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Molecular Medicine

, Volume 14, Issue 7–8, pp 365–373 | Cite as

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

  • Miroslaw Kornek
  • Veronika Lukacs-Kornek
  • Andreas Limmer
  • Esther Raskopf
  • Ursula Becker
  • Maren Klöckner
  • Tilman Sauerbruch
  • Volker Schmitz
Research Article

Abstract

Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy and nonfibrotic. The majority of hepatocellular carcinoma (HCC), however, develops in patients suffering from preexisting liver fibrosis. We investigated the efficacy of a standard experimental therapeutic approach to interrupt the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) cascade via VEGF-A silencing, with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP; cationic lipid) formulation, in HCC mice with preexisting liver fibrosis. The data show that intraperitoneal treatment with naked VEGF-A small interfering RNA (siRNA; 200 µg/kg) was inefficient to treat HCC implanted into fibrotic livers. VEGF-A siRNA containing an immunostimulatory motif in combination with DOTAP formulation significantly reduced hepatic VEGF-A expression and additionally activated the innate and adapted immune system as shown by an increased intrahepatic interferon type 1 response (68-fold increased β-interferon expression). DOTAP-formulated VEGF-A siRNA markedly improved VEGF-A siRNA uptake and enhanced the antitumor response. This study shows for the first time the therapeutic feasibility of using synergistic effects (gene silencing and activation of the immune system) united in one siRNA sequence to reduce HCC growth and metastasis in mice with preexisting liver fibrosis. We expect that these results will help to direct and improve future experimental gene-silencing approaches and establish more efficient antitumoral therapies against HCC.

Notes

Acknowledgments

This work was partly supported by a Deutsche Krebshilfe and a DFG grant to V.S. No conflicts of interest exist.

We thank Prof. P.A. Knolle, head of the Institute of Molecular Medicine and Experimental Immunology (IMMEI, Bonn, Germany) for continuous support of the project. Additionally we thank our practicum-student Bettina Schroll for her assistance during the tumor implantation surgery.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Miroslaw Kornek
    • 1
  • Veronika Lukacs-Kornek
    • 2
  • Andreas Limmer
    • 2
  • Esther Raskopf
    • 1
  • Ursula Becker
    • 1
  • Maren Klöckner
    • 1
  • Tilman Sauerbruch
    • 1
  • Volker Schmitz
    • 1
    • 3
  1. 1.Department of Internal Medicine IUniversity Hospital BonnBonnGermany
  2. 2.Institute of Molecular Medicine and Experimental Immunology (IMMEI)BonnGermany
  3. 3.Medizinische Klinik IBonnGermany

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