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

Oncotarget. 2017 May 16;8(20):33393-33404. doi: 10.18632/oncotarget.16499.

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.

Keywords: EGFR-targeting; gene therapy; genetically engineered mouse model; pancreatic ductal adenocarcinoma; sodium iodide symporter.

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / diagnostic imaging
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / therapy
  • Cell Line, Tumor
  • Disease Models, Animal
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Transfer Techniques
  • Genetic Therapy
  • Humans
  • Iodine Radioisotopes
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Pancreatic Neoplasms / diagnostic imaging
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / therapy
  • Positron-Emission Tomography
  • Radionuclide Imaging
  • Sodium Iodide / metabolism
  • Symporters / genetics*
  • Symporters / metabolism
  • Theranostic Nanomedicine* / methods
  • Xenograft Model Antitumor Assays

Substances

  • Iodine Radioisotopes
  • Symporters
  • sodium-iodide symporter
  • ErbB Receptors
  • Sodium Iodide

Supplementary concepts

  • Pancreatic Carcinoma