Restoration of p53 Function in Ovarian Cancer Mediated by Gold Nanoparticle-Based EGFR Targeted Gene Delivery System
Rajesh Kotcherlakota1,2, Kalyan Vydiam1, Durga Jeyalakshmi Srinivasan3
1Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana India.
Abstract:
Targeted gene delivery of wild type tumor suppressor gene p53 is a promising approach to inhibit the progression of ovarian cancer. Although several gene delivery vehicles have been reported earlier, there is paucity for targeted delivery of wild type p53 to ovarian cancer using gold nanoparticles. As it is well-known that EGFR (epidermal growth factor receptor) is overexpressed in ovarian cancer, in this study we hypothesized that the FDA approved monoclonal antibody C225 (cetuximab) that targets EGFR could be used for targeted delivery of wild type p53 gene. With this impetus, we devised an approach wherein cationic gold nanoparticles (AuNPs) were employed to generate gold nanoparticle-based drug delivery system (DDS, Au-C225-p53DNA where p53DNA is pCMVp53 plasmid) that was formulated and characterized by biochemical and biophysical methods. The nanoconjugate complexed with DNA (Au-C225-p53DNA) is serum-stable and protects the bound DNA from digestion by DNase-I. Additionally, in vitro reporter gene expression assays demonstrated efficient and specific gene transfection in EGFR overexpressing SK-OV-3 cells. Further, the intraperitoneal administration of Au-C225-p53DNA in SK-OV-3 xenograft mouse model displayed significant tumor targeting and tumor regression. Altogether, these studies indicated a promising nanoparticle-based approach for targeting ovarian cancers caused by mutated p53.
Insights
This study developed a targeted ovarian cancer therapy using gold nanoparticles to deliver the p53 gene, showing effective tumor regression in mice. This novel drug delivery system offers a promising approach for treating ovarian cancers.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Ovarian cancer progression can be inhibited by targeted gene delivery of the wild type tumor suppressor gene p53.
- Existing gene delivery vehicles lack targeted delivery of wild type p53 to ovarian cancer using gold nanoparticles.
- Epidermal growth factor receptor (EGFR) is overexpressed in ovarian cancer, presenting a therapeutic target.
Purpose of the Study:
- To develop a targeted drug delivery system (DDS) for wild type p53 gene delivery to ovarian cancer.
- To utilize EGFR-targeting antibody C225 (cetuximab) conjugated with gold nanoparticles (AuNPs) for targeted delivery.
- To evaluate the efficacy of the Au-C225-p53DNA nanoconjugate in vitro and in vivo.
Main Methods:
- Formulation and characterization of cationic gold nanoparticles (AuNPs) conjugated with C225 antibody and p53 DNA (pCMVp53 plasmid) into a DDS (Au-C225-p53DNA).
- Biochemical and biophysical characterization of the nanoconjugate, including serum stability and DNase-I protection assays.
- In vitro reporter gene expression assays in EGFR-overexpressing SK-OV-3 cells and in vivo studies using a SK-OV-3 xenograft mouse model.
Main Results:
- The Au-C225-p53DNA nanoconjugate demonstrated serum stability and protected the p53 DNA from degradation.
- Efficient and specific gene transfection was observed in EGFR-overexpressing SK-OV-3 cells.
- Intraperitoneal administration resulted in significant tumor targeting and regression in the mouse model.
Conclusions:
- The developed gold nanoparticle-based DDS (Au-C225-p53DNA) enables targeted delivery of wild type p53 to ovarian cancer cells.
- This approach shows significant potential for treating ovarian cancers, particularly those associated with mutated p53.
- The study highlights a promising nanoparticle-based strategy for ovarian cancer gene therapy.
