Design and Preclinical Evaluation of a Novel Prostate-Specific Membrane Antigen Radioligand Modified with a Transthyretin Binder.
In: Cancers, Jg. 16 (2024-04-01), Heft 7, S. 1262-1274
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Simple Summary: Prostate-specific membrane antigen (PSMA)-targeting radioligands have been used clinically to treat metastatic prostate cancer. To deliver a sufficient radiation dose to eliminate cancer cells, the accumulation of the radioligand in the tumor should be high. Therefore, small-molecular-weight molecules have been modified with albumin binders to enhance their blood circulation time and, hence, increase the tumor uptake. The goal of this study was to investigate the utility of a transthyretin binder (TB-01) to achieve high tumor uptake of the resultant PSMA radioligand. Indeed, the newly developed [ 177 Lu]Lu-PSMA-TB-01 demonstrated enhanced blood circulation as compared to the clinically employed [ 177 Lu]Lu-PSMA-617. Consequently, a significantly higher accumulation of activity was observed in the tumor tissue, while activity retention in off-target tissue was only higher in the kidneys, but otherwise in the same range as for [ 177 Lu]Lu-PSMA-617. Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored "albumin binder concept". In this study, a novel PSMA ligand modified with a transthyretin-binding entity (TB-01) was synthesized and labeled with lutetium-177 to obtain [ 177 Lu]Lu-PSMA-TB-01. A high and specific uptake of [ 177 Lu]Lu-PSMA-TB-01 was found in PSMA-positive PC-3 PIP cells (69 ± 3% after 4 h incubation), while uptake in PSMA-negative PC-3 flu cells was negligible (<1%). In vitro binding studies showed a 174-fold stronger affinity of [ 177 Lu]Lu-PSMA-TB-01 to transthyretin than to human serum albumin. Biodistribution studies in PC-3 PIP/flu tumor-bearing mice confirmed the enhanced blood retention of [ 177 Lu]Lu-PSMA-TB-01 (16 ± 1% IA/g at 1 h p.i.), which translated to a high tumor uptake (69 ± 13% IA/g at 4 h p.i.) with only slow wash-out over time (31 ± 8% IA/g at 96 h p.i.), while accumulation in the PC-3 flu tumor and non-targeted normal tissue was reasonably low. Further optimization of the radioligand design would be necessary to fine-tune the biodistribution and enable its use for therapeutic purposes. This study was the first of this kind and could motivate the use of the "transthyretin binder concept" for the development of future radiopharmaceuticals. [ABSTRACT FROM AUTHOR]
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Titel: |
Design and Preclinical Evaluation of a Novel Prostate-Specific Membrane Antigen Radioligand Modified with a Transthyretin Binder.
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Autor/in / Beteiligte Person: | Vaccarin, Christian ; Mapanao, Ana Katrina ; Deberle, Luisa M. ; Becker, Anna E. ; Borgna, Francesca ; Marzaro, Giovanni ; Schibli, Roger ; Müller, Cristina |
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Zeitschrift: | Cancers, Jg. 16 (2024-04-01), Heft 7, S. 1262-1274 |
Veröffentlichung: | 2024 |
Medientyp: | academicJournal |
ISSN: | 2072-6694 (print) |
DOI: | 10.3390/cancers16071262 |
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