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Highly Efficient In Vivo Agonist-Induced Internalization of sst₂ Receptors in Somatostatin Target Tissues

¹ Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland; and ² Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland

Correspondence: For correspondence or reprints contact: Jean Claude Reubi, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, P.O. Box 62, Murtenstrasse 31, CH-3010 Berne, Switzerland. E-mail: reubi{at}pathology.unibe.ch

The successful peptide receptor imaging of tumors, as exemplified for somatostatin receptors, is based on the overexpression of peptide receptors in selected tumors and the high-affinity binding to these tumors of agonist radioligands that are subsequently internalized into the tumor cells in which they accumulate. Although in vitro studies have shown ample evidence that the ligand–receptor complex is internalized, in vivo evidence of agonist-induced internalization of peptide receptors, such as somatostatin receptors, is missing. Methods: Rats subcutaneously transplanted with the somatostatin receptor subtype 2 (sst₂)–expressing AR42J tumor cells were treated with intravenous injections of various doses of the sst₂ agonist [Tyr³, Thr⁸]-octreotide (TATE) or of the sst₂ antagonist 1,4,7,10-tetraazacyclododecane-N,N',N'',N''',-tetraacetic acid (DOTA)-Bass and were sacrificed at various times ranging from 2.5 min to 24 h after injection. The tumors and pancreas were then removed from each animal. All tissue samples were processed for sst₂ immunohistochemistry using sst₂-specific antibodies. Results: Compared with the sst₂ receptors in untreated animals, which localized at the plasma membrane in pancreatic and AR42J tumor cells, the sst₂ receptors in treated animals are detected intracellularly after an intravenous injection of the agonist TATE. Internalization is fast, as the receptors are already internalizing 2.5 min after TATE injection. The process is extremely efficient, as most of the cell surface receptors internalize into the cell and are found in endosomelike structures after TATE injection. The internalization is most likely reversible, because 24 h after injection the receptors are again found at the cell surface. The process is also agonist-dependent, because internalization is seen with high-affinity sst₂ agonists but not with high-affinity sst₂ antagonists. The same internalization properties are seen in pancreatic and AR42J tumor cells. They can further be confirmed in vitro in human embryonic kidney–sst₂ cells, with an immunofluorescence microscopy–based sst₂ internalization assay. Conclusion: These animal data strongly indicate that the process of in vivo sst₂ internalization after agonist stimulation is fast, extremely efficient, and fully functional under in vivo conditions in neoplastic and physiologic sst₂ target tissues. This molecular process is, therefore, likely to be responsible for the high and long-lasting uptake of sst₂ radioligands seen in vivo in sst₂-expressing tumors.

Key Words: peptide receptor targeting • somatostatin receptor • in vivo internalization • tumor imaging • neuropeptides

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