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

  • James Kelly
  • Alejandro Amor-Coarasa
  • Shashikanth Ponnala
  • Anastasia Nikolopoulou
  • Clarence WilliamsJr
  • David Schlyer
  • Yize Zhao
  • Dohyun Kim
  • John W. Babich
Original Article



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+.


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+.


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.


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.


PSMA Albumin Prostate cancer Targeted radioligand therapy Pharmacokinetics 



This work was supported by a Pilot Award from the Weill Cornell Medical College Clinical and Translational Science Center, funded by NIH/NCATS UL1TR00457. The authors wish to thank Dr. J. David Warren of the Milstein Chemistry Core Facility at Weill Cornell Medicine for providing equipment for compound purification and access to equipment for reaction analysis and compound characterization. They would also like to acknowledge Dr. Yiauchung “Howard” Shen and Calvin Lom of Memorial-Sloan-Kettering Cancer Center for assistance with the production of Ga-66.

Compliance with ethical standards

Conflict of interest

James Kelly, Alejandro Amor-Coarasa, Shashikanth Ponnala, and John W. Babich are co-inventors on the constructs described in this manuscript and hold equity in Noria Therapeutics, Inc. Anastasia Nikolopoulou, Clarence Williams, Jr., David Schlyer, Yize Zhao, and Dohyun Kim declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2018_4004_MOESM1_ESM.pdf (902 kb)
ESM 1 (PDF 902 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • James Kelly
    • 1
  • Alejandro Amor-Coarasa
    • 1
  • Shashikanth Ponnala
    • 1
  • Anastasia Nikolopoulou
    • 1
    • 2
  • Clarence WilliamsJr
    • 1
  • David Schlyer
    • 3
  • Yize Zhao
    • 4
  • Dohyun Kim
    • 2
  • John W. Babich
    • 1
    • 2
    • 5
  1. 1.Division of Radiopharmaceutical Sciences and MI3, Department of RadiologyWeill Cornell MedicineNew YorkUSA
  2. 2.Citigroup Biomedical Imaging CenterWeill Cornell MedicineNew YorkUSA
  3. 3.Brookhaven National LaboratoryUptonUSA
  4. 4.Division of Biostatistics and Epidemiology, Department of Healthcare Policy and ResearchWeill Cornell MedicineNew YorkUSA
  5. 5.Sandra and Edward Meyer Cancer CenterWeill Cornell MedicineNew YorkUSA

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