Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression

PurposeEvans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression.Methods[Lu-177]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1 tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [Lu-177]Lu-LNC1003.ResultsLNC1003 showed high binding affinity (IC50 = 10.77 nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC50 = 27.49 nM) and EB-PSMA-617 (IC50 = 7.91 nM). SPECT imaging of [Lu-177]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [Lu-177]Lu-EB-PSMA and [Lu-177]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [Lu-177]Lu-LNC1003 (138.87 +/- 26.53%ID/g) over [Lu-177]Lu-EB-PSMA-617 (29.89 +/- 8.86%ID/g) and [Lu-177]Lu-PSMA-617 (4.28 +/- 0.25%ID/g) at 24 h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5 MBq [Lu-177]Lu-LNC1003. There was no obvious antitumor effect after [Lu-177]Lu-PSMA-617 treatment under the same condition.ConclusionIn this study, [Lu-177]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [Lu-177]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of Lu-177 that promises clinical translation to treat prostate cancer with various levels of PSMA expression.