title: Trastuzumab-targeted gene delivery to Her2-overexpressing breast cancer cells.
abstract: We describe a novel gene delivery system that specifically targets human epidermal growth factor receptor 2 (Her2)-overexpressing breast cancer cells. The targeting complexes consist of a PEGylated polylysine core that is bound to DNA molecules coding for either green fluorescent protein or shrimp luciferase. The complex is disulfide linked to the monoclonal antibody trastuzumab and to a pore-forming protein, Listeriolysin O (LLO). Trastuzumab is responsible for specific targeting of Her2 receptors and uptake of the gene delivery complex into endosomes of recipient cells, whereas LLO ensures that the DNA molecules are capable of transit from the endosomes into the cytoplasm. Omission of either trastuzumab or LLO from the nanocomplexes results in minimal gene product in targeted cells. Treatment of isogeneic MCF7 and MCF7/Her18 cell lines, differing only in number of Her2 receptors, with the complete gene delivery system results in a 30-fold greater expression of luciferase activity in the Her2-overexpressing MCF7/Her18 cells. Our nanocomplexes are small (150-250 nm), stable to storage, nontoxic and generic in make-up such that any plasmid DNA or antibody specific for cell-surface receptors can be coupled to the PEGylated polylysine core.
authors.affiliation: Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK, USA.|WWAMI Medical Education Program, University of Alaska Anchorage, Anchorage, AK, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mann
authors.affiliation: WWAMI Medical Education Program, University of Alaska Anchorage, Anchorage, AK, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kullberg
mesh_terms: D001427:Bacterial Toxins / Q000494:pharmacology; D001943:Breast Neoplasms / Q000628:therapy*; D002470:Cell Survival; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D061986:MCF-7 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D001427:Bacterial Toxins; D049452:Green Fluorescent Proteins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008156:Luciferases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C038705:hlyA protein, Listeria monocytogenes