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Nuclear Uptake and Dosimetry of ⁶⁴Cu-Labeled Chelator–Somatostatin Conjugates in an SSTr2-Transfected Human Tumor Cell Line

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri; and ² Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri

Correspondence: For correspondence or reprints contact: Carolyn J. Anderson, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63130. E-mail: andersoncj{at}wustl.edu

⁶⁴Cu radiopharmaceuticals have shown tumor growth inhibition in tumor-bearing animal models with a relatively low radiation dose that may be related to nuclear localization of the ⁶⁴Cu in tumor cells. Here we address whether the nuclear localization of ⁶⁴Cu from a ⁶⁴Cu-labeled chelator–somatostatin conjugate is related to the dissociation of the radio-copper from its chelator. The ⁶⁴Cu complex of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) has demonstrated instability in vivo, whereas ⁶⁴Cu-CB-TE2A (CB-TE2A is 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) was highly stable. Methods: Receptor binding, nuclear uptake, internalization, and efflux assays were performed to characterize the interaction with the somatostatin receptor and the intracellular fate of ⁶⁴Cu-labeled chelator–peptide conjugates in A427-7 cells. From these data, the absorbed dose to cells was calculated. Results: ⁶⁴Cu-TETA-Y3-TATE (⁶⁴Cu-[1]) and ⁶⁴Cu-CB-TE2A-Y3-TATE (⁶⁴Cu-[2]) had high affinity for somatostatin receptor subtype 2 (SSTr2) in A427-7 cells. After 3 h, ⁶⁴Cu-[2] showed greater internalization (>30%) compared with ⁶⁴Cu-[1] (15%). There was uptake of ⁶⁴Cu-[1] in nuclei of 427–7 cells (9.4% ± 1.7% at 24 h), whereas ⁶⁴Cu-[2] showed minimal nuclear accumulation out to 24 h (1.3% ± 0.1%). A427-7 cells were exposed to 0.40 Gy from ⁶⁴Cu-[1] and exposed to 1.06 Gy from ⁶⁴Cu-[2]. External beam irradiation of A427-7 cells showed <20% cell killing at 1 Gy. Conclusion: These results are consistent with our hypothesis that dissociation of ⁶⁴Cu from TETA leads to nuclear localization. Dosimetry calculations indicated that the nuclear localization of ⁶⁴Cu-[1] was not significant enough to increase the absorbed dose to the nuclei of A427-7 cells. These studies show that ⁶⁴Cu localization to cell nuclei from internalizing, receptor-targeted radiopharmaceuticals is related to chelate stability.

Key Words: ⁶⁴Cu • targeted radiotherapy • somatostatin receptor • somatostatin analog • dosimetry

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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