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Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma.
Witzigmann, Dominik; Grossen, Philip; Quintavalle, Cristina; Lanzafame, Manuela; Schenk, Susanne H; Tran, Xue-Ting; Englinger, Bernhard; Hauswirth, Patrick; Grünig, David; van Schoonhoven, Sushilla; Krähenbühl, Stephan; Terracciano, Luigi M; Berger, Walter; Piscuoglio, Salvatore; Quagliata, Luca; Rommelaere, Jean; Nüesch, Jürg P F; Huwyler, Jörg.
Affiliation
  • Witzigmann D; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland; Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, V6T 1Z3 Vancouver, British Columbia, Canada.
  • Grossen P; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
  • Quintavalle C; Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland.
  • Lanzafame M; Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland.
  • Schenk SH; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
  • Tran XT; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
  • Englinger B; Applied and Experimental Oncology, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • Hauswirth P; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
  • Grünig D; Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, 4031 Basel, Switzerland.
  • van Schoonhoven S; Applied and Experimental Oncology, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • Krähenbühl S; Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, 4031 Basel, Switzerland.
  • Terracciano LM; Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland.
  • Berger W; Applied and Experimental Oncology, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
  • Piscuoglio S; Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland; Visceral Surgery laboratory, Clarunis, Department of Biomedicine, 4031 Basel, Switzerland.
  • Quagliata L; Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland.
  • Rommelaere J; Infection, Inflammation and Cancer Program, Division of Tumor Virology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Nüesch JPF; Infection, Inflammation and Cancer Program, Division of Tumor Virology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Huwyler J; Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.
J Control Release ; 334: 138-152, 2021 06 10.
Article in En | MEDLINE | ID: mdl-33894304
ABSTRACT
Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2021 Document type: Article Affiliation country: Canada
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2021 Document type: Article Affiliation country: Canada