Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China.
Eur J Nucl Med Mol Imaging. 2023 Jul;50(8):2342-2352. doi: 10.1007/s00259-023-06155-x. Epub 2023 Mar 6.
This study aimed to explore the feasibility of using [Lu]Lu-prostate-specific membrane antigen (PSMA)-617 and [Lu]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.
[Lu]Lu-PSMA-617 and [Lu]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 [Lu]Lu-PSMA-617 or [Lu]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 [Lu]Lu-PSMA-617, 18.5 MBq [Lu]Lu-PSMA-617, 7.4 MBq [Lu]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.
[Lu]Lu-PSMA-617 and [Lu]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 [Lu]Lu-EB-PSMA-617 compared with [Lu]Lu-PSMA-617. [Lu]Lu-PSMA-617 was rapidly cleared from the blood, while [Lu]Lu-EB-PSMA-617 persisted for significantly longer. In radioligand therapy studies, tumor growth was significantly suppressed in the 37 MBq [Lu]Lu-PSMA-617, 18.5 MBq [Lu]Lu-PSMA-617, and 7.4 MBq [Lu]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 [Lu]Lu-PSMA-617 and [Lu]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.
本研究旨在探索单次给药[Lu]Lu-前列腺特异性膜抗原（PSMA）-617 和 [Lu]Lu-Evans 蓝（EB）-PSMA-617 在 PSMA 阳性肝癌（HCC）异种移植小鼠模型中进行体内放射配体治疗的可行性。
制备[Lu]Lu-PSMA-617 和 [Lu]Lu-EB-PSMA-617，测定其标记效率和放射化学纯度。建立 HepG2 人 HCC 皮下异种移植小鼠模型。将[Lu]Lu-PSMA-617 或[Lu]Lu-EB-PSMA-617（37 MBq）静脉注射入小鼠模型后，进行单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）。进行生物分布研究以验证靶向特异性和药代动力学。在放射配体治疗研究中，将小鼠随机分为 4 组：37 MBq [Lu]Lu-PSMA-617、18.5 MBq [Lu]Lu-PSMA-617、7.4 MBq [Lu]Lu-EB-PSMA-617 和生理盐水（对照）。在治疗研究开始时进行单次给药。每隔 2 天监测肿瘤体积、体重和存活情况。治疗结束后，处死小鼠。然后称重肿瘤，并通过血液检测和健康器官的组织学检查评估全身毒性。
成功制备了具有高纯度和稳定性的[Lu]Lu-PSMA-617 和 [Lu]Lu-EB-PSMA-617。SPECT/CT 和生物分布显示，与 [Lu]Lu-PSMA-617 相比，[Lu]Lu-EB-PSMA-617 肿瘤摄取更高且持续时间更长。[Lu]Lu-PSMA-617 从血液中迅速清除，而 [Lu]Lu-EB-PSMA-617 则持续时间明显更长。在放射配体治疗研究中，与生理盐水组相比，37 MBq [Lu]Lu-PSMA-617、18.5 MBq [Lu]Lu-PSMA-617 和 7.4 MBq [Lu]Lu-EB-PSMA-617 组的肿瘤生长均受到显著抑制。中位生存时间分别为 40、44、43 和 30 天。在安全性和耐受性评估中未观察到健康器官毒性。
在 PSMA 阳性 HCC 异种移植小鼠中，使用[Lu]Lu-PSMA-617 和 [Lu]Lu-EB-PSMA-617 的放射配体治疗显著抑制了肿瘤生长并延长了存活时间，且无明显毒性。这些放射性配体在临床上对人类使用有很大的前景，值得进一步研究。
