Synthesis, radiolabeling, and biodistribution evaluation of novel hyperbranched polyglycerols-based radiotracers for targeting PSMA in prostate cancer
نویسندگان
1 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
2 Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Mechanical Engineering, Shiraz University of Technology, Shiraz, Iran
4 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Pharmaceutical Chemistry and Radiopharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
6 Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
7 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
8 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
9 Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
10 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
11 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
doi
10.22038/ijbms.2026.94567.20396چکیده
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.
