Prime

Type your tag names separated by a space and hit enter

Systemic tumor-targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes.

Abstract

BACKGROUND

Non-viral polymer-based gene transfer represents an adaptable system for tumor-targeted gene therapy, as various design strategies of shuttle systems together with the mechanistic concept of active tumor targeting lead to improved gene delivery vectors resulting in higher tumor specificity, efficacy and safety.

METHODS

Using the sodium iodide symporter (NIS) as theranostic gene, non-viral gene delivery vehicles based on linear polyethylenimine (LPEI), polyethylene glycol (PEG) and coupled with the synthetic peptide B6 (LPEI-PEG-B6), which specifically binds to tumor cells, were investigated in a hepatocellular carcinoma (HCC) xenograft model for tumor-selectivity and transduction efficiency.

RESULTS

In vitro incubation of three different tumor cell lines with LPEI-PEG-B6/NIS resulted in significant increase in iodide uptake activity as compared to untargeted and empty vectors. After establishment of subcutaneous HuH7 tumors, NIS-conjugated nanoparticles were injected intravenously followed by analysis of radioiodide biodistribution using (123) I-scintigraphy showing significant perchlorate-sensitive iodide accumulation in tumors of LPEI-PEG-B6/NIS-treated mice (8.0 ± 1.5% ID/g (123) I; biol. half-life 4 h). After four cycles of repetitive polyplex/(131) I applications, significant delay of tumor growth was observed, which was associated with markedly improved survival in the therapy group.

CONCLUSIONS

These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled with B6 tumor-targeting ligand is capable of inducing tumor-specific radioiodide uptake. This promising gene therapy approach opens the exciting prospect of NIS-mediated radionuclide therapy in metastatic cancer together with the possibility of combining several targeting ligands to enhance selective therapeutic efficacy in a broad field of cancer types with various receptor expression profiles.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.

    ,

    Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Germany.

    ,

    Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.

    ,

    Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.

    ,

    Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology and Center for Nanoscience (CeNS), LMU Munich, Germany.

    Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Germany.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    28423213