Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies

We designed and evaluated a novel albumin-binder-conjugated Lu-177-PSMA-617 derivative, Lu-177-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-( p-iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay. Lu-177 labeling was performed in acetate buffer (pH 4.5) at 90 degrees C for 15 min. SPECT/CT imaging, biodistribution, and endoradiotherapy studies were conducted in mice bearing PSMA-expressing LNCaP tumor xenografts. Radiation dosimetry was calculated using OLINDA software. Lu-PSMA-617 and Lu-HTK01169-bound PSMA with high affinity (K-i values = 0.24 and 0.04 nM, respectively). SPECT imaging and biodistribution studies showed that Lu-177-PSMA-617 and Lu-177-HTK01169 were excreted mainly via the renal pathway. With fast blood clearance (0.68%ID/g at 1 h postinjection), the tumor uptake of Lu-177-PSMA-617 peaked at 1 h postinjection (15.1%ID/g) and gradually decreased to 7.91%ID/g at 120 h postinjection. With extended blood retention (16.6 and 2.10%ID/g at 1 and 24 h, respectively), the tumor uptake of Lu-177-HTK01169 peaked at 24 h postinjection (55.9%ID/g) and remained at the same level by the end of the study (120 h). Based on dosimetry calculations, Lu-177-HTK01169 delivered an 8.3-fold higher radiation dose than Lu-177-PSMA-617 to LNCaP tumor xenografts. For the endoradiotherapy study, the mice treated with Lu-177-PSMA-617 (18.5 MBq) all reached humane end point (tumor volume >1000 mm(3)) by Day 73 with a median survival of 58 days. Mice treated with 18.5, 9.3, 4.6, or 2.3 MBq of Lu-177-HTK01169 had a median survival of >120, 103, 61, and 28 days, respectively. With greatly enhanced tumor uptake and treatment efficacy compared to Lu-177-PSMA-617 in preclinical studies, Lu-177-HTK01169 warrants further investigation for endoradiotherapy of prostate cancer.