Imageological/Structural Study regarding the Improved Pharmacokinetics by (68)Ga-Labeled PEGylated PSMA Multimer in Prostate Cancer

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series (68)Ga/(177)Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [(68)Ga]Ga-DOTA-(1P-PEG(4)), [(68)Ga]Ga-DOTA-(2P-PEG(0)), [(68)Ga]Ga-DOTA-(2P-PEG(4)), and [(68)Ga]Ga/[(177)Lu]Lu-DOTA-(2P-PEG(4))(2), which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe’s tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes’ affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG(4) and PSMA dimer optimizations enhanced the probes’ tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [(68)Ga]Ga-DOTA-(2P-PEG(4))(2) exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG(4))(2) was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG(4))(2) is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice.