1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

Kornek, Miroslaw; Lukacs‐Kornek, Veronika; Limmer, Andreas; Raskopf, E.; Becker, Ursula; Klöckner, Maren; Sauerbruch, Tilman; Schmitz, Volker

doi:10.2119/2008-00003.kornek

Cited by 20 publications

(18 citation statements)

References 43 publications

(56 reference statements)

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“…Then, the combination of siRNA-VEGF with DOTAP led to a 68-fold increase in IFN-beta expression compared to naked siRNA-VEGF. The siRNA used in this study contains a poly-U rich motif which -only in combination with DOTAP -presumably stimulates the innate immune response [21,28]. Two other studies also showed that the immunomodulatory effect of siRNA-VEGF is DOTAP-depen- dent [31,32].…”

Section: Discussionmentioning

confidence: 65%

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siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo

Raskopf

Vogt

Sauerbruch

et al. 2008

Journal of Hepatology

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Section: Discussionmentioning

confidence: 65%

“…PCR products were separated with agarose gel electrophoresis. LightCycler analysis was performed as described previously [21].…”

Section: Analysis Of Vegf and Vegfr Expressionmentioning

confidence: 99%

siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo

Raskopf

Vogt

Sauerbruch

et al. 2008

Journal of Hepatology

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“…Schmitz et al made a complex of VEGF-targeting siRNA with DOTAP and injected the complex intraperitoneally multiple times to mice with pre-existing liver fibrosis as well as orthotopic HCC (Hepa129 cells injected to the left liver lobe) [129]. The VEGF-siRNA/DOTAP complexes resulted in significant reduction in the number of HCC satellites in the liver (82% mice had <30 satellites), whereas free VEGF-siRNA and control siRNA had a minimal effect (22.1% and 12.5% mice with <30 satellites, respectively).…”

Section: Pharmacological Effects Of Sirna Therapeuticsmentioning

confidence: 99%

“…DOTAP helped VEGF-siRNA enter HCC satellites and silence VEGF expression in hepatic tissues. However, the effect of the internalized VEGF-siRNA-DOTAP complex on tumors was more likely through immune activation via interferon-1 upregulation than VEGF silencing [129]. In fact, intratumoral VEGF expression was not reduced by VEGF-siRNA/DOTAP complexes but rather increased [129].…”

Section: Pharmacological Effects Of Sirna Therapeuticsmentioning

confidence: 99%

Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

Park

Pei

et al. 2016

Advanced Drug Delivery Reviews

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Small interfering RNA (siRNA) is a promising drug candidate, expected to have broad therapeutic potentials toward various diseases including viral infections and cancer. With recent advances in bioconjugate chemistry and carrier technology, several siRNA-based drugs have advanced to clinical trials. However, most cases address local applications or diseases in the filtering organs, reflecting remaining challenges in systemic delivery of siRNA. The difficulty in siRNA delivery is in large part due to poor circulation stability and unfavorable pharmacokinetics and biodistribution profiles of siRNA. This review describes the pharmacokinetics and biodistribution of siRNA nanomedicines, focusing on those reported in the past 5 years, and their pharmacological effects in selected disease models such as hepatocellular carcinoma, liver infections, and respiratory diseases. The examples discussed here will provide an insight into the current status of the art and unmet needs in siRNA delivery.

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“…To overcome the previously mentioned delivery challenges, lipid-based delivery systems, such as cationic liposomes and stable nucleic acid–lipid particle (SNALP), have been employed to mask the negative charges on the siRNA phosphodiester backbone and facilitate uptake. 7–9 Building on this theme, other delivery vehicles based on the variety of cationic and biodegradable polymers have been developed. 10–15 Many proposed approaches have demonstrated limited delivery of siRNA, and this research has revealed a need for combination strategies and new formulations.…”

mentioning

confidence: 99%

In Vivo Sustained Release of siRNA from Solid Lipid Nanoparticles

et al. 2011

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Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with a challenge of being delivered in a sustained manner. Nanoparticle drug delivery systems allow for incorporating and controlled release of therapeutic payloads. We demonstrate that solid lipid nanoparticles can incorporate and provide sustained release of siRNA. Tristearin solid lipid nanoparticles, made by nanoprecipitation, were loaded with siRNA (4.4–5.5 weight percent loading ratio) using a hydrophobic ion pairing approach that employs the cationic lipid DOTAP. Intradermal injection of these nanocarriers in mouse footpads resulted in prolonged siRNA release over a period of 10–13 days. In vitro cell studies showed that the released siRNA retained its activity. Nanoparticles developed in this study offer an alternative approach to polymeric nanoparticles for encapsulation and sustained delivery of siRNA with the advantage of being prepared from physiologically well-tolerated materials.

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1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

Cited by 20 publications

References 43 publications

siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo

siRNA targeting VEGF inhibits hepatocellular carcinoma growth and tumor angiogenesis in vivo

Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

In Vivo Sustained Release of siRNA from Solid Lipid Nanoparticles

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