Targeted Gene Delivery

Receptor targeting of gene vectors

Fig 1 Polyplex formation: Nucleic acid (plasmid DNA, RNA) will interact by electrostatic interaction with a molecular conjugate consisting of polycationic nucleic acid compaction domain. Receptor targeting is achieved by covalently coupling a ligand (protein, peptide, sugar, others) via a shielding domain (PEG, polyethyleneglycol) to the polycation.

Delivery of therapeutically active nucleic acids into target cells requires a delivery system, either based on recombinant viruses or on synthetic carrier molecules. Although for localized delivery physical methods like electroporation can be used, systemic delivery to e.g. disseminated tumors requires a particulate delivery system mimicking viral functions. We use polycationic carrier molecules, which condense nucleic acid by electrostatic interaction with their negatively charges phosphate backbone leading to formation of virus sized particles, termed polyplexes. Such positively charged particles usually interact with cells by interaction via negatively charged cell surface components leading to adsorptive endocytosis. Specificity and efficiency of macromolecular drug delivery can be boosted by utilizing cell binding and –internalizing ligands. In this project receptors being frequently upregulated in tumors, like the transferrin receptor or the epidermal growth factor receptor (EGFR) are targeted by covalent attachment of their ligands or receptor binding peptides to polyplexes. For the EGF/EGFR system we observed rapid binding and internalization of EGF-containing polyplexes within a time frame similar to free EGF. Besides (recombinant) proteins, we now develop fully synthetic peptide based ligands for targeting of tumor cells and tumor endothelium, which allow a more convenient carrier synthesis but also will simplify processes in the further preclinical development of such targeted carriers.