Receptor-mediated targeting of gene delivery vectors: Insights from molecular mechanisms for improved vehicle design

Abstract

One way to deliver transgenes to cells in a selective manner is to target the delivery vehicles, or vectors, to specific cell‐surface receptors as a first step toward ulimate transport of the gene to the nucleus for expression. While selective delivery, although often to undesired cell types, occurs naturally for some viral vectors and can be achieved for nonviral vehicles, current understanding and control of the delivery mechanism is inadequate for many therapeutic applications. The complicated nature of receptor‐mediated transgene uptake and transport requires improved analysis to more effectively evaluate delivery vehicles. As receptor‐mediated pathways for gene delivery typically involve vector binding, internalization, subcellular trafficking, vesicular escape, nuclear translocation, and unpackaging for transcription, each of these processes offer mechanisms that can be exploited to enhance targeted gene delivery via properly designed vehicles. For the purpose of this review, current targeted gene delivery vehicles are divided into three approaches: viral, synthetic, and hybrid vectors. Each approach possesses advantages as well as disadvantages at the present time for in vitro and in vivo application, and provides particular challenges to overcome in order to gain significantly improved targeted delivery properties. Quantitative experiments and mathematical modeling of the gene delivery pathway will serve to provide insight into molecular mechanisms and rate‐limiting steps for effective gene expression. Information on molecular mechanisms obtained by such methodologies can then be applied to specific vectors, whether viral, synthetic, or hybrid, allowing for the creation of targeted, effective, and safe gene therapeutics. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 70: 593–605, 2000.

Quantitative comparison of polyethylenimine formulations and adenoviral vectors in terms of intracellular gene delivery processes

“…1 Based on published literature reports and dedicated transient vector uptake and nuclear accumulation data, a mathematical model has been previously constructed and validated, which permits parameters representing cell binding, internalization, endosomal escape, unpackaging, and nuclear import to be estimated ( Figure 1). 2 Application of this model to similar experimental data for any given vector and cell type of interest should enable quantitative elucidation of which steps are rate-limiting for that vector/cell system.…”

Gene Transfer by DNA/mannosylated Chitosan Complexes into Mouse Peritoneal Macrophages

“…Active targeting using receptor-mediated interaction has been effective in gene delivery (Varga et al 2000). For example, macrophages express a mannose receptor that is used for endocytosis and phagocytosis of a variety of antigens (Stahl et al 1980).…”

Utilization of synthetic peptides containing nuclear localization signals for nonviral gene transfer systems

“…However, this requires proper sorting of the endosome, a process depending on physico-chemical properties of the endocytosed material. 12 Different strategies are used to allow the release of the vector into the cytoplasm, including the application of endosomolytic peptides or lipids 11,13 and polyethyleneimines acting as a protonic sponge and inducing osmotic disruption of the endosome. 14,15 Once in the cytoplasm, the heteroplex is exposed to soluble and insoluble factors, which may lead to cytoplasmic entrapment and subsequent degradation.…”