Impact of the mouse model and molar amount of injected ligand on the tissue distribution profile of PSMA radioligands

Abstract

Purpose Various preclinical study designs are described in the literature for the evaluation of PSMA radioligands. In this study, [177Lu]Lu-Ibu-DAB-PSMA, an albumin-binding radioligand, and [177Lu]Lu-PSMA-617 were investigated and compared under variable experimental conditions. Methods In vitro cell uptake studies were performed with PC-3 PIP and LNCaP tumor cells using a range of molar concentrations (0.75–500 nM) of both radioligands. Biodistribution and SPECT/CT imaging studies were carried out with the respective tumor mouse models using 0.05 nmol and 1.0 nmol injected ligand per mouse. Results In both tumor cell lines, the uptake of the radioligands was increased when using low molar concentrations of the respective ligand. The observed saturation effect at high ligand concentrations was more pronounced for LNCaP cells that express PSMA at lower levels than for PC-3 PIP cells. At all investigated timepoints, the in vivo uptake of both radioligands was higher in PC-3 PIP tumors than in LNCaP tumors. A low molar amount of injected ligand increased the PC-3 PIP tumor uptake mainly for [177Lu]Lu-Ibu-DAB-PSMA; however, the molar amount of ligand was relevant for both radioligands when using LNCaP tumors. Renal retention of both radioligands was, however, up to fourfold higher during the first hours after application of a low ligand amount compared to the high ligand amount. Conclusion The results of this preclinical study underline the relevance of the tumor model and applied ligand amount for the characterization of PSMA radioligands. The application of equal preclinical study designs is crucial to allow the comparison of novel radioligands with existing ones and, thus, predict potential advantages of new radioligands in view of a clinical application.

Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand 212Pb-NG001

“…However, the direct comparison of published data from various research groups is challenging because a range of prostate cancer cell lines, mouse strains, and molar amounts and activities of the radioligands have been used. The human prostate cancer PC-3 PIP, LNCaP, and C4-2 cell lines are the most often used in preclinical evaluations of PSMA-targeting radioligands [ 15 , 17 , 18 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. LNCaP and C4-2 display 1.4–5.9 × 10 5 PSMA sites per cell [ 23 , 29 , 31 , 32 , 33 , 34 , 35 , 36 ], whereas PC-3 PIP has been genetically engineered to stably express PSMA levels 10–20 times higher (4.9 × 10 6 sites per cell) [ 35 ].…”

“…However, the use of the same cell line in variable ratios does not consider other characteristics that may differ in various tumors, e.g., cellular binding and internalization, growth pattern of the cell line in vivo, and tumor vascularization. Tschan et al showed that the cell type plays an important role in evaluating radioligands in vitro and in vivo [ 25 ].…”

“…Another aspect that makes direct comparisons of different radiopharmaceuticals challenging is the use of a range of molar amounts and activities of radioligands. This can lead to variable degrees of receptor saturation in PSMA-expressing tissues, thereby influencing uptake [ 25 , 43 , 44 , 45 ]. Some studies report increased tumor and kidney uptake at increasing effective molar activities (MBq/nmol of ligand) [ 25 , 43 , 44 , 46 , 47 ], whereas others observe no such correlation [ 45 , 48 , 49 ].…”

Assessment of Malignancy and PSMA-expression of Uncertain Bone Lesions in [18F]PSMA-1007 PET/CT for Prostate Cancer- a Single Centre Experience of PET-guided Biopsies

“…The lack of IHC PSMA-expression, and lack of histopathological evidence for benign, in ammatory or other malignant entities suggests a potential non-PSMA-receptor-mediated uptake mechanism for UBL in [ 18 F]PSMA-1007 PET/CT; further studies are needed to elucidate the true mechanism for this which remains unclear. For example, variation in molar activity has been demonstrated to in uence the biodistribution of some PSMA-radioligands [22]. Quality control of the GMP manufactured radiopharmaceutical and the high frequency with which UBL are observed in other centres makes a local radiochemical purity problem unlikely [4,5].…”

Radiolabeled PSMA Inhibitors

“…In a recently published clinical study, ten patients with metastatic castration resistant prostate cancer (mCRPC) received [ 177 Lu]Lu-PSMA-ALB-56 endoradiotherapy with a higher absorbed dose in tumor lesions and similar salivary gland-uptake compared to PSMA-617 and PSMA I&T [ 155 ]. Nevertheless, kidney and red marrow uptake in these patients remains high, this demands further preclinical optimization of albumin-binding PSMA radioligands (e.g., upon utilization of ibuprofen as an albumin-binding entity) [ 156 , 157 , 158 ].…”