[177Lu]Lu-PSMA-617 theranostic probe for hepatocellular carcinoma imaging and therapy

Abstract

Purpose: This study aimed to explore the feasibility of using [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-617 and [¹⁷⁷Lu]Lu-Evans blue (EB)-PSMA-617 for in vivo radioligand therapy by single-dose administration in a PSMA-positive hepatocellular carcinoma (HCC) xenograft mouse model.

Methods: [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-EB-PSMA-617 were prepared, and labelling efficiency and radiochemical purity were determined. A HepG2 human HCC subcutaneous xenograft mouse model was established. After intravenous injection of [¹⁷⁷Lu]Lu-PSMA-617 or [¹⁷⁷Lu]Lu-EB-PSMA-617 (37 MBq) into the mouse model, single-photon emission computed tomography/computed tomography (SPECT/CT) was performed. Biodistribution studies were conducted to verify targeting specificity and pharmacokinetics. In the radioligand therapy study, mice were randomized into 4 groups: 37 MBq [¹⁷⁷Lu]Lu-PSMA-617, 18.5 MBq [¹⁷⁷Lu]Lu-PSMA-617, 7.4 MBq [¹⁷⁷Lu]Lu-EB-PSMA-617, and saline (control). A single-dose administration was applied at the beginning of therapy studies. Tumor volume, body weight, and survival were monitored every 2 days. After the end of therapy, mice were euthanized. Tumors were then weighed, and systemic toxicity was evaluated via blood testing and histological examination of healthy organs.

Results: [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-EB-PSMA-617 were successfully prepared with high purity and stability. SPECT/CT and biodistribution showed that tumor uptake was higher and persisted longer for [¹⁷⁷Lu]Lu-EB-PSMA-617 compared with [¹⁷⁷Lu]Lu-PSMA-617. [¹⁷⁷Lu]Lu-PSMA-617 was rapidly cleared from the blood, while [¹⁷⁷Lu]Lu-EB-PSMA-617 persisted for significantly longer. In radioligand therapy studies, tumor growth was significantly suppressed in the 37 MBq [¹⁷⁷Lu]Lu-PSMA-617, 18.5 MBq [¹⁷⁷Lu]Lu-PSMA-617, and 7.4 MBq [¹⁷⁷Lu]Lu-EB-PSMA-617 groups compared to the saline group. Median survival was 40, 44, 43, and 30 days, respectively. No healthy organ toxicity was observed in safety and tolerability evaluation.

Conclusions: Radioligand therapy using [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-EB-PSMA-617 significantly suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice without obvious toxicity. These radioligands appear promising for clinical use in humans, and future studies are warranted.

Keywords: Hepatocellular carcinoma; Lutetium-177; Prostate-specific membrane antigen; Radioligand therapy; Tumor-associated endothelium.