LAUSR

Simple Summary Prostate-specific membrane antigen (PSMA) radioligands have proven effective to treat patients with metastatic castration-resistant prostate cancer. Targeted α-therapy using actinium-225 has been used for patients with end-stage disease who no longer responded to βࢤ-therapy through the use of 177Lu-based radioligand therapy (RLT). In this study, we investigated and compared the therapeutic efficacy of [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 and assessed potential undesired side effects in the preclinical setting. Due to a dedicated albumin-binding entity integrated into [225Ac]Ac-SibuDAB, this radioligand showed an enhanced blood circulation time and, hence, increased tumor uptake but also higher retention in normal tissues. The therapeutic efficacy of [225Ac]Ac-SibuDAB was enhanced as compared to that of [225Ac]Ac-PSMA-617, yet, undesired side effects were in the same range for both radioligands. Our data suggest that [225Ac]Ac-SibuDAB could be a powerful alternative to [225Ac]Ac-PSMA-617, however, the safe therapeutic window should be carefully defined in clinical dose escalation studies. Abstract 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 [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-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 [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]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 [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]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 [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.