Preclinical Evaluation of a New Series of Albumin-Binding [sup.177]Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-08, Vol.28 (16)
• Main Authors: Boinapally, Srikanth, Alati, Suresh, Jiang, Zirui, Yan, Yu, Lisok, Alla, Singh, Rajan, Lofland, Gabriela, Minn, Il, Hobbs, Robert F, Pomper, Ma, Banerjee, Sangeeta Ray
• Format: Article
• Language: English
• Subjects: Albumin; Analysis; Antigens; Diagnosis; Medical equipment and supplies industry; Medical test kit industry; Prostate cancer
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28166158

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, [sup.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 [sup.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 [sup.177]Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with [sup.177]Lu following standard protocols. All [sup.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 [sup.177]Lu-Alb-L2–[sup.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[sub.0-192h]) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (K[sub.i]s) of the ligands were in the ≤10 nM range. The long-linker-based agents, [sup.177]Lu-Alb-L4 and [sup.177]Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing [sup.177]Lu-Alb-L2 and [sup.177]Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, [sup.177]Lu-Alb-L6. The area under the curve (AUC[sub.0-192h]) of the PSMA+ PC3 PIP tumor uptake of [sup.177]Lu-Alb-L4 and [sup.177]Lu-Alb-L5 were >4-fold higher than [sup.177]Lu-Alb-L2, [sup.177]Lu-Alb-L3, and [sup.177]Lu-Alb-L6, respectivel