Yantai Lannacheng Biotechnology Co., Ltd.

Prostate-specific membrane antigen (PSMA) radioligand therapy (PRLT) has become a promising option for treating metastatic castration-resistant prostate cancer (mCRPC). Radioligands labelled with the ⁶⁸Ga/¹⁷⁷Lu theranostic pair have been most widely used in the clinic for diagnosis and therapy, respectively. This study aims to develop a novel PSMA-targeted radioligand, LNC1011, radiolabeled with alpha-emitter ²²⁵Ac, to optimise pharmacokinetic properties and assess its potential for targeted alpha therapy (TAT) in prostate cancer treatment.

LNC1011 (Dan-PSMA) was synthesised based on a PSMA-binding ligand with the addition of a dansylated amino acid. Systematic radiochemical analyses were conducted to confirm the successful synthesis and radiolabelling of [²²⁵Ac]Ac-LNC1011. Cell uptake and competition binding assays were performed in PSMA-positive PC3-PIP tumour cells to evaluate the binding affinity and PSMA targeting specificity. The pharmacokinetics properties and tumour uptake were characterised by biodistribution studies using healthy mice and a PC3-PIP xenograft mouse model injected with [²²⁵Ac]Ac-LNC1011. Radioligand therapy studies and maximum tolerated dose (MTD) assays were conducted to systematically evaluate the therapeutic efficacy and the safety of [²²⁵Ac]Ac-LNC1011.

[²²⁵Ac]Ac-LNC1011 was successfully radiolabelled with high radiochemical purity (> 97%) and high stability within 96 h (radiochemical purity > 96%). The high binding affinity of LNC1011 (IC₅₀ = 16.28 nM) to PSMA was comparable to that of PSMA-617 (IC₅₀ = 27.93 nM). Biodistribution studies confirmed that [²²⁵Ac]Ac-LNC1011 had moderate blood elimination half-life (T_1/2z = 13.4 ± 0.57 h), which was at an optimised level between [²²⁵Ac]Ac-PSMA-617 (T_1/2z = 5.19 ± 0.12 h) and [²²⁵Ac]Ac-PSMA-EB-01 (T_1/2z = 25.18 ± 2.78 h). In addition, high tumour uptake of [²²⁵Ac]Ac-LNC1011 was identified to be 38.28 ± 10.04%ID/g at 1 h post-injection. The specific uptake gradually increased and peaked at 24 h (80.57 ± 3.00%ID/g) and persisted at a high level up to 72 h post-injection (50.58 ± 5.37%ID/g). Targeted alpha therapy results showed the complete inhibition of PC3-PIP tumour growth after administration of a single dose of 1 µCi and 0.5 µCi of [²²⁵Ac]Ac-LNC1011 similar to 0.5 µCi [²²⁵Ac]Ac-PSMA-617. At the 0.1 µCi dose level, partial remission was observed for [²²⁵Ac]Ac-LNC1011, as recurrence was found 20 days after administration. In contrast, mice treated with 0.1 µCi [²²⁵Ac]Ac-PSMA-617 showed incomplete tumour inhibition under the same conditions.

[²²⁵Ac]Ac-LNC1011 was successfully radiolabelled with high radiochemical purity and stability. With significantly improved tumour uptake and retention over PSMA-617, [²²⁵Ac]Ac-LNC1011 showed significantly better therapeutic efficacy than [²²⁵Ac]Ac-PSMA-617 for targeted alpha therapy of prostate cancer.