Improving Pharmacokinetics of PSMA/GRPR-Targeting Radiolabeled Heterodimer through Enhanced Albumin Binding.

Radiolabeled heterodimers targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have been extensively investigated to overcome heterogeneous target expression in prostate cancer. However, low tumor retention and high kidney uptake remain major challenges. In this study, we designed and synthesized a novel albumin binder (ALB)-modified PSMA/GRPR-targeting heterodimer, PADA, to improve tumor retention and tumor-to-kidney ratios. [111In]In-PADA exhibited marked binding ability to albumin, PSMA, and GRPR in vitro. In biodistribution studies, the tumor retention of [111In]In-PADA was improved by the introduction of ALB in both PSMA-positive and GRPR-positive tumor-bearing mice. Overall, the tumor AUC values and tumor-to-kidney AUC value ratios of [111In]In-PADA were higher than those of a control agent without an ALB moiety in both model mice. In single-photon emission computed tomography (SPECT) imaging studies, [111In]In-PADA could be used to successfully visualize both PSMA-positive and GRPR-positive tumors and exhibited enhanced tumor-to-kidney contrast due to the introduction of ALB. These results suggest that [111In]In-PADA exhibits favorable pharmacokinetics as a PSMA/GRPR-targeting heterodimer.