Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery
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Ikramy A. Khalil, Kentaro Kogure, Hideta
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Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Hokkaido, Japan (I.A.K., K.K., H.A., H.H.)
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan (I.A.K., K.K., H.A., H.H.)
Abstract
The successful delivery of therapeutic genes to the designated target cells and their availability at the intracellular site of action are crucial requirements for successful gene therapy. Nonviral gene delivery is currently a subject of increasing attention because of its relative safety and simplicity of use; however, its use is still far from being ideal because of its comparatively low efficiency. Most of the currently available nonviral gene vectors rely on two main components, cationic lipids and cationic polymers, and a variety of functional devices can be added to further optimize the systems. The design of these functional devices depends mainly on our understanding of the mechanisms involved in the cellular uptake and intracellular disposition of the therapeutic genes as well as their carriers. Macromolecules are internalized into cells by a variety of mechanisms, and their intracellular fate is usually linked to the entry mechanism. Therefore, the successful design of a nonviral gene delivery system requires a deep understanding of gene/carrier interactions as well as the mechanisms involved in the interaction of the systems with the target cells. In this article, we review the different uptake pathways that are involved in nonviral gene delivery from a gene delivery point of view. In addition, available knowledge concerning cellular entry and the intracellular trafficking of cationic lipid-DNA complexes (lipoplexes) and cationic polymer-DNA complexes (polyplexes) is summarized.
I. Introduction
Gene therapy is a new therapeutic strategy that offers the promise of treating diseases via the production of therapeutic proteins within cells. In general, any drug molecule must reach its intended site of action to exert its therapeutic effect. If this does not occur, the drug will have no therapeutic activity and may even cause nonspecific effects through interactions with nonintended targets. The problem of drug delivery is even more complicated when large, charged molecules such as DNA are used as drugs, as is the case in gene therapy. For nucleic acid molecules that are used in gene therapy, the target sites are mostly inside the cells, in the cytoplasm or the nucleus. Therefore, it is essential that these molecules traverse the plasma membrane to reach their target sites (Bally et al., 1999). The plasma membrane of living cells is a dynamic structure that is relatively lipophilic in nature. As a result, it restricts the entry of large, hydrophilic, or charged molecules. Most genetic molecules are both large and charged, making it difficult for them to traverse the plasma membrane on their own, and an appropriate gene delivery system is therefore required for their efficient cellular uptake ......
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