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Subcellular Localization of Radiolabeled Somatostatin Analogues

Implications for Targeted Radiotherapy of Cancer¹

Mallinckrodt Institute of Radiology [M. W., A. L. C., M. R. L., L. A. M., C. J. A.], and Department of Radiation Oncology [R. P. V.], Washington University School of Medicine, St. Louis, Missouri 63110

Copper-64 (T_1/2 = 12.7 h; ß⁺, 17.4%; ß^-, 39%) has been used both in positron emission tomography imaging and in radiotherapy. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. These studies incorporate the use of somatostatin receptor-positive AR42J rat pancreatic tumor cells in vitro to understand the cell killing mechanism of ⁶⁴Cu by focusing on subcellular distribution of the somatostatin analogues ⁶⁴Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide (⁶⁴Cu-TETA-OC) and ¹¹¹In-labeled diethylenetriaminepentaacetic acid-octreotide (¹¹¹In-DTPA-OC). Cell uptake and organelle isolation studies were conducted on ⁶⁴Cu-TETA-OC and ¹¹¹In-DTPA-OC. Nuclear localization of ⁶⁴Cu and ¹¹¹In from ⁶⁴Cu-TETA-OC and ¹¹¹In-DTPA-OC, respectively, increased over time, with 19.5 ± 1.4% and 6.0 ± 1.0% in the cell nucleus at 24 h, respectively. In pulse-chase experiments, in which ⁶⁴Cu-TETA-OC was incubated with AR42J cells for 4 h, it was found that the nuclear localization of ⁶⁴Cu increased significantly over the next 20 h (from 9.8 ± 1.0% to 26.3 ± 5.4%). In a control pulse-chase experiment, levels of ⁶⁴Cu from [⁶⁴Cu]cupric acetate decreased from 4 to 24 h postadministration (20.6 ± 8.7 to 5.4 ± 1.9), suggesting that the redistribution mechanism, or the kinetics of ⁶⁴Cu from ⁶⁴Cu-TETA-OC is different from that for ⁶⁴Cu from [⁶⁴Cu]cupric acetate. The amount of ⁶⁴Cu from ⁶⁴Cu-TETA-OC also increased in the mitochondria over time, with 21.1 ± 3.6% in the mitochondria at 24 h postadministration. These results suggest that localization of substantial quantities of ⁶⁴Cu to the cell nucleus and mitochondria may contribute to cell killing with ⁶⁴Cu radiopharmaceuticals.

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