title: Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer.
abstract: Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research, Ludwig Maximilians University Munich, Butenandtstrasse 5-13, D-81377 Munich, Germany. ernst.wagner@cup.uni-muenchen.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Kos
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
authors.forename: Annika
authors.initials: A
authors.lastname: Herrmann
authors.forename: Frauke Martina
authors.initials: FM
authors.lastname: Mickler
authors.forename: Markus
authors.initials: M
authors.lastname: Döblinger
authors.forename: Dongsheng
authors.initials: D
authors.lastname: He
authors.forename: Ana
authors.initials: A
authors.lastname: Krhač Levačić
authors.forename: Stephan
authors.initials: S
authors.lastname: Morys
authors.forename: Christoph
authors.initials: C
authors.lastname: Bräuchle
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism*; D002412:Cations; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D004058:Diffusion; D004355:Drug Stability; D006639:Histidine / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000737:chemistry / Q000648:ultrastructure; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D014162:Transfection / Q000379:methods*
chemical_list: D002412:Cations; C000715470:MAS1 protein, human; D053769:Nanocapsules; D000090063:Proto-Oncogene Mas; D006639:Histidine; D004247:DNA; D019859:Proto-Oncogene Proteins c-met