Preclinical Evaluation of a New Series of Albumin-Binding 177 Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.
In: Molecules, Jg. 28 (2023-08-15), Heft 16, S. 6158-6173
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academicJournal
Zugriff:
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, 177 Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177 Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1–Alb-L6) were synthesized based on the structure of 177 Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177 Lu following standard protocols. All 177 Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177 Lu-Alb-L2– 177 Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA− PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC 0-192h ) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (K i s) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177 Lu-Alb-L4 and 177 Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177 Lu-Alb-L2 and 177 Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177 Lu-Alb-L6. The area under the curve (AUC 0-192h ) of the PSMA+ PC3 PIP tumor uptake of 177 Lu-Alb-L4 and 177 Lu-Alb-L5 were >4-fold higher than 177 Lu-Alb-L2, 177 Lu-Alb-L3, and 177 Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC 0-192h ) of 177 Lu-Alb-L2 and 177 Lu-Alb-L3 was ~1.5-fold higher than 177 Lu-Alb-L6. However, the lowest blood AUC 0-192h and kidney AUC 0-192h were associated with 177 Lu-Alb-L6 from the series. Consequently, 177 Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177 Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177 Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177 Lu-Alb-L4 and 177 Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent. [ABSTRACT FROM AUTHOR]
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Titel: |
Preclinical Evaluation of a New Series of Albumin-Binding 177 Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.
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Autor/in / Beteiligte Person: | Boinapally, Srikanth ; Alati, Suresh ; Jiang, Zirui ; Yan, Yu ; Lisok, Alla ; Singh, Rajan ; Lofland, Gabriela ; Minn, Il ; Hobbs, Robert F. ; Pomper, Martin G. ; Banerjee, Sangeeta Ray |
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Zeitschrift: | Molecules, Jg. 28 (2023-08-15), Heft 16, S. 6158-6173 |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 1420-3049 (print) |
DOI: | 10.3390/molecules28166158 |
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