Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland.
J Nucl Med. 2018 Nov;59(11):1699-1705. doi: 10.2967/jnumed.118.209841. Epub 2018 Apr 13.
Radiolabeled somatostatin analog therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogs in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-humans study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analog, Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (Lu-DOTA-EB-TATE). Eight patients (6 men and 2 women; age range, 27-61 y) with advanced metastatic NETs were recruited. Five patients received a single dose, 0.35-0.70 GBq (9.5-18.9 mCi), of Lu-DOTA-EB-TATE and underwent serial whole-body planar and SPECT/CT scans at 2, 24, 72, 120, and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24, and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Administration of Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with Lu-DOTATATE, Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved a 7.9-fold increase of tumor dose delivery. The total-body effective doses were 0.205 ± 0.161 mSv/MBq for Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving Lu-DOTA-EB-TATE compared with those receiving Lu-DOTATATE (3.2 and 18.2-fold, respectively). By introducing an albumin-binding moiety, Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NETs as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in peptide receptor radionuclide therapy for NETs with lower dose and less frequency of administration.
放射性标记生长抑素类似物治疗已成为治疗无法切除或转移性神经内分泌肿瘤（NET）的良好至中度分化患者的既定方法。在临床实践中最常使用的生长抑素类似物是奥曲肽和奥曲肽。然而，这两种肽在肿瘤内的保留效果都不理想。这项首例人体研究旨在探索长效放射性标记生长抑素类似物 Lu-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-Evans 蓝-奥曲肽（Lu-DOTA-EB-TATE）的安全性和剂量学。8 名（6 名男性和 2 名女性；年龄范围，27-61 岁）患有晚期转移性 NET 的患者被招募。5 名患者接受了单次剂量为 0.35-0.70GBq（9.5-18.9mCi）的 Lu-DOTA-EB-TATE，并在注射后 2、24、72、120 和 168 小时进行了全身平面和 SPECT/CT 扫描。另外 3 名患者在注射后 1、3、4、24 和 72 小时进行了相同的成像采集程序，静脉注射了 0.28-0.41GBq（7.5-11.1mCi）的 Lu-DOTATATE。使用 OLINDA/EXM 1.1 软件计算剂量学。Lu-DOTA-EB-TATE 的给药耐受性良好，没有任何不良反应被注意到或报告。与 Lu-DOTATATE 相比，Lu-DOTA-EB-TATE 在血液中的循环时间更长，肿瘤剂量传递增加了 7.9 倍。Lu-DOTA-EB-TATE 的全身有效剂量为 0.205±0.161mSv/MBq，Lu-DOTATATE 的全身有效剂量为 0.174±0.072mSv/MBq。与 Lu-DOTATATE 相比，接受 Lu-DOTA-EB-TATE 治疗的患者的肾脏和骨髓的剂量也显著增加（分别为 3.2 和 18.2 倍）。通过引入白蛋白结合部分，Lu-DOTA-EB-TATE 在 NET 中的摄取和保留明显增加，在肾脏和红骨髓中的积累也显著增加。它具有成为 NET 肽受体放射性核素治疗的潜力，可降低剂量和减少给药频率。
