Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC

Fehring, Volker; Schaeper, Ute; Ahrens, Klaus; Santel, Ansgar; Keil, Oliver; Eisermann, Mona; Giese, Klaus; Kaufmann, Jörg

doi:10.1038/mt.2013.291

Cited by 86 publications

(84 citation statements)

References 33 publications

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“…Confocal microscopy also found that cRGD-siEGFR only aggregated around tumor tissues that had high expression of anb3 receptors, while no such aggregation was found in normal tissues or tumor tissues with low anb3 receptor expression. Compared with normal nanoparticles and liposomes, cRGD-siEGFR highly and specifically targeted tumors (Dahlman et al, 2014;Fehring et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo

Cen

Liao

et al. 2017

Drug Delivery

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The epidermal growth factor receptor (EGFR) is an important anti-tumor target. The development of novel molecular-targeted anti-tumor drugs that can target the interior of tumor cells and specifically silence EGFR expression is valuable and promising. In this work, a promising anti-tumor conjugate comprising methoxy-modified EGFR siRNA and cyclic arginineglycine-aspartic acid (cRGD) peptides, which selectively bind to avb3 integrins, was synthesized and examined. To prepare cRGD-EGFR siRNA (cRGD-siEGFR), cRGD was covalently conjugated to the 5 0 -end of an siRNA sense strand using a thiol-maleimide linker. The cellular uptake and cytotoxicity of cRGD-siEGFR in vitro were tested using an avb3-positive U87MG cell line. In vivo bio-distribution, anti-tumor activity, immunogenicity and toxicity were investigated in a nude mouse tumor model through repeated i.v. administration of cRGD-siEGFR (7 times over a 48 h interval). Analyses of in vitro data showed that cRGD-siEGFR silenced EGFR expression effectively, with high tumor targeting ability. Administration of cRGD-siEGFR to tumor-bearing nude mice led to significant inhibition of tumor growth, obvious reduction of EGFR expression and down-regulation of EGFR mRNA and protein in tumor tissue. Furthermore, serum biochemistry and pathological section evaluation did not indicate any serious toxicity of cRGDsiEGFR in vivo. cRGD-siEGFR is likely a promising candidate with high targeting ability, substantial anti-tumor effects and low toxicity in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo

Cen

Liao

et al. 2017

Drug Delivery

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“…In another recent study, Fehring et al [135] characterized a novel siRNA delivery system modulating target gene expression specifically in the lung endothelium, even if they did not investigate the mechanism by which this delivery system targets specifically the lung vasculature.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 97%

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

Gioia

Trapani

Castellani

et al. 2015

Pulmonary Pharmacology & Therapeutics

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“…Target protein expression was assessed by Western blotting of whole tissue lysates as described previously [17]. Snap frozen tissues were homogenized in a Mixer Mill and proteins were extracted in Riper-lysis buffer.…”

Section: Western Blot Analysismentioning

confidence: 99%

Liver-specific Fas silencing prevents galactosamine/lipopolysaccharide-induced liver injury

et al. 2015

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Acute liver failure (ALF) is a life threatening disease for which only few treatment options exist. The molecular pathways of disease progression are not well defined, but the death receptor Fas (CD95/Apo-1) appears to play a pivotal role in hepatocyte cell death and the development of ALF. Here, we explored posttranscriptional gene silencing of Fas by RNAi to inhibit pathophysiological gene expression. For targeting Fas expression in mice, Fas siRNA was formulated with the liver-specific siRNA delivery system DBTC. Treatment of mice with DBTC/siRNA(Fas) reduced Fas expression in the liver, but not in the spleen, lung, kidney or heart. Furthermore, silencing of Fas receptor was effective in blocking or reducing several aspects of ALF when it was tested in mice exposed to galactosamine/lipopolysaccharide (G/L), a well-known model of ALF. The application of DBTC/siRNA(Fas) 48 h prior G/L exposure resulted in amelioration of hepatic perfusion, reduction of hepatocellular death and increase of survival rate. The administration of DBTC/siRNA(Fas) formulation further diminished the inflammatory response upon G/L challenge, as indicated by a marked decrease of TNFα mRNA expression. However, IL-6 plasma concentration remained unaffectedly by DBTC/siRNA(Fas) formulation. Since the specific silencing of hepatic Fas expression only partially protected from inflammation, but completely attenuated apoptotic and necrotic cell death as well as microcirculatory dysfunction, the development of therapeutic strategies with DBTC lipoplex formulations to treat ALF should be combined with anti-inflammatory strategies to reach maximal therapeutic efficacy.

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Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC

Cited by 86 publications

References 33 publications

A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo

A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

Liver-specific Fas silencing prevents galactosamine/lipopolysaccharide-induced liver injury

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