title: Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene.
abstract: The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery.
authors.affiliation: Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany.
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Schmohl
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Aayush
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Grünwald
authors.affiliation: Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.|German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marija
authors.initials: M
authors.lastname: Trajkovic-Arsic
authors.affiliation: Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.affiliation: Department of Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.affiliation: Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Vienna, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience, LMU Munich, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.|Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.|German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D049268:Positron-Emission Tomography; D011877:Radionuclide Imaging; D012974:Sodium Iodide / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000068936:Theranostic Nanomedicine / Q000379:methods; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D066246:ErbB Receptors; D007457:Iodine Radioisotopes; D012974:Sodium Iodide; D027981:Symporters; D000099209:Sodium-Iodide Symporters
keywords: EGFR-targeting; gene therapy; genetically engineered mouse model; pancreatic ductal adenocarcinoma; sodium iodide symporter