Polyethylenimine but Not Cationic Lipid Improves Antisense Activity of 3′-Capped Phosphodiester Oligonucleotides

Dheur, Sonia; Dias, Nathalie; Aerschot, Arthur Van; Herdewijn, Piet; Bettinger, Thierry; Rémy, Jean-Serge; Hélène, Claude; Saison-Behmoaras, E.

doi:10.1089/oli.1.1999.9.515

Cited by 66 publications

(29 citation statements)

References 25 publications

(25 reference statements)

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“…Polyplexes formed by complexation of PEI and nucleic acids have shown efficient in vitro delivery of DNA [111], ODN [183] and siRNA [184] in various cell lines. In vivo, these polyplexes also displayed antitumoral activity after subcutaneous or intraperitoneal administration, as shown with a siRNA targeted against the growth factor pleiotrophin [185] and the HER-2 receptor [186] in murine subcutaneous tumor models.…”

Section: Delivery Of Nucleic Acidsmentioning

confidence: 99%

Nanocarriers’ entry into the cell: relevance to drug delivery

Hillaireau

Couvreur

2009

Cell. Mol. Life Sci.

1,339

1,015

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Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles' physicochemical properties. Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered. This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand, the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless, various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic acids, proteins and peptides for therapeutic applications by these non-phagocytic routes.

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Section: Delivery Of Nucleic Acidsmentioning

confidence: 99%

Nanocarriers’ entry into the cell: relevance to drug delivery

Hillaireau

Couvreur

2009

Cell. Mol. Life Sci.

1,339

1,015

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“…PEI is a polycation that is widely used to deliver nucleic acids, including DNA (13), siRNA (14Y17), ribozymes (18,19), and oligonucleotides (13,20). The prevailing hypothesis is that the positively charged amine groups of PEI electrostatically complex with the negatively charged phosphate groups of nucleic acids to produce a neutral or positively charged complex with sufficient stability to allow intracellular delivery of the genetic material.…”

Section: Introductionmentioning

confidence: 99%

Biophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro

2006

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“…This indicates that the PBAE polymers deliver PSODNs in a different way than PO-ODNs, with the PO-ODNs being more easily released. It has been reported that other polymers like poly-ethylene-imine (PEI) also formed stronger complexes with PS-ODNs when compared to PO-ODNs, which could explain the difference in the release profile (24). From time to time, PS-ODNs could be found in the nuclei of the cells, although not as frequently as the PO-ODNs (data not shown).…”

Section: Intracellular Distribution and Integrity Of Po-and Ps-odns Dmentioning

confidence: 96%

Efficient delivery of intact phosphodiester oligonucleotides by poly-β-amino esters

Remaut

Symens

Lucas

et al. 2010

Journal of Controlled Release

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Due to their great instability, phosphodiester antisense oligonucleotides (PO-ODNs) are rapidly degraded in the intracellular environment, which limits their biological activity. The release of PO-ODNs during a prolonged period of time could however greatly enhance their antisense effect by creating a pool of intact PO-ODNs at any time point. Poly-β-aminoesters are biodegradable cationic polymers which show potential for the controlled release of short DNA fragments like ODNs and small interfering RNA (siRNA). In this research we evaluated biodegradable poly-β-aminoesters as carriers for PO-ODNs and compared the antisense activity with nuclease stable phosphothioate (PS) ODNs. PBAE1 polymers were not able to generate an antisense effect with PO-or PS-ODNs, most likely due to their poor cellular uptake. When complexed to PBAE2 polymers at N/P ratio 10, both PO-and PS-ODNs downregulated the targeted protein expression with 70%. By confocal imaging we observed a high concentration of released PO-ODNs that formed nuclear bodies in the nucleoplasm. The ODNs in this nuclear bodies were still intact as could be demonstrated by Fluorescence Resonance Energy Transfer (FRET) and acceptor photobleaching. This was in clear contrast to PO-ODNs delivery by cationic liposomes where the ODNs that accumulated in the nucleus were degraded and nuclear bodies were not observed. We conclude that PBAE2 shows potential for the delivery of nuclease sensitive POODNs. This occurs however not through a time controlled release profile, but rather due to the rapid delivery of a high concentration of intact PO-ODNs that form nuclear bodies in the nuclei of the cells. These nuclear bodies can most likely act as a depot of intact PO-ODNs, resulting in efficient antisense activity.keywords : poly β aminoesters, Fluorescence Correlation Spectroscopy, Fluorescence Resonance Energy Transfer, oligonucleotides, nucleases, delivery 2 INTRODUCTIONDelivery of small DNA fragments such as antisense oligonucleotides (ODNs) and small interfering RNA (siRNA) remains an attractive research domain to achieve the therapeutic regulation of gene expression. Antisense oligonucleotides are short single stranded DNA strands which naturally consist of a phosphodiester (PO) backbone. Due to the high instability of this PO backbone, however, the routinely used ODNs consist of the more stabile phosphothioate (PS) backbone (1;2). ODNs can act both in the cytoplasm and the nucleus by a sequence-specific recognition of the complementary mRNA. Through a variety of mechanisms, the complementary mRNA is then destroyed which results in the downregulation of the corresponding protein (3;4).siRNAs are short double-stranded RNA fragments with a 2 nucleotides overhang at the 3' end. They are very potent molecules since they are recognised by intracellular RNA-induced silencing complexes (RISCs) which specifically and repeatedly destroy the targeted mRNA molecules. SiRNA can be used in much lower concentrations and generally achieves a higher knockdown efficiency when comp...

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Polyethylenimine but Not Cationic Lipid Improves Antisense Activity of 3′-Capped Phosphodiester Oligonucleotides

Cited by 66 publications

References 25 publications

Nanocarriers’ entry into the cell: relevance to drug delivery

Nanocarriers’ entry into the cell: relevance to drug delivery

Biophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro

Efficient delivery of intact phosphodiester oligonucleotides by poly-β-amino esters

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