Receptor-Mediated Gene Delivery with Non-Viral DNA Carriers

Abstract

To achieve effective nucleic acid-based therapy, natural carriers, i.e. viruses, as well as synthetic carriers have been developed. The majority of the non-viral systems are based on DNA compaction into small particles by cationic compounds, which are most often polymers and lipids. Optimal in vitro gene delivery with the cationic carriers requires an excess of positive charges with respect to DNA phosphates. However, the overall positive charge of these particles limits their application in vivo because: i) the half-life of positively charged DNA complexes, injected intravenously, is very short, and ii) it does not allow site-specific delivery of the gene of interest. To overcome this problem, the most attractive strategy consists in replacing the non-specific electrostatic interactions between cells and the transfection complexes with a cell-specific interaction that triggers a receptor-mediated endocytosis of the targeted DNA complexes. Such an active targeting requires the identification of receptors present at the surface of the target cells and the use of ligands which binds with a high specificity and affinity to such recognition sites. In this review, we will focus on three examples of receptors that have been used for the targeting of DNA complexes: the Gal/GalNAc receptor followed by the integrin- and folate receptors. Some important principles underlying targeted transfection will also be evoked such as the importance of the conjugation chemistry, the nature of the ligand-receptor interactions, the occurrence of limited windows of the complex charge where targeting is observed.

Keywords::

• Gene transfer
• Receptor-mediated endocytosis
• Gal/GalNAc
• Folate
• RGD