Cationic lipids and polymers mediated vectors for delivery of siRNA

Zhang, Shubiao; Zhao, Budiao; Jiang, Huiming; Wang, Bing; Ma, Baoshan

doi:10.1016/j.jconrel.2007.07.016

Cited by 385 publications

(259 citation statements)

References 105 publications

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“…Cationic lipids represent one of the most well-studied classes of synthetic materials for siRNA delivery. To date, the most advanced examples of these materials demonstrate the ability to bind and condense siRNA into nanocomplexes through electrostatic interactions and to deliver the payload across the cellular membrane into the cytoplasm of target cells (16,17).…”

mentioning

confidence: 99%

Lipid-like materials for low-dose, in vivo gene silencing

Love

Mahon

Levins

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

812

803

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Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.

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mentioning

confidence: 99%

Lipid-like materials for low-dose, in vivo gene silencing

Love

Mahon

Levins

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

812

803

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“…[14,38] The structure of the PEI significantly impacts the transfection efficiency. [20] A number of studies have shown that, in selected cell lines, branched PEI generates stronger transgene expression that linear PEI.…”

Section: Discussionmentioning

confidence: 99%

“…[4] One of the most efficient non-viral vectors in vitro and in vivo is the cationic polymer, polyethylenimine (PEI). [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] PEI is a water-soluble polymer in which the repeat unit of PEI is two carbon atoms followed by a nitrogen atom. Under physiological conditions, approximately 20% of the nitrogens are protonated.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Intra¹,

Salem²

2008

Journal of Controlled Release

125

119

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Polyethylenimine (PEI) is a cationic polymer that has shown significant potential for delivering genes in vitro and in vivo. Mixing cationic PEI with negatively charged plasmid DNA (pDNA) results in the spontaneous electrostatic formation of stable nanoparticle complexes. The structure of PEI can be branched or linear. In this study, we show that branched PEI has a stronger electrostatic interaction with pDNA than linear PEI, which accounts for greater compaction, higher zeta potentials and smaller nanoparticle sizes at equivalent pDNA concentrations. For both linear and branched PEI, increasing the concentration of pDNA mixed in the same volume and at the same nitrogen to phosphate (N:P) ratio results in larger average particle sizes. Increasing the N:P ratio increases luciferase activity generated by branched PEI-pDNA nanoparticles and linear PEI-pDNA nanoparticles in HEK293, COS7 and HeLa cell lines. Increasing the N:P ratio at which branched PEI-pDNA nanoparticles are prepared also increases luciferase expression in HepG2 cells but does not increase luciferase expression generated by linear PEI-pDNA nanoparticles. In all of the cell lines, branched PEI-pDNA nanoparticles prepared at N:P ratios of 10 and above generated significantly higher luciferase activity than linear PEI-pDNA nanoparticles. Luciferase activity was highest in the HEK293 cells and luciferase expression in each of the cell lines followed the order of HEK293

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“…Moreover, it lacks the ability to penetrate the cellular lipid membranes due to its negative charge, resulting in poor cellular uptake and 1 Introduction pharmacokinetics. [63][64][65] Therefore, successful application of RNA interference in mammalian cells requires an efficient transfection agent that will enhance their pharmacological properties. [39] The appropriate delivery system should be able to: (i) complex/condense the siRNA, (ii) facilitate targeting to and uptake into the target cells, (iii) protect it from degradation through serum nucleases, and (iv) promote trafficking to the cytoplasm to provide the siRNA in clinically relevant doses.…”

Section: Gene Delivery Systemsmentioning

confidence: 99%

“…As a result, a wide variety of chemical modifications have been proposed to improve the serum stability, their intracellular penetration, and bioavailability. [45,63,[204][205][206][207][208][209][210] Since most siRNAs were produced through chemical synthesis, it is technically possible to incorporate various modifications into siRNA backbones. [211] In principle, three sites for chemical modifications can be distinguished (Fig.…”

Section: Chemical Modificationmentioning

confidence: 99%