PMSA (prostate-specific membrane
antigen) is currently the most significant target for diagnosing and treating PCa (
prostate cancer). Herein, we reported a series 68Ga/177Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [68Ga]Ga-
DOTA-(1P-PEG4), [68Ga]Ga-
DOTA-(2P-PEG0), [68Ga]Ga-
DOTA-(2P-PEG4), and [68Ga]Ga/[177Lu]Lu-
DOTA-(2P-PEG4)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 PEG4 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. [68Ga]Ga-
DOTA-(2P-PEG4)2 exhibited higher
tumor-to-organ ratios. When labeled by
lutetium-177, relatively high accumulation of DOTA-(2P-PEG4)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-PEG4)2 is expected to be a promising
tumor-targeting diagnostic molecular probe in future clinical practice.