Oncotarget

Research Papers:

Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene

Kathrin A. Schmohl, Aayush Gupta, Geoffrey K. Grünwald, Marija Trajkovic-Arsic, Kathrin Klutz, Rickmer Braren, Markus Schwaiger, Peter J. Nelson, Manfred Ogris, Ernst Wagner, Jens T. Siveke and Christine Spitzweg _

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Oncotarget. 2017; 8:33393-33404. https://doi.org/10.18632/oncotarget.16499

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Abstract

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

Correspondence to:

Christine Spitzweg, email: christine.spitzweg@med.uni-muenchen.de

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

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.


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