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Cationic Liposome–Nucleic Acid Complexes for Gene Delivery and Silencing: Pathways and Mechanisms for Plasmid DNA and siRNA

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Nucleic Acid Transfection

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 296))

Abstract

Motivated by the promises of gene therapy, there is great interest in developing non-viral lipid-based vectors for therapeutic applications due to their low immunogenicity, low toxicity, ease of production, and the potential of transferring large pieces of DNA into cells. In fact, cationic liposome (CL) based vectors are among the prevalent synthetic carriers of nucleic acids (NAs) currently used in gene therapy clinical trials worldwide. These vectors are studied both for gene delivery with CL–DNA complexes and gene silencing with CL–siRNA (short interfering RNA) complexes. However, their transfection efficiencies and silencing efficiencies remain low compared to those of engineered viral vectors. This reflects the currently poor understanding of transfection-related mechanisms at the molecular and self-assembled levels, including a lack of knowledge about interactions between membranes and double stranded NAs and between CL–NA complexes and cellular components. In this review we describe our recent efforts to improve the mechanistic understanding of transfection by CL–NA complexes, which will help to design optimal lipid-based carriers of DNA and siRNA for therapeutic gene delivery and gene silencing.

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Abbreviations

Chol:

Cholesterol

CL:

Cationic liposome

DL:

Lipid with dendritic headgroup

DOPC:

1,2-Dioleoyl-sn-glycero-3-phosphatidylcholine

DOPE:

1,2-Dioleoyl-sn-glycero-3-phosphatidylethanolamine

DOTAP:

1,2-Dioleoyl-3-trimethylammonium-propane

FF:

Firefly

MEF:

Mouse embryonic fibroblast

MVL:

Multivalent lipid

NA:

Nucleic acid

NL:

Neutral lipid

PEG:

Poly(ethylene glycol)

RL:

Renilla

RNAi:

RNA interference

SE:

Silencing efficiency

siRNA:

Short interfering RNA

TE:

Transfection efficiency

UVL:

Univalent lipid

XRD:

X-ray diffraction

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Acknowledgments

KKE, AZ, AA, NFB, HME, and CRS were supported primarily by NIH GM-59288-11 and in part, by DOE-BES grant DE-FG02-06ER46314 (lipid microstructure) and NSF-DMR 0803103 (lipid phase behavior). CSM and CES were supported by NIH AI-12520 and AI-20611. Cryo-TEM experiments were conducted at the National Resource for Automated Molecular Microscopy which is supported by the National Institutes of Health though the National Center for Research Resources’ P41 program (RR17573). The X-ray diffraction work was carried out at the Stanford Synchrotron Radiation Laboratory which is supported by the Department of Energy.

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Authors and Affiliations

  1. Physics, Materials & Molecular, Cellular and Developmental Biology Department, University of California at Santa Barbara, Santa Barbara, CA, 93106, USA

    Kai K. Ewert, Alexandra Zidovska, Ayesha Ahmad, Nathan F. Bouxsein, Heather M. Evans & Cyrus R. Safinya

  2. Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    Alexandra Zidovska

  3. Dynavax Technologies, Berkeley, CA, USA

    Ayesha Ahmad

  4. National Nanotechnology Coordination Office, Washington, DC, USA

    Heather M. Evans

  5. Molecular, Cellular and Developmental Biology Department & Biomolecular Science and Engineering Program, University of California at Santa Barbara, Santa Barbara, CA, 93106, USA

    Christopher S. McAllister & Charles E. Samuel

  6. Department of Medicine, University of California, San Diego, CA, USA

    Christopher S. McAllister

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  1. Kai K. Ewert
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  8. Cyrus R. Safinya
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Correspondence to Cyrus R. Safinya .

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  1. Cell Biology/RNAi, QIAGEN GmbH, Qiagen Str. 1, Hilden, 40724, Germany

    Wolfgang Bielke

  2. Cell Biology/RNAi, QIAGEN GmbH, Qiagen Str. 1, Hilden, 40724, Germany

    Christoph Erbacher

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Ewert, K.K. et al. (2010). Cationic Liposome–Nucleic Acid Complexes for Gene Delivery and Silencing: Pathways and Mechanisms for Plasmid DNA and siRNA. In: Bielke, W., Erbacher, C. (eds) Nucleic Acid Transfection. Topics in Current Chemistry, vol 296. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2010_70

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