Synthesis, radiolabeling, and biodistribution evaluation of novel hyperbranched polyglycerols-based radiotracers for targeting PSMA in prostate cancer

Objective(s): Prostate-specific membrane antigen (PSMA) is a valuable target for prostate cancer imaging and therapy. This study aimed to improve the rapid blood clearance and suboptimal tumor uptake and retention of radiolabeled PSMA by developing a hyperbranched polyglycerol (HPG)-based PSMA conjugate.Materials and Methods: HPG was synthesized via a one-step ring-opening multibranching polymerization (ROMBP) technique and sequentially functionalized with a PSMA-targeting ligand and a tris (hydroxypyridinone) (THP) chelator. The final construct was radiolabeled with gallium-68 or technetium-99m. Physicochemical properties, including lipophilicity (log P) and in vitro stability, were evaluated. In vivo biodistribution and imaging were assessed in LNCaP tumor-bearing nude mice using PET/SPECT/CT.Results: The THP-HPGs-PSMA derivative (170 kDa, 5-6 PSMA ligands, and 7-8 THP chelators per polymer molecule) achieved radiochemical purity >99%. [68Ga]Ga THP HPG PSMA had high stability (>95% after 120 min), and log P of -1.56 ± 0.18. Blood uptake was 13.95 ± 0.75 and 11.82 ± 0.88 %ID/g at 30 and 120 min, respectively. Tumor uptake reached 7.12 ± 0.27, 7.40 ± 0.63, and 7.91 ± 0.20 %ID/g at 30, 60, and 120 min, respectively. Clearance was predominantly hepatobiliary with reduced renal excretion. [⁹⁹ᵐTc]Tc-THP-HPG-PSMA showed tumor uptake of 8.74 ± 0.25, 9.41 ± 0.42, and 9.80 ± 0.41 %ID/g at 4, 8, and 16 hr. Blocking studies reduced tumor uptake from 7.12 ± 0.27 to 0.93 ± 0.53 %ID/g.Conclusion: Radiolabeled THP-HPG-PSMA demonstrates improved pharmacokinetics, enhanced tumor uptake, prolonged tumor retention, and favorable tumor-to-blood ratios, indicating strong potential for PSMA-targeted prostate cancer applications.