Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors

James Kelly, Alejandro Amor-Coarasa, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams, David Schlyer, Yize Zhao, Dohyun Kim, John W. Babich

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Purpose: Treatment of late-stage prostate cancer by targeted radiotherapeutics such as 131I-MIP-1095 and 177Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with 177Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as 68Ga3+, 177Lu3+ and 225Ac3+. Methods: Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an Nε-(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to 177Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using 66Ga3+ and biodistribution studies at 4 h, 24 h and 96 h p.i. with 177Lu3+. Results: PSMA affinity was high (IC50 = 1–10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for 177Lu-PSMA-617 over 96 h. The highest uptake was achieved with 177Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand 177Lu-RPS-067. Each of the compounds showed slower blood clearance than 177Lu-PSMA-617, with clearance proportional to linker length. Conclusions: The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with 177Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.

Original languageEnglish (US)
Pages (from-to)1841-1851
Number of pages11
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number11
StatePublished - Oct 1 2018
Externally publishedYes


  • Albumin
  • PSMA
  • Pharmacokinetics
  • Prostate cancer
  • Targeted radioligand therapy

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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