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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality in developed countries despite its comparably low incidence of less than 3 %, clearly demonstrating the lack of effective therapeutic strategies
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
In order to optimize transfection conditions for linear polyethylenimine (LPEI)-polyethylene glycol (PEG)-GE11 polymers condensed with the NIS plasmid (LPEI-PEG-GE11/NIS) in high EGFR-expressing PDAC cell explants derived from Kras;p53 mice (Figure 1A), radioiodide uptake activity was evaluated 24 h after polyplex application
Summary
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality in developed countries despite its comparably low incidence of less than 3 %, clearly demonstrating the lack of effective therapeutic strategies. The genetic hallmark of PDAC development is an activating mutation in the KRAS oncogene, followed by other genetic changes, commonly including inactivation of the tumor suppressors TP53, CDKN2A (P16INK4A) and SMAD4, and activation of several growth factor receptors, such as the epidermal growth factor receptor (EGFR) [3, 7]. Against this background, several complex genetically modified mouse models of PDAC that mirror the typical changes found in human patients, have been generated in recent years [3, 4, 8,9,10]. The morphological and molecular composition of endogenous tumors far better reflects human disease, making them highly suitable to predict the clinical effectiveness of a specific treatment strategy
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