Tumor-targeted gene delivery via anti-HER2 antibody (trastuzumab, Herceptin) conjugated polyethylenimine

J Control Release. 2004 Jun 18;97(2):357-69. doi: 10.1016/j.jconrel.2004.03.019.

Abstract

A series of novel nonviral vectors targeting the HER-2/neu gene product human epidermal growth factor receptor-2 (HER2) were constructed and evaluated in breast cancer cell lines to optimize vector formulation for receptor-specific gene transfer. These vectors were DNA/polycation complexes (polyplexes) prepared by mixing, at varying ratios, plasmid DNA carrying a luciferase reporter gene to HerPEI, which is a conjugate of linear polyethylenimine (PEI), a cationic polymer, and trastuzumab (Herceptin), a HER2-specific monoclonal antibody. Transfection studies were carried out in both HER2 overexpressing Sk-Br-3 and HER2 low-expressing MDA-MB-231 breast cancer cells. The HerPEI polyplexes showed significantly greater transfection activity up to 20-folds than nonderivatized PEI-based polyplexes in the Sk-Br-3 cells. The transfection efficiency of targeted polyplexes was dependent on the trastuzumab:PEI ratio and can be blocked by excess free trastuzumab, suggesting HER2-mediated gene delivery. In contrast, no significant difference in transfection activities was observed between HER2-targeted and nontargeted polyplexes in the HER2 low-expressing MDA-MB-231 cells. The transfection efficiency of HerPEI polyplexes was retained in serum-containing medium. In summary, HerPEI polyplexes have shown promising HER2 receptor-specific gene transfer properties and warrant further evaluation as a tumor-targeted vector for gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal, Humanized
  • Cell Line, Tumor
  • DNA / administration & dosage
  • Drug Carriers / chemistry*
  • Electrophoresis, Agar Gel
  • Humans
  • Luciferases, Firefly / biosynthesis
  • Luciferases, Firefly / genetics
  • Plasmids
  • Polyethyleneimine / chemistry*
  • Receptor, ErbB-2 / biosynthesis*
  • Receptor, ErbB-2 / immunology
  • Transfection / methods*
  • Trastuzumab

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Drug Carriers
  • Polyethyleneimine
  • DNA
  • Luciferases, Firefly
  • Receptor, ErbB-2
  • Trastuzumab