&T in kidneys was blocked with 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) using increasing amounts (10-50 nmol) and different times of administration. Pharmacokinetics of 111In-PSMA I&T were assessed with and without co-injection of 2-PMPA. SPECT/CT was performed in mice with s.c. LS174T-PSMA tumors and sub-millimeter intraperitoneal LS174T-PSMA lesions with and without 2-PMPA co-injection. Toxicity and therapeutic efficacy of 177Lu-PSMA I&T were evaluated in non-tumor bearing mice and in LS174T-PSMA xenografted mice.
Results 111In-PSMA I&T specifically accumulated in LS174T-PSMA tumors, kidneys, spleen, adrenals, lung and salivary glands. Renal uptake was reduced 7-fold by co-injection of 2-PMPA. Subcutaneous tumors and sub-millimeter metastases could be clearly visualized in both conditions using SPECT/CT imaging, but in mice that did not receive 2-PMPA, high kidney and spleen intensity interfered with visualization of metastases in the vicinity of those organs. Co-administration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio 2.5-fold. At equivalent absorbed dose to the tumor (36 Gy), co-injection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T alone showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not.
Conclusions These preclinical data indicate that PSMA I&T is a promising theranostic tool for PCa. Moreover, PSMA-specific uptake in kidneys and spleen can be successfully tackled using blocking agents such as 2-PMPA, thereby improving the visualization of tumor lesions in the vicinity of those organs, and reducing nephrotoxicity during radionuclide therapy.