RT Journal Article
SR Electronic
T1 Preclinical Evaluation of <sup>213</sup>Bi- and <sup>225</sup>Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 980
OP 988
DO 10.2967/jnumed.120.256388
VO 62
IS 7
A1 Sangeeta Ray Banerjee
A1 Ala Lisok
A1 Il Minn
A1 Anders Josefsson
A1 Vivek Kumar
A1 Mary Brummet
A1 Srikanth Boinapally
A1 Cory Brayton
A1 Ronnie C. Mease
A1 George Sgouros
A1 Robert F. Hobbs
A1 Martin G. Pomper
YR 2021
UL http://jnm.snmjournals.org/content/62/7/980.abstract
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 β-particle–emitting low-molecular-weight compound, 177Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here, we leveraged that scaffold to synthesize α-particle–emitting analogs of L1, 213Bi-L1 and 225Ac-L1, to evaluate their safety and cell kill effect in PSMA-positive (+) xenograft models. 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 PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administration were evaluated for 225Ac-L1. The absorbed radiation dose of 225Ac-L1 was determined using the biodistribution data and α-camera imaging. Results: 213Bi- and 225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. The biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of 225Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with 177Lu-L1. Activity-escalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was about 1 MBq/kg. α-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.