Tumor-targeted gene delivery via anti-HER2 antibody (trastuzumab, Herceptin) conjugated polyethylenimine.
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.
Chiu
Shih-Jiuan
SJ
Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, 500 W 12th Ave., L.M. Parks Hall, Columbus, OH 43210, USA.
Ueno
Naoto T
NT
Lee
Robert J
RJ
D000911:Antibodies, Monoclonal / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage; D004337:Drug Carriers / Q000737:chemistry*; D004587:Electrophoresis, Agar Gel; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D010957:Plasmids; D011094:Polyethyleneimine / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D014162:Transfection / Q000379:methods*; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004247:DNA; D004337:Drug Carriers; D049409:Luciferases, Firefly; D011094:Polyethyleneimine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab