Abstract
Background: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy.Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour cells are obtained.Methods: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with 212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2 human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts).Results: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15 µg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb-NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA-617. Radium-224 was not chelated and, hence, showed high uptake in bones.Conclusion: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted.
Highlights
Radiopharmaceuticals have recently gained significant attention in the treatment of metastatic cancer [1]
The 212Pb-labelling of NG001 and prostate-specific membrane antigen (PSMA)-617 in the 224Ra-solution in transient equilibrium with progeny was tested at different ligand concentrations (2.5-500 μg/ml), temperatures and pH values
For NG001, the Radiochemical purity (RCP) of 212Bi was around 45% at a ligand concentration of 10 μg/ml and around 65-75% at concentrations above 50 μg/ml, demonstrating that 212Bi is conjugated by the TCMC chelator though not to the same extent as 212Pb (Fig. 4, Supplementary Table S2)
Summary
Radiopharmaceuticals have recently gained significant attention in the treatment of metastatic cancer [1]. One alpha-emitting and several beta-emitting radiopharmaceuticals have been approved for cancer therapy in the last decade [1]. Lead-212 is a beta emitter that produces alpha parti-. It should be noted that the needed activity levels of 212Pb would be much less than for a 212Bi-based product [17]. This is because 1 Bq of 212Pb would produce about. New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy
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