Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
Nucligen AS, Oslo, Norway
Curr Radiopharm. 2020;13(2):130-141. doi: 10.2174/1874471013666200511000532.
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.
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.
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).
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.
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.
对于转移性去势抵抗性前列腺癌患者，需要新的治疗方法来对抗骨和骨骼外转移。大多数转移灶过度表达前列腺特异性膜抗原（PSMA），使其成为靶向放射性核素治疗的理想候选物。
本研究旨在测试一种新型的液体 224Ra/212Pb 发生器，用于快速制备双α靶向溶液。在这里，PSMA 靶向配体在 224Ra 溶液中与子核素处于瞬态平衡，用 212Pb 标记。因此，获得了天然骨靶向 224Ra 治疗硬化性骨转移和 212Pb 螯合 PSMA 配体靶向 PSMA 表达肿瘤细胞的双重靶向作用。
两种 PSMA 靶向配体，即专门用于螯合 212Pb 的 p-SCN-Bn-TCMC-PSMA 配体（NG001）和最常用于临床的 DOTA 基 PSMA-617，用 212Pb 标记。在原位、体外（PSMA 阳性 C4-2 人前列腺癌细胞）和体内（C4-2 异种移植肿瘤荷瘤裸鼠）研究了放射性标记和靶向潜力。
使用液体 224Ra/212Pb 发生器，NG001 可快速用 212Pb 标记（浓度≥15μg/ml 时，放射性化学纯度＞94%）。在抗坏血酸和白蛋白存在的情况下，[212Pb]Pb-NG001 的高放射性化学纯度和稳定性在 48 小时内得到证实。212Pb 标记的配体在 C4-2 细胞中的结合能力相似。两种 PSMA 配体在 2 小时后显示出相似的肿瘤摄取，但 NG001 的肾脏摄取比 PSMA-617 低 3.5 倍。镭-224 未螯合，因此在骨骼中摄取量较高。
开发了一种在 224Ra/212Pb 溶液中用 212Pb 标记 PSMA 配体的快速方法。因此，需要进一步进行双肿瘤靶向α粒子的体内研究。
