Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene
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Kathrin A. Schmohl1,*, Aayush Gupta2,*, Geoffrey K. Grünwald1,*, Marija Trajkovic-Arsic3,4, Kathrin Klutz1, Rickmer Braren5, Markus Schwaiger6, Peter J. Nelson7, Manfred Ogris8, Ernst Wagner9, Jens T. Siveke2,3,4 and Christine Spitzweg1
1Department of Internal Medicine II and IV, University Hospital of Munich, LMU Munich, Munich, Germany
2Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
3Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
4German Cancer Consortium (DKTK), Partner Site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany
5Department of Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
6Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
7Clinical Biochemistry Group, Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
8Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics (MMCT), University of Vienna, Vienna, Austria
9Pharmaceutical Biotechnology, Department of Pharmacy, Center for System-Based Drug Research and Center for Nanoscience, LMU Munich, Munich, Germany
*These authors have contributed equally to this work
Christine Spitzweg, email: firstname.lastname@example.org
Keywords: gene therapy, sodium iodide symporter, EGFR-targeting, pancreatic ductal adenocarcinoma, genetically engineered mouse model
Received: October 13, 2016 Accepted: February 27, 2017 Published: March 23, 2017
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.
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