Preclinical Evaluation of [ ¹⁷⁷ Lu]Lu-ART-101 for Radiopharmaceutical Therapy of Advanced Prostate Cancer

Radiopharmaceutical therapy with [¹⁷⁷Lu]Lu-PSMA-617 has improved outcomes for patients with advanced prostate cancer (PCa), yet modest survival benefits underscore the need for more effective agents. Here, we describe the development of [¹⁷⁷Lu]Lu-ART-101, a next-generation prostate-specific membrane antigen (PSMA)–targeting radioligand, and evaluate its biodistribution, dosimetry, therapeutic efficacy, and toxicity in advanced PSMA-expressing PCa models. Methods: Lipophilic ART-101 was synthesized and radiolabeled with ¹⁷⁷Lu. [¹⁷⁷Lu]Lu-ART-101 longitudinal biodistribution and dosimetry were assessed through SPECT/CT imaging in human PC3-PIP (PC3 cells engineered to overexpress PSMA) xenograft–bearing mice and compared with those of [¹⁷⁷Lu]Lu-PSMA-617. The therapeutic efficacy of [¹⁷⁷Lu]Lu-ART-101 was evaluated in the PC3-PIP and LNCaP xenograft–bearing mice, whereas toxicity was assessed in normal ICR mice. Results: [¹⁷⁷Lu]Lu-ART-101 demonstrated patterns of cell binding and internalization similar to those of [¹⁷⁷Lu]Lu-PSMA-617 in PC3-PIP cells. Internalization was effectively blocked by PSMA-617, indicating the PSMA-specific binding of [¹⁷⁷Lu]Lu-ART-101. In vitro competition assays revealed potent nanomolar binding, with unlabeled ART-101 competitively displacing [¹⁷⁷Lu]Lu-PSMA-617, with 0.4 ± 0.1 nM of inhibitory concentration of 50%, in PC3-PIP cells. In nude mice bearing PC3-PIP xenografts, [¹⁷⁷Lu]Lu-ART-101 displayed higher tumor uptake (peak at 14.3 ± 1.5 %IA/g at 48 h after injection) and prolonged retention (8.1 ± 0.8 and 6.4 ± 1.0 %IA/g at 120 and 168 h, respectively) versus [¹⁷⁷Lu]Lu-PSMA-617 (peak at 10.0 ± 2.0 %IA/g at 2 h) followed by a rapid decrease (2.2 ± 1.5 %IA/g at 120 h), leading to a 2-fold higher tumor absorbed dose with [¹⁷⁷Lu]Lu-ART-101 (1.2 ± 0.1 vs. 0.6 ± 0.1). Notably, [¹⁷⁷Lu]Lu-ART-101 showed a distinctive normal tissue distribution compared with [¹⁷⁷Lu]Lu-PSMA-617, with longer blood circulation, negligible salivary gland uptake, and primarily hepatic rather than renal clearance. [¹⁷⁷Lu]Lu-ART-101’s favorable tumor dosimetry translated to enhanced tumor control and prolonged survival in both the PC3-PIP and LNCaP xenograft models. Safety studies in ICR mice revealed mild transient cytopenia in animals receiving the highest tested injected activity (55.5 MBq), which resolved by day 28, without concomitant renal, hepatic, or histologic abnormalities, including those in the bone marrow and salivary glands. Conclusion: [¹⁷⁷Lu]Lu-ART-101 demonstrates significant potential as a novel radiopharmaceutical for advanced PCa, with superior therapeutic efficacy and a favorable safety profile. These findings support our ongoing clinical translation effort in advanced PCa.