Linear Polyethylenimine as a Tool for Comparative Studies of Antisense and Short Double-Stranded RNA Oligonucleotides

Bologna, Jean‐Charles; Dorn, Gabriele; Natt, François; Weiler, Jan

doi:10.1081/ncn-120023124

Cited by 24 publications

(9 citation statements)

References 3 publications

(2 reference statements)

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“…PEI has been used for gene delivery with increasing popularity since its description as a transfection agent. 8 PEI forms non-covalent interpolyelectrolyte complexes with DNA, 8 oligonucleotides 9 and RNA. 10 Long PEI chains are more effective, but more cytotoxic in gene transfection.…”

Section: Resultsmentioning

confidence: 99%

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

et al. 2011

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Introducing small DNA molecules (Dbait) impairs the repair of damaged chromosomes and provides a new method for enhancing the efficiency of radiotherapy in radio-resistant tumors. The radiosensitizing activity is dependent upon the efficient delivery of Dbait molecules into the tumor cells. Different strategies have been compared, to improve this key step. We developed a pipeline of assays to select the most efficient nanoparticles and administration protocols before preclinical assays: (i) molecular analyses of complexes formed with Dbait molecules, (ii) cellular tests for Dbait uptake and activity, (iii) live zebrafish embryo confocal microscopy monitoring for in vivo distribution and biological activity of the nanoparticles and (iv) tumor growth and survival measurement on mice with xenografted tumors. Two classes of nanoparticles were compared, polycationic polymers with linear or branched polyethylenimine (PEI) and covalently attached cholesterol (coDbait). The most efficient Dbait transfection was observed with linear PEI complexes, in vitro and in vivo. Doses of coDbait ten-fold higher than PEI/Dbait nanoparticles, and pretreatment with chloroquine, were required to obtain the same antitumoral effect on xenografted melanoma. However, with a 22-fold lower ‘efficacy dose/toxicity dose' ratio as compared with Dbait/PEI, coDbait was selected for clinical trials.

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Section: Resultsmentioning

confidence: 99%

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

et al. 2011

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“…Optimization of this drug delivery system for siRNA revealed a lower optimal ratio of Nitrogen to Phosphate (N/P ratio) for siRNA than for pDNA (5 vs. 10), when using linear PEI. This led to an in vitro target downregulation comparable to the lipidic transfection agent Oligofectamine [79].…”

Section: Polyethyleneimine (Pei)mentioning

confidence: 99%

Using drug-excipient interactions for siRNA delivery

Bruno

2011

Advanced Drug Delivery Reviews

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SiRNA is the trigger of RNA interference, a mechanism discovered in the late 1990s. To release the therapeutic potential of this versatile but large and fragile molecule, excipients are used which either interact by electrostatic interaction, passively encapsulate siRNA or are covalently attached to enable specific and safe delivery of the drug substance. Controlling the delicate balance between protective complexation and release of siRNA at the right point and time is done by understanding excipients-siRNA interactions. These can be lipids, polymers such as PEI, PLGA, Chitosans, Cyclodextrins, as well as aptamers and peptides. This review describes the mechanisms of interaction of the most commonly used siRNA delivery vehicles, and looks at the results of their clinical and preclinical studies.

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“…The electrostatic interaction between the anionic phosphates in siRNA and the cationic polymer also assembles nanoparticles that are more suitable for cellular uptake. High molecular weight polyethylenimines (PEIs) are one class of polymers that have been shown to be effective siRNA delivery agents. − These polymers create an opportunity for endosomal escape after cellular uptake, due to the presence of unprotonated PEI amines that act as “proton sponges” . However, the toxicity of high molecular weight PEIs has been an important obstacle for their clinical use. − Lower molecular weight PEIs present acceptable toxicity profiles but, unfortunately, do not display efficacious siRNA delivery into cells.…”

Section: Introductionmentioning

confidence: 99%

Induction of Apoptosis by Survivin Silencing through siRNA Delivery in a Human Breast Cancer Cell Line

et al. 2011

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Post-transcriptional silencing of antiapoptotic genes is a promising strategy for cancer therapy, but delivering short interfering RNA (siRNA) molecules against such targets is challenging due to inability of anionic siRNA to cross cellular membranes. Lipid substitution on small molecular weight, nontoxic polyethylenimine (PEI) has been investigated as a promising approach for effective siRNA delivery. In this study, we report on the ability of low molecular weight, lipid-substituted PEI to deliver siRNA against the antiapoptotic protein survivin. Toxicity of a library of lipid-substituted PEIs, as well as their siRNA delivery and survivin silencing efficiency, was evaluated in MDA-MB-231 human breast cancer cells. A significant increase in cellular delivery of siRNA was observed as a result of lipid substitution. Most significant downregulation of survivin was established by caprylic acid-substituted polymers, which resulted in significant levels of apoptosis induction and resultant loss of cell viability. Survivin downregulation prior to anticancer drug treatment decreased the IC(50) of several drugs by 50- to 120-fold. Our experiments indicated an effective downregulation of survivin, a cell protective protein upregulated in tumor cells, by delivering siRNA with hydrophobically modified PEI. This study introduces a promising delivery system for safe and effective siRNA delivery that will be suitable for further investigation in preclinical animal models.

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Linear Polyethylenimine as a Tool for Comparative Studies of Antisense and Short Double-Stranded RNA Oligonucleotides

Cited by 24 publications

References 3 publications

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems

Using drug-excipient interactions for siRNA delivery

Induction of Apoptosis by Survivin Silencing through siRNA Delivery in a Human Breast Cancer Cell Line

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