Crosslinked nanocarriers based upon poly(ethylene imine) for systemic plasmid delivery: In vitro characterization and in vivo studies in mice

Neu, Michael; Germershaus, Oliver; Mao, Shirui; Voigt, Karlheinz; Béhé, Martin; Kissel, Thomas

doi:10.1016/j.jconrel.2007.01.007

Cited by 96 publications

(81 citation statements)

References 56 publications

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“…Reasons for the failure to reverse the changes in cellular redox state induced by Bcl-2 expression are currently unknown. Most published studies that investigated the role of GSH in the activity of redox complexes used BSO, which specifically inhibits GSH biosynthesis in the cytoplasm [6,12,22,23]. Typically, a small decrease in the transfection activity of pDNA complexes was reported.…”

Section: Discussionmentioning

confidence: 99%

“…It is reasonable to hypothesize that changes in intracellular GSH concentrations will alter activity of redox polyplexes. Indeed, available evidence suggests that artificially changing cellular GSH levels leads to changes in biological activity of polyplexes [6,12,22,23]. Modulation of GSH levels using either buthionine sulfoximine (BSO), an inhibitor of cytosolic GSH synthesis or enhancement of GSH levels using GSH monoethyl ester (GSH-Et) demonstrated a small, but significant effect on the transfection activity of plasmid DNA (pDNA) complexes.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

et al. 2008

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Redox-sensitive non-viral delivery systems exploit intracellular reducing environment to improve the efficacy of the delivery of nucleic acids by selectively releasing the cargo in the subcellular space. Bcl-2 overexpression is frequently observed in human cancers and is closely associated with increased resistance to chemotherapy and radiotherapy. One of the biochemical alterations accompanying Bcl-2 overexpression is the increase in cellular glutathione (GSH) levels. In this study, we hypothesize that such increase of GSH concentrations will selectively enhance the transfection activity of redox-sensitive delivery systems in cells overexpressing Bcl-2. Transfection studies were conducted in MCF-7 mammary carcinoma cells and MCF-7 clones overexpressing Bcl-2. It was confirmed that Bcl-2 overexpression resulted in the expected increase in GSH concentrations. Redoxsensitive complexes containing plasmid DNA, mRNA, antisense oligodeoxynucleotides, and siRNA exhibited selectively increased activity in cells overexpressing Bcl-2 compared to non-redox complexes. The effect of Bcl-2 overexpression on the selective enhancement of transfection was highly dependent on the type of the delivered nucleic acid, and was most pronounced for mRNA. This study shows that Bcl-2 overexpression can serve as a proxy redox stimulus to enhance the activity of all major classes of potential nucleic acid therapeutics, when delivered using redoxsensitive vectors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

et al. 2008

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“…[146] In in vivo experiments, disulfide-crosslinked polyplexes showed increased blood concentrations and longer circulation times, both of which depended on the crosslinking degree. [147] Lee et al used thiolated hyaluronic acid for the encapsulation of oligonucleotides as well. Nanogels were formed by crosslinking via disulfide-bond formation in the presence of siRNA.…”

Section: Disulfides For the Stabilization Of The Carriermentioning

confidence: 99%

Delivery of Nucleic Acids via Disulfide‐Based Carrier Systems

et al. 2009

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Nucleic acids are not only expected to assume a pivotal position as "drugs" in the treatment of genetic and acquired diseases, but could also act as molecular cues to control the microenvironment during tissue regeneration. Despite this promise, the efficient delivery of nucleic acids to their side of action is still the major hurdle. One among many prerequisites for a successful carrier system for nucleic acids is high stability in the extracellular environment, accompanied by an efficient release of the cargo in the intracellular compartment. A promising strategy to create such an interactive delivery system is to exploit the redox gradient between the extra- and intracellular compartments. In this review, emphasis is placed on the biological rationale for the synthesis of redox sensitive, disulfide-based carrier systems, as well as the extra- and intracellular processing of macromolecules containing disulfide bonds. Moreover, the basic synthetic approaches for introducing disulfide bonds into carrier molecules, together with examples that demonstrate the benefit of disulfides at the individual stages of nucleic acid delivery, will be presented.

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“…CHO-K1 cell line had been well investigated for membrane protein associated disulfide cleavage (22,(37)(38)(39). The cleavage began in the first hour of cell membrane binding and continued for more than 6 h (38).…”

Section: Effects Of Polyplex Incubation Time On the Transfection Effimentioning

confidence: 99%

Influence of the Molecular Weight of Bioreducible Oligoethylenimine Conjugates on the Polyplex Transfection Properties

Ruß

Wagner

2009

AAPS J

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Abstract. The purpose of the present study was to investigate the influence of molecular weights on the chemical, biophysical, and biological properties of bioreducible oligoethylenimine conjugates. The cationic conjugates were synthesized by polyaddition between branched oligoethylenimine 800 Da (OEI) and the disulfide bond containing N,N′-cystamine bisacrylamide (CBA) linker. A correlation between the copolymer molecular weights and the polyplex transfection properties was found. The OEI-CBA copolymers differing in molecular weights (from 8.6 to 37 kDa) showed good plasmid DNA binding ability resulting in compact 90-to 150-nm-sized polyplexes. Colloidal stability of the polyplexes was lost in reductive environment. A low concentration of dithiothreitol of 5 µM was sufficient to render polyplexes unstable in size. Reducing conditions at physiological salt concentration triggered polyplex dissociation. The bioreducible polymers displayed much lower cytotoxicity (IC 50 ∼100 μg/mL in cell culture) than branched polyethylenimine 25 kDa (BPEI) and linear polyethylenimine 22 kDa (LPEI). Reporter gene transfection experiments were done with CHO-K1 and B16-F10 cells. The largest (37 kDa) copolymer HC-6-8 demonstrated highest transfection levels among all the bioreducible copolymers, which was comparable with LPEI and much more effective than BPEI.

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Crosslinked nanocarriers based upon poly(ethylene imine) for systemic plasmid delivery: In vitro characterization and in vivo studies in mice

Cited by 96 publications

References 56 publications

Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors

Delivery of Nucleic Acids via Disulfide‐Based Carrier Systems

Influence of the Molecular Weight of Bioreducible Oligoethylenimine Conjugates on the Polyplex Transfection Properties

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