Development of Improved radioconjugates for Prostate Cancer Theranostics

Prostate cancer is one of the most common malignancies in men, and the prostate-specific membrane antigen (PSMA) has emerged as a key molecular target for imaging and targeted radionuclide therapy (TRT). However, current PSMA-targeted radiopharmaceuticals often display rapid blood clearance and high renal uptake, which can limit their therapeutic performance. This work focused on the design, synthesis, and preclinical evaluation of a novel heterobivalent radiocomplex aimed at improving the pharmacokinetic properties of PSMA-targeted agents. The developed conjugate, DOTA–IPBA–PEG–PSMA, integrates a PSMA-binding moiety with an albumin-binding unit, 4-(p-iodophenyl)butyric acid (IPBA), to promote a reversible interaction with serum albumin. This dual-targeting strategy was intended to prolong systemic circulation and enhance tumor accumulation while minimizing non-specific uptake. The conjugate was synthesized through a stepwise procedure enabling the independent coupling of the PSMA-recognition and albumin-binding fragments. Radiolabeling with indium-111 was achieved in high yield, affording [¹¹¹In]In– DOTA–IPBA–PEG–PSMAwith excellent radiochemical purity and stability in both PBS and serum. Indium-111 was employed as the γ-emitting isotope for imaging and biodistribution studies, while the same DOTA chelator allows for complexation with lutetium-177, supporting a theranostic application. In vitro assays performed on PSMA-positive (PC3-PIP) and PSMA-negative (PC3-FLU) prostate cancer cell lines confirmed a receptor-mediated uptake mechanism. Serum-binding studies demonstrated the expected interaction with albumin. Biodistribution experiments in healthy CD-1 mice revealed prolonged blood retention and slower clearance for the heterobivalent compound compared to the PSMA-only reference complex. Overall, the incorporation of the IPBA-based albumin-binding domain effectively improved the pharmacokinetic and biological profile of PSMA-targeted radiocomplexes, supporting its potential as a promising theranostic agent for prostate cancer.