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²¹³Bi-[DOTA⁰, Tyr³]Octreotide Peptide Receptor Radionuclide Therapy of Pancreatic Tumors in a Preclinical Animal Model

Authors' Affiliations: ¹ College of Pharmacy and ² Cancer Research Treatment Center, University of New Mexico, Albuquerque, New Mexico; ³ Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; and ⁴ Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Jeffrey P. Norenberg, College of Pharmacy, University of New Mexico, 2502 Marble Avenue, North East MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131-0001. Phone: 505-272-4322; Fax: 505-272-6749; E-mail: jpnoren{at}unm.edu.

Purpose: The somatostatin analogue [DOTA⁰, Tyr³]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) ß-emitters, such as ¹⁷⁷Lu or ⁹⁰Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET -emitter, ²¹³Bi, was evaluated.

Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of ²¹³Bi-DOTATOC (specific activity 7.4 MBq/µg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq ²¹³Bi-DOTATOC was determined in a rat pancreatic carcinoma model.

Results: Radiolabeling of the ²¹³Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield 99.9%. Biodistribution data showed specific binding to somatostatin receptor–expressing tissues. Administration of free ²¹³Bi, compared with ²¹³Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 ± 1.40% injected dose/g (ID/g) tissue versus 11.15 ± 0.46%, P < 0.0001] and bone marrow (0.31 ± 0.01% ID/g versus 0.06 ± 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of ²¹³Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of ²¹³Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02).

Conclusions: ²¹³Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. ²¹³Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

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