[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma.
OBJECTIVE
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 [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4, an (111)In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.


METHODS
[Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-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 [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4. Other GLP-1R-positive organs showed > or =30 times lower dose deposition. A single injection of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-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 radiopharmaceuticals such as (111)In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.
Wicki
Andreas
A
Institute of Biochemistry and Genetics, DKBW, Medical School, University of Basel, Basel, Switzerland.
Wild
Damian
D
Storch
Daniel
D
Seemayer
Christian
C
Gotthardt
Martin
M
Behe
Martin
M
Kneifel
Stefan
S
Mihatsch
Michael J
MJ
Reubi
Jean-Claude
JC
Mäcke
Helmut R
HR
Christofori
Gerhard
G
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007340:Insulinoma / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D004369:Pentetic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000378:metabolism*; D014018:Tissue Distribution
C517541:(Lys(40)(Ahx-DTPA-111In)NH2)exendin-14; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon; D004369:Pentetic Acid