Abstract
BACKGROUND: The March 2022 approval of [¹⁷⁷Lu]Lu-PSMA-617-the first targeted radioligand therapy (TRT) for metastatic castration-resistant prostate cancer (mCRPC)-addressed a critical need in therapeutic diagnostics. However, approximately 30% of patients fail to respond to PSMA-targeted therapies, with suboptimal pharmacokinetics implicated as a key factor. To address this challenge, fatty acids, known for their role in binding albumin and enhancing drug pharmacokinetics, were explored. Although commonly used in small molecules and peptides, their application in radiopharmaceuticals remains limited. In response, a novel fatty acid-modified PSMA-targeting agent was developed to optimize pharmacokinetics by enhancing circulation half-life, tumor uptake, radioligand selectivity, and safety while reducing off-target accumulation. This innovative approach aims to maximize therapeutic efficacy, improve patient outcomes in mCRPC care, and reduce the overall treatment burden. RESULTS: In vitro studies confirmed the strong binding affinity and high specificity of [(177)Lu]Lu-BT-117016 for PSMA. Biodistribution studies in LNCaP clone FGC tumor-bearing mice demonstrated significantly enhanced tumor uptake and retention of [(177)Lu]Lu-BT-117016 compared to [(177)Lu]Lu-PSMA-617. SPECT/CT imaging and therapy studies highlighted the superior profile of [(177)Lu]Lu-BT-117016. It achieved significant tumor growth suppression with favorable tolerability at a minimal dose of 3 MBq, demonstrating comparable efficacy to a nearly 6-fold higher dose (20 MBq) of [177Lu]Lu-PSMA-617. The improved safety profile of [¹⁷⁷Lu]Lu-BT-117016 over [¹⁷⁷Lu]Lu-PSMA-617 was confirmed through radiation dosimetry. CONCLUSION: Preclinical studies demonstrate that [¹⁷⁷Lu]Lu-BT-117016, a novel fatty acid-modified PSMA-targeting agent, optimizes albumin binding and harmonizes ligand-isotope half-lives. This results in advantageous biodistribution-characterized by high tumor uptake, rapid non-target clearance, and extended circulation-leading to complete tumor remission in LNCaP models with reduced toxicity. Crucially, [¹⁷⁷Lu]Lu-BT-117016 achieved equivalent efficacy to [¹⁷⁷Lu]Lu-PSMA-617 at 3-6 times lower doses. These findings indicate [¹⁷⁷Lu]Lu-BT-117016's potential as a safer, more potent CRPC therapy enabling reduced dosages and less frequent administration. Further clinical trials are warranted to confirm these benefits.