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OtherReview Article

Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery

Ikramy A. Khalil, Kentaro Kogure, Hidetaka Akita and Hideyoshi Harashima
Pharmacological Reviews March 2006, 58 (1) 32-45; DOI: https://doi.org/10.1124/pr.58.1.8
Ikramy A. Khalil
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Kentaro Kogure
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Hidetaka Akita
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Hideyoshi Harashima
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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.

Footnotes

  • ↵1 Abbreviations: CME, clathrin-mediated endocytosis; LDL, low-density lipoprotein; Tf, transferrin; CCV, clathrin-coated vesicle; PEI, polyethyleneimine; SV40, simian virus 40; PTD, protein transduction domain; His-pLK, histidylated poly-l-lysine; CIDIQ, confocal image-assisted three-dimensionally integrated quantification; STR-R8, stearylated-octaarginine; R8, octaarginine; DOPE, dioleoylphosphatidylethanolamine; PLL, poly-l-lysine.

  • This work was supported in part by grants-in-aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by grants-in-aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science.

  • Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

  • doi:10.1124/pr.58.1.8.

  • The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 58 (1)
Pharmacological Reviews
Vol. 58, Issue 1
1 Mar 2006
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OtherReview Article

Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery

Ikramy A. Khalil, Kentaro Kogure, Hidetaka Akita and Hideyoshi Harashima
Pharmacological Reviews March 1, 2006, 58 (1) 32-45; DOI: https://doi.org/10.1124/pr.58.1.8

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OtherReview Article

Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery

Ikramy A. Khalil, Kentaro Kogure, Hidetaka Akita and Hideyoshi Harashima
Pharmacological Reviews March 1, 2006, 58 (1) 32-45; DOI: https://doi.org/10.1124/pr.58.1.8
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  • Article
    • Abstract
    • I. Introduction
    • II. Uptake Pathways for Nonviral Gene Delivery
    • III. Tools to Study Intracellular Trafficking in Nonviral Gene Delivery
    • IV. Uptake Mechanisms and Intracellular Trafficking of Gene Delivery Mediated by Cationic Lipids and Polymers
    • V. Conclusions
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