title: Combination of sequence-defined oligoaminoamides with transferrin-polycation conjugates for receptor-targeted gene delivery.
abstract: BACKGROUND
  Transferrin receptor (TfR), over-expressed on a majority of malignant cells, has been widely studied as a target for drug, protein and gene delivery. Both stable nucleic acid compact ability and efficient cytosol gene release capability are essential for the success of gene delivery.
  
  
  METHODS
  In the present study, a novel nonviral TfR-targeted gene delivery system was developed based on sequence-defined cationic oligoaminoamide oligomers with endolysosomal buffer capacity and DNA binding transferrin (Tf) polycation conjugates.
  
  
  RESULTS
  Gene transfer activities were significantly increased in a series of TfR over-expressing human tumour cell lines (K562, DU145 and KB) with mixed ternary polyplexes containing Tf-conjugates and 3-arm (386 and 689) or 4-arm (577, 579 and 607) sequence-defined oligomers. Especially polyplexes containing a histidine-rich 4-arm oligomer (607) and Tf-PEG-PEI achieved a 100-fold increase in gene expression compared to previously established formulations. Tf competition experiments indicate enhanced polyplex internalization via TfR as prerequisite for the high transfection activity. The additional histidines in the oligoaminoamide oligomer structure are required for more effective endolysosomal escape of the gene delivery vehicle. Polyplexes formed by first mixing pDNA with the oligomer as a cationic core, followed by the addition of the Tf-polycation conjugate for presentation at the exterior nanoparticles, exhibited the highest transfection activity.
  
  
  CONCLUSIONS
  Utilizing the synergistic effects of Tf for receptor targeting and oligomer for packaging and endolysosomal escape, an efficient gene delivery carrier was developed. The mixed polyplex containing Tf-polycation conjugates and histidinylated 4-arm oligomer with succinoyl tetraethylene pentamine or glutaroyltriethylene tetramine building blocks exhibited the highest gene transfection efficiency in TfR over-expressing human tumour cell lines.
authors.affiliation: Pharmaceutical Biotechnology, Centre for System-Based Drug Research, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Biotechnology, Centre for System-Based Drug Research, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rödl
authors.affiliation: Pharmaceutical Biotechnology, Centre for System-Based Drug Research, Ludwig-Maximilians-Universität Munich, Munich, Germany.|Nanosystems Initiative Munich, Munich, Germany.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität Munich, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Döblinger
authors.affiliation: Pharmaceutical Biotechnology, Centre for System-Based Drug Research, Ludwig-Maximilians-Universität Munich, Munich, Germany.|Nanosystems Initiative Munich, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
authors.affiliation: Pharmaceutical Biotechnology, Centre for System-Based Drug Research, Ludwig-Maximilians-Universität Munich, Munich, Germany.|Nanosystems Initiative Munich, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000577:Amides / Q000737:chemistry; D045744:Cell Line, Tumor; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011073:Polyamines / Q000737:chemistry; D000071228:Polyelectrolytes; D011990:Receptors, Transferrin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry
chemical_list: D000577:Amides; D011073:Polyamines; D000071228:Polyelectrolytes; D011990:Receptors, Transferrin; D014168:Transferrin
keywords: endosomal escape; gene delivery; oligoaminoamide oligomer; transfection; transferrin