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

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.

[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.

[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.

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.