title: Dual-targeted polyplexes based on sequence-defined peptide-PEG-oligoamino amides.
abstract: For active cell targeting, viruses frequently capitalize on dual-receptor binding. With the intention to mimic this natural process, a dual peptide-based approach for targeting cancer cells was evaluated. For this purpose, sequence-defined pDNA binding oligo (ethane amino) amides containing a PEG chain with a peptidic targeting ligand at its distal end were applied. Integrin receptor-directed cyclic peptide cRGDfk, transferrin receptor-addressing peptide B6, and epidermal growth factor receptor-targeting peptide GE11 were used in the study in DU145 prostate cancer cells that express all three receptors. Dual-receptor targeted pDNA polyplexes were designed by combining two of the above ligands at various ratios, in order to find an optimal ligand combination. Two polycation/pDNA ratios of nitrogen/phosphate (N/P) 6 and 12 were tested. Dual targeting effects were most pronounced at the lower N/P ratio and found for all three combinations. Cell binding studies and pDNA transfections revealed GE11 plus B6 as the most potent combination. In general, a good correlation of cell binding with gene transfer was observed. Interestingly, GE11 peptide-based polyplexes-mediated bimodal cell association profiles. In contrast, B6 ligand, cRGD ligand, and dual-targeted polyplexes triggered more homogenous monomodal cell binding characteristics.
authors.affiliation: Pharmaceutical Biotechnology, Center for System-Based Drug Research, Ludwig-Maximilians-University Munich, Munich, D-81377, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kos
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
authors.forename: Dongsheng
authors.initials: D
authors.lastname: He
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010316:Particle Size; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010957:Plasmids; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D013499:Surface Properties; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D010455:Peptides; D011092:Polyethylene Glycols; D004247:DNA
keywords: EGFR; gene delivery; integrin; pegylation; peptides; plasmid DNA; polyplex; receptors; targeting; transferrin