Sticky overhangs enhance siRNA-mediated gene silencing

Bolcato-Bellemin, Anne-Laure; Bonnet, Marie-Elise; Creusat, Gaëlle; Erbacher, Patrick; Behr, Jean‐Paul

doi:10.1073/pnas.0707831104

Cited by 224 publications

(200 citation statements)

References 30 publications

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“…For example, some PEI formulations that effectively work for pDNA delivery show only moderate siRNA delivery capacity. Behr and colleagues 37 showed that Gene therapy progress and prospects D Schaffert and E Wagner making siRNAs 'gene-like,' by incorporating short complementary sticky overhangs, increased PEI polyplex stability and gene silencing up to 10-fold. Alternatively, novel polymers, 25,38 or modifications of existing polymers, 3,39,40 have been generated with improved siRNA transfer potential.…”

Section: Combinatorial Chemistry Allows Rapid Polymer Development Formentioning

confidence: 99%

Gene therapy progress and prospects: synthetic polymer-based systems

2008

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Low efficiency, significant toxicity, polymer polydispersity and poorly understood delivery mechanisms have initially plagued the field of polymer-based gene therapy. Numerous strategies have helped to improve polyplexes, including the development of biodegradable polymers with reduced toxicity, incorporation of cell targeting, surface shielding and additional transport domains for effective and specific delivery, or improved chemistry for syntheses of polymers with uniform size and topology. Combined biooptical imaging and bioinformatics, providing insights into transfer bottlenecks, have helped to design improved polyplexes. Bioresponsive multifunctional polymers adapt in a dynamic manner to delivery barriers for efficient transfer of pDNA or siRNA to the target site.

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Section: Combinatorial Chemistry Allows Rapid Polymer Development Formentioning

confidence: 99%

Gene therapy progress and prospects: synthetic polymer-based systems

2008

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“…In fact, it was demonstrated that the high activity depends on complete removal of propionamide residues from the polyisoxazoline precursor polymer (14). Linear PEI22 on its own has limited efficiency in siRNA delivery (7); the activity however can be enhanced with concatemerizing "sticky" siRNA (ssiRNA) applied for polyplex formation (15).…”

Section: Introductionmentioning

confidence: 99%

Simple Modifications of Branched PEI Lead to Highly Efficient siRNA Carriers with Low Toxicity

et al. 2008

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Polymer carriers like PEI which proved their efficiency in DNA delivery were found to be far less effective for the applications with siRNA. In the current study, we generated a number of nontoxic derivates of branched PEI through modification of amines by ethyl acrylate, acetylation of primary amines, or introduction of negatively charged propionic acid or succinic acid groups to the polymer structure. The resulting products showed high efficiency in siRNA-mediated knockdown of target gene. In particular, succinylation of branched PEI resulted in up to 10-fold lower polymer toxicity in comparison to unmodified PEI. Formulations of siRNA with succinylated PEI were able to induce remarkable knockdown (80% relative to untreated cells) of target luciferase gene at the lowest tested siRNA concentration of 50 nM in Neuro2ALuc cells. The polyplex stability assay revealed that the efficiency of formulations which are stable in physiological saline is independent of the affinity of siRNA to the polymer chain. The improved properties of modified PEI as siRNA carrier are largely a consequence of the lower polymer toxicity. In order to achieve significant knockdown of target gene, the PEI-based polymer has to be applied at higher concentrations, required most probably for sufficient accumulation and proton sponge effects in endosomes. Unmodified PEI is highly toxic at such polymer concentrations. In contrast, the far less toxic modified analogues can be applied in concentrations required for the knockdown of target genes without side effects.

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“…The reduced efficacy of PEI in the later case arises due to the short length of siRNA. The weak electrostatic cohesion between the negatively charged siRNA and the cationic PEI polymer plays crucial role in dissociation of PEI/siRNA complexes at the anionic cell surface (Spagnou et al, 2004;Bolcato-Bellemin et al, 2007). Additionally the associated toxicity of PEI becomes one of the major concerns for all kinds of nucleic acid delivery (Hunter and Moghimi, 2002;Moghimi et al, 2005).…”

Section: Polyethyleniminementioning

confidence: 99%

Polymers in Small-Interfering RNA Delivery

Singha

Namgung

Kim

2011

Nucleic Acid Therapeutics

181

112

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This review will cover the current strategies that are being adopted to efficiently deliver small interfering RNA using nonviral vectors, including the use of polymers such as polyethylenimine, poly(lactic-co-glycolic acid), polypeptides, chitosan, cyclodextrin, dendrimers, and polymers-containing different nanoparticles. The article will provide a brief and concise account of underlying principle of these polymeric vectors and their structural and functional modifications which were intended to serve different purposes to affect efficient therapeutic outcome of small-interfering RNA delivery. The modifications of these polymeric vectors will be discussed with reference to stimuli-responsiveness, target specific delivery, and incorporation of nanoconstructs such as carbon nanotubes, gold nanoparticles, and silica nanoparticles. The emergence of small-interfering RNA as the potential therapeutic agent and its mode of action will also be mentioned in a nutshell.

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Sticky overhangs enhance siRNA-mediated gene silencing

Cited by 224 publications

References 30 publications

Gene therapy progress and prospects: synthetic polymer-based systems

Gene therapy progress and prospects: synthetic polymer-based systems

Simple Modifications of Branched PEI Lead to Highly Efficient siRNA Carriers with Low Toxicity

Polymers in Small-Interfering RNA Delivery

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