Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

Int J Mol Sci. 2021 May 1;22(9):4815. doi: 10.3390/ijms22094815.


Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3-10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001.

Keywords: 212Pb; metastatic castration-resistant prostate cancer; p-SCN-Bn-TCMC-PSMA ligand (NG001); prostate-specific membrane antigen; targeted alpha therapy.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Lead / pharmacology
  • Ligands
  • Male
  • Mice
  • Neoplasm Metastasis
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Prostatic Neoplasms, Castration-Resistant / radiotherapy*
  • Radioisotopes / pharmacology
  • Radioligand Assay*
  • Radiopharmaceuticals / pharmacology*
  • Spheroids, Cellular / pathology
  • Spheroids, Cellular / radiation effects*
  • Tissue Distribution / radiation effects


  • Ligands
  • Radioisotopes
  • Radiopharmaceuticals
  • Lead