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Preclinical Evaluation of the -Particle Generator Nuclide ²²⁵Ac for Somatostatin Receptor Radiotherapy of Neuroendocrine Tumors

Authors' Affiliations: ¹ Nuklearmedizinische Klinik und Poliklinik, Klinikum-rechts-der-Isar, Munich, Germany and ² Institute of Pathology, GSF National Research Center for Environment and Health, Neuherberg, Germany

Requests for reprints: Matthias Miederer, Klinikum-rechts-der-Isar, Ismaningerstr. 22, 81675 Munich, Germany. Phone: 49-89-4140-2965; Fax: 49-89-4140-4950; E-mail: mail{at}matthiasmiederer.de.

Purpose: Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues labeled with β-particle–emitting isotopes such as ⁹⁰Y or ¹⁷⁷Lu has been a promising treatment strategy for metastasized neuroendocrine tumors. Although remission can be accomplished in a high percentage of neuroendocrine tumors, some tumors do not respond to this treatment. -Emitting isotopes—such as the 10-day half-life -emitting generator nuclide Actinum-225 (²²⁵Ac)—are characterized by extremely high cytotoxic activity on the cellular level, and may be superior in the treatment of neuroendocrine tumors not responding to PRRT using β-emitting isotopes.

Experimental Design: Radiolabeling of ²²⁵Ac 1,4,7,10-tetra-azacylododecane N,N',N'',N'''-J-tetraacetic acid-Tyr³-octreotide (DOTATOC) was done at pH 5 (60 minutes at 70°C) without further purification. Biodistribution in nude mice bearing AR42J rat pancreas neuroendocrine tumor xenografts were measured for up to 24 hours. Toxicity was tested by weight changes, retention variables (blood urea nitrogen and creatine), and histopathology in mice 7 months after treatment with 10 to 130 kBq (n = 4-5). Therapeutic efficacy was assessed by tumor weighing in animals treated 4 days after xenotransplantation and compared with ¹⁷⁷Lu-DOTATOC as a reference.

Results: Activities up to 20 kBq had no significant toxic effects in mice. In contrast, activities higher than 30 kBq induced tubular necrosis. Biodistribution studies revealed that ²²⁵Ac-DOTATOC effectively accumulated in neuroendocrine xenograft tumors. ²²⁵Ac-DOTATOC activities were shown to be nontoxic (12-20 kBq), reduced the growth of neuroendocrine tumors, and showed improved efficacy compared with ¹⁷⁷Lu-DOTATOC.

Conclusions: ²²⁵Ac might be suitable to improve PRRT in neuroendocrine tumors.