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

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.

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review

“…To this day FAPI α-therapy has only been reported in preclinical settings in mice with 225-Actinium ( 225 Ac-FAPI-04) [ 72 ]. 225 Ac is a pure α emitter that has seen application in prostate and neuroendocrine cancers [ 73 , 74 , 75 ]. This would require FAPI ligands with a long retention time in tumor lesions to make up for the long half-life of 225 Ac (9920 days) as well as 177 Lu (66,443 days).…”

Comparison of the tolerability of161Tb- and177Lu-labeled somatostatin analogues in the preclinical setting

“…Tissue sections (4 µm thickness) of paraffin-embedded spleen, kidneys and liver of mice from Study II were stained using hematoxylin and eosin and the histo(patho)logical analysis was performed by a board-certified veterinary pathologist (AnaPath Services GmbH, Liestal, Switzerland) using a pre- defined scoring system (Supplementary Material) [29].…”

Actinium-225 targeted alpha particle therapy for prostate cancer

“…A study by Meyer et al demonstrated that incorporating an extended linker with supplementary naphthyl groups enhances ligand binding to albumin, thereby extending circulating half-life 29 . Using a similar strategy, Busslinger et al developed ibuprofen containing ligand [ 225 Ac]Ac-SibuDAB, which showed similar radiolabeling and hematological effect as [ 225 Ac]Ac-PSMA-617, whereas the tumor uptake of the [ 225 Ac]Ac-SibuDAB doubled at 48 h as compared to [ 225 Ac]Ac-PSMA-617 (64 ± 11% IA/g vs. 31 ± 3% IA/g), resulting in improved therapeutic response and overall survival in animal models 30 . Another study with macropa chelator conjugated to albumin binding unit (4-(p-iodophenyl)butyrate) and one or two PSMA ligands also showed that the uptake of an albumin-bound [ 225 Ac]Ac-PSMA molecule was four times higher than the non-albumin binding counterpart 31 .…”