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-۶۸ or technetium-۹۹m. 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 (۱۷۰ kDa, ۵-۶ PSMA ligands, and ۷-۸ THP chelators per polymer molecule) achieved radiochemical purity >۹۹%. [۶۸Ga]Ga THP HPG PSMA had high stability (>۹۵% after ۱۲۰ min), and log P of -۱.۵۶ ± ۰.۱۸. Blood uptake was ۱۳.۹۵ ± ۰.۷۵ and ۱۱.۸۲ ± ۰.۸۸ %ID/g at ۳۰ and ۱۲۰ min, respectively. Tumor uptake reached ۷.۱۲ ± ۰.۲۷, ۷.۴۰ ± ۰.۶۳, and ۷.۹۱ ± ۰.۲۰ %ID/g at ۳۰, ۶۰, and ۱۲۰ min, respectively. Clearance was predominantly hepatobiliary with reduced renal excretion. [⁹⁹ᵐTc]Tc-THP-HPG-PSMA showed tumor uptake of ۸.۷۴ ± ۰.۲۵, ۹.۴۱ ± ۰.۴۲, and ۹.۸۰ ± ۰.۴۱ %ID/g at ۴, ۸, and ۱۶ hr. Blocking studies reduced tumor uptake from ۷.۱۲ ± ۰.۲۷ to ۰.۹۳ ± ۰.۵۳ %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.

کلیدواژه ها:

Chelator ، Hyperbranched - polyglycerol ، Molecular imaging ، PET Imaging ، Prostate cancer ، PSMA