title: Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene.
abstract: The sodium iodide symporter (NIS) as well-characterized theranostic gene represents an outstanding tool to target different cancer types allowing noninvasive imaging of functional NIS expression and therapeutic radioiodide application. Based on its overexpression on the surface of most cancer types, the cMET/hepatocyte growth factor receptor serves as ideal target for tumor-selective gene delivery. Sequence-defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding peptide (cMBP2) were complexed with NIS-DNA and tested for receptor-specificity, transduction efficiency, and therapeutic efficacy in hepatocellular cancer cells HuH7. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS-encoding polyplexes (cMBP2-PEG-Stp/NIS) compared to polyplexes without targeting ligand (Ala-PEG-Stp/NIS) and without coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo in a subcutaneous xenograft mouse model showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6 ± 1.6% ID/g (123)I, biological half-life 3 hours) by (123)I-scintigraphy. Therapy studies with three cycles of polyplexes and (131)I application resulted in significant delay in tumor growth and prolonged survival. These 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 toxicity.
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Urnauer
authors.affiliation: Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Morys
authors.affiliation: Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Krhac Levacic
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schug
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Schmohl
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schwenk
authors.affiliation: Department of Nuclear Medicine, LMU Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.affiliation: Department of Nuclear Medicine, LMU Munich, Munich, Germany.
authors.forename: Janette
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Nuclear Medicine, LMU Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine II, LMU Munich, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D018014:Gene Transfer Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D027981:Symporters / Q000235:genetics*; D000068936:Theranostic Nanomedicine; D014162:Transfection; D000099209:Sodium-Iodide Symporters
chemical_list: D011092:Polyethylene Glycols; D011108:Polymers; D019859:Proto-Oncogene Proteins c-met; D027981:Symporters; D000099209:Sodium-Iodide Symporters