Radiotherapeutic for Glucagon-Like Peptide-1Receptor ^ Targeted Therapy for Insulinoma

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-1receptors (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 (Lys 40 (Ahx-DTPA- 111 In)NH2)-Exendin-4, an 111 In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma. Experimental Design: (Lys 40 (Ahx-DTPA- 111 In)NH2)-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic h-cell carcinogenesis, which exhibits a GLP-1R expression compara- ble 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 3G y/MBq at 40 pmol (Lys 40 (Ahx-DTPA- 111 In)NH2)-Exendin-4. Other GLP-1R ^ positive organs showed z30 times lower dose deposition. A single injection of (Lys 40 (Ahx-DTPA- 111 In)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 (Lys 40 (Ahx-DTPA- 111 In)NH 2)-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiophar- maceuticals such as 111 In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.