Conjugates of Oligonucleotides and Analogues with Cell Penetrating Peptides as Gene Silencing Agents

Zatsepin, Timofei S.; Turner, John; Oretskaya, Tatiana S.; Gait, Michael J.

doi:10.2174/138161205774580769

Cited by 90 publications

(83 citation statements)

References 106 publications

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“…Because the lipophilicity of nano-Pt is quite low, it was necessary to improve its penetrating activity by other methods. A novel approach to delivering bio-active macromolecules into cells is the use of cell-penetrating peptides (CPPs) [13,14]. HIV-1 TAT-derived peptide is a CPP that enhances translocation through the cellular membrane and into the cytoplasm by a receptor-independent, non-endocytic mechanism [15,16].…”

Section: Introductionmentioning

confidence: 99%

The effect of TAT conjugated platinum nanoparticles on lifespan in a nematode Caenorhabditis elegans model

2010

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Section: Introductionmentioning

confidence: 99%

The effect of TAT conjugated platinum nanoparticles on lifespan in a nematode Caenorhabditis elegans model

2010

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“…Two strategies are utilised for the attachment of cargo molecules. By far the majority of studies include a covalent attachment of carrier and cargo [for a review see: (23)]. This approach might be effective for a specific application (e.g.…”

Section: Introductionmentioning

confidence: 99%

Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect

Veldhoen¹,

Laufer²,

Trampe³

et al. 2006

Nucleic Acids Research

170

167

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Cell-penetrating peptides (CPPs) have evolved as promising new tools to deliver nucleic acids into cells. So far, the majority of these delivery systems require a covalent linkage between carrier and cargo. To exploit the higher flexibility of a non-covalent strategy, we focused on the characterisation of a novel carrier peptide termed MPGα, which spontaneously forms complexes with nucleic acids. Using a luciferase-targeted small interfering RNA (siRNA) as cargo, we optimised the conditions for MPGα-mediated transfection of mammalian cells. In this system, reporter gene activity could be inhibited up to 90% with an IC50 value in the sub-nanomolar range. As a key issue, we addressed the cellular uptake mechanism of MPGα/siRNA complexes applying various approaches. First, transfection of HeLa cells with MPGα/siRNA complexes in the presence of several inhibitors of endocytosis showed a significant reduction of the RNA interference (RNAi) effect. Second, confocal laser microscopy revealed a punctual intracellular pattern rather than a diffuse distribution of fluorescently labelled RNA-cargo. These data provide strong evidence of an endocytotic pathway contributing significantly to the uptake of MPGα/siRNA complexes. Finally, we quantified the intracellular number of siRNA molecules after MPGα-mediated transfection. The amount of siRNA required to induce half maximal RNAi was 10 000 molecules per cell. Together, the combination of methods provided allows for a detailed side by side quantitative analysis of cargo internalisation and related biological effects. Thus, the overall efficiency of a given delivery technique as well as the mechanism of uptake can be assessed.

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“…The first strategy requires chemical synthesis of the modified peptide to facilitate the covalent conjugation of the cargo (18)(19)(20)(21). Thioether, thiolmaleimide, ester formation, and click chemistry ( Figure 1B) are some of the possible conjugation methods available (22,23).…”

Section: Different Strategies For Peptidemediated Delivery Covalent Smentioning

confidence: 99%

Peptide-based vectors: recent developments

Cerrato

Lehto

Langel

2014

Biomolecular Concepts

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Peptides and peptide-cargo complexes have been used for drug delivery and gene therapy. One of the most used delivery vectors are cell-penetrating peptides, due to their ability to be taken up by a variety of cell types and deliver a large variety of cargoes through the cell membrane with low cytotoxicity. In vitro and in vivo studies have shown their possibility and full effectiveness to deliver oligonucleotides, plasmid DNA, small interfering RNAs, antibodies, and drugs. We report in this review some of the latest strategies for peptide-mediated delivery of nucleic acids. It focuses on peptide-based vectors for therapeutic molecules and on nucleic acid delivery. In addition, we discuss recent applications and clinical trials.

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Conjugates of Oligonucleotides and Analogues with Cell Penetrating Peptides as Gene Silencing Agents

Cited by 90 publications

References 106 publications

The effect of TAT conjugated platinum nanoparticles on lifespan in a nematode Caenorhabditis elegans model

The effect of TAT conjugated platinum nanoparticles on lifespan in a nematode Caenorhabditis elegans model

Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect

Peptide-based vectors: recent developments

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