Preclinical Investigations to Explore the Difference between the Diastereomers [¹⁷⁷Lu]Lu-SibuDAB and [¹⁷⁷Lu]Lu-RibuDAB toward Prostate Cancer Therapy

Abstract

Lu-Ibu-DAB-PSMA, a radioligand modified with ibuprofen as the albumin binder, showed higher accumulation in PSMA-positive tumors of mice than the clinically used [ 177 Lu]Lu-PSMA-617 but lower retention in non-targeted tissues than previously developed albumin-binding PSMA radioligands. The aim of this study was to investigate whether the stereochemistry of the incorporated ibuprofen affects the radioligand's in vitro and in vivo properties and to select the more favorable radioligand for further development. For this purpose, SibuDAB and RibuDAB containing (S)-and (R)-ibuprofen, respectively, were synthesized and labeled with lutetium-177. In vitro, the two isomers had similar properties; however, [ 177 Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [ 177 Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). In vivo, [ 177 Lu]Lu-SibuDAB was metabolically more stable than [ 177 Lu]Lu-RibuDAB with ∼90 vs ∼67% intact radioligand detected in the blood at 4 h post injection (p.i.). In line with the lower albumin-binding affinity, the blood clearance of [ 177 Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [ 177 Lu]Lu-SibuDAB (50% IA, 1 h p.i.). Time-dependent biodistribution studies performed in tumor-bearing athymic nude mice showed high PSMA-specific tumor uptake for both isomers. A twofold increased area under the curve (AUC 0→8d ) of the blood retention was determined for [ 177 Lu]Lu-SibuDAB as compared to [ 177 Lu]Lu-RibuDAB, whereas the kidney AUC 0→8d value of [ 177 Lu]Lu-SibuDAB was only half as high as for [ 177 Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC 0→8d ratio was obtained for [ 177 Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [ 177 Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [ 177 Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [ 177 Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [ 177 Lu]Lu-SibuDAB as compared to those injected with [ 177 Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.

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

“…The PSMA ligands used in this study were synthesized using solid-phase chemistry methods as previously reported [ 17 , 18 ]. The labeling of the PSMA ligands with actinium-225 was performed at ITM Medical Isotopes GmbH, Munich, Germany ( Supplementary Material: Section S1 ).…”

“…Depending on the experiment, the molar activity of the radioligands was adjusted by adding unlabeled ligand and the final formulation was prepared by adding vehicle (saline with 0.05% bovine serum albumin (BSA)) to obtain the desired activity concentration. Radiolabeling of SibuDAB with lutetium-177 (5–10 MBq/nmol) was performed as previously reported [ 17 ].…”

“…The logD values, cell uptake and internalization as well as PSMA-binding affinities (K D values) of [ 225 Ac]Ac-SibuDAB and [ 225 Ac]Ac-PSMA-617 (~50 kBq/nmol) were determined according to previously reported protocols ( Supplementary Material: Sections S3–S5 ) [ 16 , 17 ]. Relative albumin-binding affinities were determined using an ultrafiltration assay according to an adapted version of a recently published protocol ( Supplementary Material: Section S6 ) [ 20 ].…”

“…After tumor cell inoculation, mice bearing PC-3 PIP tumor xenografts were intravenously injected with vehicle only ( n = 6) or with [ 225 Ac]Ac-SibuDAB or [ 225 Ac]Ac-PSMA-617, respectively, applied at 5 kBq or 10 kBq (1 nmol per mouse; n = 6 per group; Table 1 ). The control group consisted of mice from several studies ( n = 12 mice) and the data from this group were published previously [ 17 ].…”

“…Recently, we have developed a new class of PSMA ligands comprising ibuprofen as an albumin-binding entity [ 16 ], whereof SibuDAB emerged as the most promising candidate [ 17 ]. The calculation of the area under the curve (AUC) values revealed higher tumor uptake for [ 177 Lu]Lu-SibuDAB than for [ 177 Lu]Lu-PSMA-617 but reduced retention in blood and kidneys as compared to [ 177 Lu]Lu-PSMA-ALB-56.…”