Receptor-Mediated Gene Delivery with Non-Viral DNA Carriers

Kichler, Antoine; B, Frisch; Souza, Debora Lima de; Schuber, Francis

doi:10.3109/08982100009031110

Cited by 9 publications

(8 citation statements)

References 67 publications

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“…Current methods for effecting delivery of nucleic acid therapeutics are often based on liposome-or polymersome-mediated membrane fusion [10-12] and ligand-mediated endocytosis [13-14]. Cationic liposomes have been widely used to transfect DNA in cell culture but its use in vivo is oftentimes compromised by its cytotoxicity and poor biodistribution.…”

Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of cationic shell-crosslinked knedel-like nanoparticles: Shell composition and transfection efficiency/cytotoxicity

et al. 2010

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Cationic nanoparticles are a promising class of transfection agents for oligonucleotide and gene delivery, but vary greatly in their effectiveness and cytotoxicity. Recently, we developed a new class of cationic transfection agents based on cationic shell-crosslinked nanoparticles (cSCKs) that efficiently transfect mammalian cells with both oligonucleotides and plasmid DNA. In an effort to further improve transfection efficiency without increasing cytotoxicity, we examined the effects of the composition of primary amine (pa), tertiary amine (ta) and carboxylic acid (ca) groups in the shell of these nanoparticles. A series of discrete complexes of the cSCKs with plasmid DNA (pDNA) or phosphorothioate 2′-OMe oliogonucleotides (ps-MeON) were prepared over a broad range of amine to phosphate ratios (N/P ratio) of 4:1 to 40:1. The sizes of the complexes and the ability of the nanoparticles to completely bind ODNs were found to depend on the cSCK amine to DNA phosphate (N/P) ratio and the cSCK buffering capacity. The cSCKs were then evaluated for their ability to transfect cells with plasmid DNA by monitoring fluorescence from an encoded EGFP, and for delivery of ps-MeON by monitoring luminescence from luciferase resulting from ps-MeONmediated splicing correction. Whereas the cationic cSCK-pa 25 -ta 75 was found to be best for transfecting plasmid DNA into HeLa cells at an N/P ratio of 20:1, cSCK-pa 50 -ta 50 , at an N/P ratio 10:1 was best for ps-MeON delivery. We also found that increasing the proportion of tertiary relative to primary amine reduced the cytotoxicity. These results demonstrate that a dramatic improvement in gene and oligonucleotide delivery efficiency with decreased cytotoxicity in HeLa cells can be achieved by incorporation of tertiary amines into the shells of cSCKs.

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Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of cationic shell-crosslinked knedel-like nanoparticles: Shell composition and transfection efficiency/cytotoxicity

et al. 2010

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“…Such an active targeting requires the identification of receptors present at the surface of the target cells and the use of ligands that bind with a high specificity and affinity to the recognition sites. The ligands, of natural or synthetic origin, can be conjugated to the polymers by using different techniques [25]. It is, however, important to develop strategies that allow the preparation of conjugates with precise ligand densities, that expose the ligands at the surface of the transfection particles, and which are not detrimental to the recognition of the ligands by their receptor.…”

Section: Ligand-pei Conjugates For Cell Targetingmentioning

confidence: 99%

Gene transfer with modified polyethylenimines

2004

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Branched and linear polyethylenimines (PEIs) have proven to be efficient and versatile agents for gene delivery in vitro. In addition, systemic administration of positively charged DNA/PEI complexes results in significant reporter gene expression in lungs. However, re-targeting of complexes to organs other than the lung is hampered by non-specific interactions of polyplexes with blood components and non-target cells. Thus, despite considerable transfectional activity, the properties of PEIs need to be further improved. Therefore, various modifications of PEIs have been explored in recent years. For example, to increase the circulation half-life of the DNA complexes, the surface charge of the particles was shielded by grafting hydrophilic polymers such as polyethylene glycols (PEGs) onto their surface. Alternatively, incorporation of certain ligands into the DNA complexes also resulted in charge shielding even without PEGylation. Herein, I review the most recent PEI derivatives, with a special focus on PEGylated and targeted polymers.

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“…The GPI-anchored glycoprotein folate receptor is proposed to be internalized via a clathrin-independent endocytic process (Kichler et al, 2000). A nondegrading route of uptake of folate would contribute to the attractiveness of folate as a ligand for drug delivery systems (see further section on targeting ligands).…”

Section: Endocytic Uptakementioning

confidence: 99%

“…The folate receptor, a GPI-anchored glycoprotein, is an attractive target entity because it is absent in most tissues but is elevated in a variety of sarcomas and carcinomas (Guo et al, 2000;Kichler et al, 2000;Zhou et al, 2002). The ligand molecule, folic acid, is nonimmunogenic due to its small size (MW 441).…”

Section: Folate Receptor Targetingmentioning

confidence: 99%

Cell-Specific Targeting of Lipid-Based Carriers for ODN and DNA

Bartsch¹,

Weeke-Klimp²,

Meijer³

et al. 2005

J. of Liposome Res.

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It is well recognized that there is an urgent need for non-toxic systemically applicable vectors for biologically active nucleotides to fully exploit the current potential of molecular medicine in gene therapy. Cell-specific targeting of non-viral lipid-based carriers for ODN and DNA is a prerequisite to attain the concentration of nucleic acids required for therapeutic efficacy in the target tissue. In this review we will address the most promising approaches to selective targeting of liposomal nucleic acid carriers in vivo. In addition, the routes of entry and intracellular processing of these carrier systems are discussed as well as physiological factors potentially interfering with the biological and/or therapeutic activity of their nucleotide pay-load.

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Receptor-Mediated Gene Delivery with Non-Viral DNA Carriers

Cited by 9 publications

References 67 publications

Structure-activity relationships of cationic shell-crosslinked knedel-like nanoparticles: Shell composition and transfection efficiency/cytotoxicity

Structure-activity relationships of cationic shell-crosslinked knedel-like nanoparticles: Shell composition and transfection efficiency/cytotoxicity

Gene transfer with modified polyethylenimines

Cell-Specific Targeting of Lipid-Based Carriers for ODN and DNA

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