[ 225 Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [ 225 Ac]Ac-PSMA-617.

In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [ 225 Ac]Ac-PSMA-617. In vitro, [ 225 Ac]Ac-SibuDAB and [ 225 Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177 Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [ 225 Ac]Ac-SibuDAB as compared to [ 177 Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [ 225 Ac]Ac-SibuDAB in the blood than previously seen for [ 177 Lu]Lu-SibuDAB. Similar to [ 225 Ac]Ac-PSMA-617, [ 225 Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [ 225 Ac]Ac-SibuDAB and [ 225 Ac]Ac-PSMA-617. [ 225 Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [ 225 Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [ 225 Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [ 225 Ac]Ac-SibuDAB as compared to that of [ 225 Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.