11 Receptor-mediated Gene Delivery Strategies

Abstract

WHAT NEEDS TO BE ACCOMPLISHED FOR SUCCESSFUL GENE DELIVERY
The perceived barriers to gene delivery are summarized in Figure 1. When using these systems in vivo, the complex must avoid inactivation or aggregation by serum components such as complement (Plank et al. 1996). The material must be of the appropriate size to reach the target cells. For example, the fenestrations through which the material must reach the liver parenchyma have a limit of approximately 100 nm. The complex must avoid being recognized by neutralizing antibodies if they are present in the host serum. Furthermore, the charge properties of the complex should be adjusted to avoid nonspecific accumulation on inappropriate surfaces.

Should the complex reach the surfaces of target cells, it is important to include ligands to ensure binding to elements on the surface of the cell. Initially, ligands for receptors known to be rapidly internalized were used, such as asialoglycoproteins or transferrin, but subsequent efforts suggest that the simple binding, aggregation, or accumulation on the surface is sufficient for entry into the vesicle system of the cell.

Once internalized in a vesicle, passage through or across the vesicle membrane into the cytoplasm is required. A large amount of research in membrane disruption has occurred since this barrier was recognized in the early 1990s (see the following). Passage through the cytoplasm is required (or, alternately, disruption of the cytoplasmic organization to promote deposition at the nuclear membrane), passage into the nucleus, and the docking of transfection material in the appropriate nuclear...