Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eur J Nucl Med Mol Imaging. 2019 Nov;46(12):2545-2557. doi: 10.1007/s00259-019-04434-0. Epub 2019 Aug 10.
To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of Lu.
We synthesized 14 new PSMA-targeted, Lu-labeled radioligands (Lu-L1-Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for Lu-L1, Lu-L3, Lu-L5 and Lu-PSMA-617. Efficacy of Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice.
Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. Lu-L1, Lu-L3 and Lu-L5 demonstrated comparable uptake to Lu-PSMA-617 and Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. Lu-L1, Lu-L3 and Lu-L5 also demonstrated efficient tumor regression at 8 weeks. Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of Lu-L1, most likely related to the fast renal clearance of this agent.
Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.
开发一种针对转移性去势抵抗性前列腺癌（mCRPC）的前列腺特异性膜抗原（PSMA）靶向放射性治疗药物，以最大限度地提高疗效并最小化毒性，方法：我们使用不同的螯合剂和连接子合成了 14 种新的 PSMA 靶向、Lu 标记的放射性配体（Lu-L1-Lu-L14）。我们在人前列腺癌 PSMA(+)PC3 PIP 和 PSMA(-)PC3 flu 细胞及其相应的 flank 肿瘤模型中进行了体外评估。在单次给予 111MBq 的 Lu-L1、Lu-L3、Lu-L5 和 Lu-PSMA-617 后，评估了 8 周的疗效和毒性。使用不同剂量进一步研究了 Lu-L1 的疗效，并在健康免疫功能正常的小鼠中确定了长期毒性。结果：放射性配体以高放射化学产率和纯度合成。细胞摄取和内化表明仅在 PSMA(+)PC3 细胞中存在特异性摄取。Lu-L1、Lu-L3 和 Lu-L5 在 PSMA 表达肿瘤中的摄取与 Lu-PSMA-617 和 Lu-PSMA-I&T 相当，直至注射后 72 小时。Lu-L1、Lu-L3 和 Lu-L5 还在 8 周时显示出有效的肿瘤消退。Lu-L1 使存活率最高。8 周时的治疗组尸检研究显示，泪腺和睾丸有亚急性损伤。在接受 111MBq Lu-L1 的健康小鼠中，1 年后未观察到放射性肾病，这可能与该药物的快速肾脏清除有关。结论：Lu-L1 是一种可行的临床候选放射性核素治疗 PSMA 表达恶性肿瘤的药物，因为它具有高肿瘤靶向能力和低脱靶放射性毒性。
