ECE2016 Eposter Presentations Thyroid cancer (81 abstracts)
Sequence defined cMET/HGFR-targeted polymers as gene delivery vehicles for the theranostic sodium iodide symporter (NIS) gene
Sarah Urnauer 1 , Stephan Morys 2 , Ana Krhac Levacic 2 , Andrea M Müller 1 , Christina Schug 1 , Kathrin A Schmohl 1 , Nathalie Schwenk 1 , Christian Zach 2 , Janette Carlsen 3 , Peter Bartenstein 3 , Ernst Wagner 2 & Christine Spitzweg 1
1Department of Internal Medicine II, University Hospital of Munich, Ludwig-Maximilians-University, Munich, Germany; 2Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig-Maximilians-University, Munich, Germany; 3Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
The sodium iodide symporter (NIS) in its role as well characterized reporter and therapy gene represents an outstanding tool to target different cancer types allowing non-invasive imaging of functional NIS expression by 123I-scintigraphy and therapeutic application of 131I. Based on its overexpression on the surface of the vast majority of cancer types, the cMET/Hepatocyte growth factor receptor (HGFR) serves as an ideal target for tumor-selective gene delivery.
In the current study, we used sequence defined polymers as non-viral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding-peptide (cMBP2) to target the cMET/HGF-receptor in a human hepatocellular cancer (HuH7) mouse model. These polymers were complexed with human NIS-DNA (polyplexes) and tested for receptor-specificity, transduction efficiency and therapeutic efficacy.
In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS encoding DNA polyplexes coupled with cMBP2 (cMBP2-PEG-Stp/NIS) compared to polyplexes without ligand (Ala-PEG-Stp/NIS) and polyplexes containing non-coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6±1.6% ID/g 123I, biological half-life 3 h) by 123I-scintigraphy 48 h after intravenous polyplex application, while injection of control vectors did not result in specific iodide uptake. Therapy studies with 3 cycles of polyplexes and 131I applications resulted in a significant delay in tumor growth and prolonged survival of cMBP2-PEG-Stp/NIS-treated mice.
In conclusion, our data demonstrate the enormous potential of cMET-targeted sequence defined polymers combined with the unique theranostic function of NIS allowing for optimized transfection efficiency while eliminating adverse effects as toxicity or high immunogenicity.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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