TY - JOUR
T1 - Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low- Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer
AU - Banerjee, Sangeeta Ray
AU - Lisok, Ala
AU - Minn, Il
AU - Josefsson, Anders
AU - Kumar, Vivek
AU - Brummet, Mary
AU - Boinapally, Srikanth
AU - Brayton, Cory
AU - Mease, Ronnie C.
AU - Sgouros, George
AU - Hobbs, Robert F.
AU - Pomper, Martin G.
N1 - Funding Information:
225Ac, 212Bi, and 177Lu for this work were supplied by the U.S. Department of Energy Office of Science by the Isotope Program in the Office of Nuclear Physics. We thank Dr. Michael McDevitt for his valuable suggestion on an experiment.
Funding Information:
Financial support was received from the Patrick C. Walsh Prostate Cancer Research Fund, EB024495, CA184228, and the Commonwealth Foundation. Sangeeta Ray, Il Minn, Ronnie Mease, and Martin Pomper are coinventors on one or more U.S. patents covering compounds discussed in this submission and, as such, are entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University, following its conflict-of-interest policies. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
© 2021 by the Society of Nuclear Medicine andMolecular Imaging.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - a-particle
KW - long-termtoxicity
KW - murine
KW - prostate carcinoma
KW - prostate-specific membrane antigen (PSMA)
UR - http://www.scopus.com/inward/record.url?scp=85107260221&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107260221&partnerID=8YFLogxK
U2 - 10.2967/jnumed.120.256388
DO - 10.2967/jnumed.120.256388
M3 - Article
C2 - 33246975
AN - SCOPUS:85107260221
SN - 0161-5505
VL - 62
SP - 980
EP - 988
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 7
ER -