225 Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

The Journal of Nuclear Medicine

article

A. Paden King¹  Nicholas T. Gutsche¹  Natarajan Raju²  Stanley Fayn¹  Kwamena E. Baidoo¹  Meghan M. Bell¹  Colleen S. Olkowski¹  Rolf E. Swenson²  Frank I. Lin¹  Samira M. Sadowski³  Stephen S. Adler⁴  Nikki A. Thiele⁵  Justin J. Wilson⁶  Peter L. Choyke¹  Freddy E. Escorcia¹ 

[1] Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health;Chemical and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health;Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health;Clinical Research Directorate, Frederick National Laboratory for Cancer Research;Chemical Sciences Division, Oak Ridge National Laboratory;Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University;Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health

关键词: oncology;    actinium;    targeted α-therapy;    neuroendocrine tumors;    octreotate;    somatostatin;   

DOI  :  10.2967/jnumed.122.264707

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177Lu-DOTATATE (DOTA-octreotate), a β-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with 177Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant α-particle–emitting radionuclide 225Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225Ac-MACROPATATE than of 225Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225Ac-DOTATATE. Conclusion: 225Ac-MACROPATATE and 225Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225Ac-MACROPATATE, 225Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.

【 授权许可】

CC BY