Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low- Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer

Sangeeta Ray Banerjee, Ala Lisok, Il Minn, Anders Josefsson, Vivek Kumar, Mary Brummet, Srikanth Boinapally, Cory Brayton, Ronnie C. Mease, George Sgouros, Robert F. Hobbs, Martin G. Pomper

Research output: Contribution to journalArticlepeer-review


Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is a new option for patients with advanced prostate cancer refractory to other treatments. Previously, we synthesized a b-particle-emitting low-molecular-weight compound, 177Lu-L1 which demonstrated reduced off-target effects in a xenograftmodel of prostate cancer. Here, we leveraged that scaffold to synthesize a-particle-emitting analogs of L1, 213Bi-L1 and 225Ac-L1, to evaluate their safety and cell kill effect in PSMApositive (1) xenograftmodels.Methods: The radiochemical synthesis, cell uptake, cell kill, and biodistribution of 213Bi-L1 and 225Ac-L1 were evaluated. The efficacy of 225Ac-L1 was determined in human PSMA1subcutaneous andmicrometastaticmodels. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administrationwere evaluated for 225Ac-L1. The absorbed radiation dose of 225Ac-L1 was determined using the biodistribution data and a-camera imaging. Results: 213Bi- and 225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA1 cells. The biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA1 lesions. Treatment studies of 225Ac-L1 demonstrated activitydependent, specific inhibition of tumor growth in the PSMA1 flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with 177Lu-L1. Activityescalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximumtolerated activitywas about 1MBq/kg.a-Camera imaging of 225Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion: 225Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. 225Ac-L1 is a promising therapeutic for further clinical evaluation.

Original languageEnglish (US)
Pages (from-to)980-988
Number of pages9
JournalJournal of Nuclear Medicine
Issue number7
StatePublished - Jul 1 2021


  • a-particle
  • long-termtoxicity
  • murine
  • prostate carcinoma
  • prostate-specific membrane antigen (PSMA)

ASJC Scopus subject areas

  • Medicine(all)


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