Preclinical Evaluation of a Radiolabeled Anti-PSMA Dimeric Aptamer in a Murine Model of Human Prostate Cancer

Prostate cancer is the third-leading cause of cancer death in men. Prostate-specific membrane antigen (PSMA) is a robust biomarker that is expressed in approximately 80% of patients diagnosed with prostate cancer; several theranostic strategies have emerged based upon targeting this biomarker. This report describes a dimeric aptamer complex (DAC) which is selective for PSMA⁺ cancer cells and is amenable to derivatization with additional diagnostic and therapeutic molecules. Confocal microscopy confirmed the selective nature of the DAC for PSMA⁺ LNCAP tumor cells. In addition, the affinity of the DAC for the PSMA protein was determined to be 2.16 ± 0.15 nM using biolayer interferometry (BLI). In proof-of-principle studies, this DAC was biotinylated (BioDAC; A10), complexed with streptavidin (SA), and radiolabeled with the positron-emitting radioisotope zirconium-89 (⁸⁹Zr: t_½ = 78.4 h, β⁺: 22.8%) to form the radiopharmaceutical [⁸⁹Zr]Zr-Df-SA-BioDAC ([⁸⁹Zr]Zr-A12). Acute biodistribution studies revealed elevated levels of radioactivity in PSMA⁺ tumors when compared to PSMA^- tumors. Radioactivity retention in the kidney was high due to the presence of streptavidin, while radioactivity retention in the liver was comparable with that of other radiolabeled aptamer complexes. Accordingly, the data suggests that the radiopharmaceutical will need to be redesigned using a strategy that is not reliant on a biotin–streptavidin paradigm before additional preclinical assessments are made and clinical translation can be attempted.