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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
Systemic genetic transfer of p21WAF-1 and GM-CSF utilizing of a novel oligopeptide-based EGF receptor targeting
Xiang Liu1, Pei-Kun Tian, Dian-Wen Ju
1National Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China.
Abstract:
Based on the fact that aberrant overexpression of some growth factor receptors was observed in a variety of human cancer cells, a novel nonviral gene delivery system GE7, which contains a 16-amino-acid ligand for identifying EGF receptor was constructed for tumor-targeted gene therapy. Intravenous administration of GE7 system revealed that it has the ability to target beta-galactosidase (beta-gal) reporter gene into murine hepatoma (Hepa) cells. Owing to the limited antitumor effects elicited by a single-gene transfer, recent efforts to treat malignancy using combined gene therapy have been accomplished with varying degrees of success. In this study, the human cyclin-dependent kinase inhibitor gene p21(WAF-1) and the murine cytokine gene granulocyte-macrophage colony-stimulating factor (GM-CSF) were used simultaneously for in vivo gene therapy through systemic injection of the EGF R targeted GE7/DNA complex into murine hepatoma-bearing mice. The results demonstrated that combined administration of p21(WAF-1) and GM-CSF could remarkably inhibit the growth of subcutaneously transplanted hepatoma Hepa cells, and significantly increase the survival rate of tumor-bearing mice. The activities of natural killer (NK) cells and specific cytotoxic T lymphocytes (CTL) were clearly enhanced after combined gene therapy. In vitro experiments showed that p21(WAF-1) gene transfer exhibited a suppressive function on the growth of Hepa cells and the expression of H-2K(b) and B7-1 molecules on Hepa cells increased significantly after combined genes delivery. All these results suggested that the GE7 system was able to target therapeutic genes efficiently to cancer cells, which showed high EGF R expression. The cotransfer of p21(WAF-1) and GM-CSF genes apparently inhibited the growth of tumors through (a) the arrest of tumor cell growth and (b) the enhancement of systemic antitumor immunity.
Insights
A novel GE7 gene delivery system targets cancer cells expressing EGF receptors. Combined gene therapy using p21(WAF-1) and GM-CSF genes inhibits tumor growth and enhances antitumor immunity in mice.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Aberrant overexpression of growth factor receptors, like the EGF receptor, is common in human cancers.
- Targeted gene therapy aims to deliver therapeutic genes specifically to cancer cells.
- Combined gene therapy strategies are being explored to improve antitumor efficacy.
Purpose of the Study:
- To develop and evaluate a novel nonviral gene delivery system (GE7) for tumor-targeted gene therapy.
- To investigate the efficacy of combined gene therapy using p21(WAF-1) and GM-CSF delivered by the GE7 system in a murine hepatoma model.
- To assess the impact of this combined gene therapy on tumor growth, survival rates, and systemic antitumor immunity.
Main Methods:
- Construction of a GE7 gene delivery system with a ligand targeting the EGF receptor.
- In vivo administration of the GE7/DNA complex carrying beta-galactosidase reporter gene to target hepatoma cells.
- Systemic injection of the GE7/DNA complex carrying p21(WAF-1) and GM-CSF genes into tumor-bearing mice.
- Evaluation of tumor growth inhibition, survival rates, NK cell and CTL activity, and gene/molecule expression in vitro and in vivo.
Main Results:
- The GE7 system successfully targeted the beta-galactosidase reporter gene into murine hepatoma cells.
- Combined administration of p21(WAF-1) and GM-CSF via the GE7 system significantly inhibited hepatoma cell growth.
- Tumor-bearing mice treated with the combined gene therapy showed increased survival rates and enhanced NK cell and CTL activities.
- In vitro studies demonstrated p21(WAF-1) suppressed Hepa cell growth and increased H-2K(b) and B7-1 molecule expression.
Conclusions:
- The GE7 system efficiently targets therapeutic genes to cancer cells with high EGF receptor expression.
- Cotransfection of p21(WAF-1) and GM-CSF genes inhibits tumor growth by arresting cell proliferation and boosting systemic antitumor immunity.
- This combined gene therapy approach holds promise for treating cancers with high EGF receptor expression.
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