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[Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4 Is a Highly Efficient Radiotherapeutic for Glucagon-Like Peptide-1 Receptor–Targeted Therapy for Insulinoma

Authors' Affiliations: ¹ Institute of Biochemistry and Genetics, DKBW, Medical School, University of Basel; ² Clinic and Institute of Nuclear Medicine and ³ Division of Radiological Chemistry, University Hospital, Basel; ⁴ Institute of Pathology, University and University Hospital, Basel, Basel, Switzerland; ⁵ Department of Nuclear Medicine, University of Nijmwegen Medical Center, Nijmwegen, the Netherlands; ⁶ Division of Nuclear Medicine, University Hospital, Marburg, Maribor, Germany; and ⁷ Institute of Pathology, University of Bern, Bern, Switzerland

Requests for reprints: Gerhard Christofori, Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel Center of Biomedicine, Mattenstrasse 28, CH-4058 Basel, Switzerland. Phone: 41-61-267-3562; Fax: 41-61-267-3566; E-mail: gerhard.christofori{at}unibas.ch.

Purpose: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4, an ¹¹¹In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.

Experimental Design: [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic ß-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated.

Results: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4. Other GLP-1R–positive organs showed 30 times lower dose deposition. A single injection of [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation.

Conclusions: The results suggest that [Lys⁴⁰(Ahx-DTPA-¹¹¹In)NH₂]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as ¹¹¹In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.