Jingjing Zhang1,2,3, Hao Wang1,3, Orit Jacobson2, Yuejuan Cheng4, Gang Niu2, Fang Li1,3, Chunmei Bai4, Zhaohui Zhu5,3, Xiaoyuan Chen6. 1. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China. 2. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland. 3. Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China; and. 4. Oncology Department of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China. 5. Department of Nuclear Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China 13611093752@163.com shawn.chen@nih.gov. 6. Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland 13611093752@163.com shawn.chen@nih.gov.
Abstract
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, 177Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE). Methods: 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 177Lu-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 177Lu-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. Results: Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177Lu-DOTATATE, 177Lu-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 177Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177Lu-DOTA-EB-TATE compared with those receiving 177Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin-binding moiety, 177Lu-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.
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, 177Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE). Methods: 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 177Lu-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 177Lu-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. Results: Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177Lu-DOTATATE, 177Lu-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 177Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177Lu-DOTA-EB-TATE compared with those receiving 177Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin-binding moiety, 177Lu-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.
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