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Suppression of ovarian cancer growth via systemic administration with liposome-encapsulated adenovirus-encoding
1State Key Laboratory of Biotherapy, West China Hospital, School of life Science, Sichuan University, Gaoxin District, Chengdu, Sichuan, PRC.
Abstract:
Gene therapy using adenoviral vector containing the endostatin gene is a promising strategy for advanced cancers. However, host immune response to adenovirus and the lack of the requisite coxsackie-adenovirus receptor (CAR) in many primary cells limit the in vivo application. Liposome-complexed adenoviral vectors have proven to be useful for enhancing gene delivery in target cells that lack adenoviral receptors and avoiding a neutralizing antibody response. Here, we investigated antitumor effects of intravenous administration with PEG-PE cationic liposome-encapsulated recombinant human endostatin adenovirus (Ad-hEndo) on CAR-negative ovarian cancer. Electron micrography (EM) showed that these liposomes efficiently encapsulated the vectors, allowing CAR-independent adenovector transduction. The results showed that the complex enhanced transfection efficiency of recombinant adenovirus. Prolonged systemic administration was performed in immunocompetent mice and did not induce significant antibody response. The antitumor effect with PEG-PE cationic liposome encapsulated with Ad-hE (Ad-hE/lipo) was evaluated in the human ovarian cancer model. Systemic administration was well tolerated and resulted in marked suppression of tumor growth in an established ovarian cancer model, which was associated with a decreased number of micro-vessels and increased apoptosis of tumor cells. Our study shows that PEG-PE cationic liposome-encapsulated Ad-hE (Ad-hE/Lipo) can be administrated intravenously and lastingly to inhibit angiogenesis, thus showing promising clinical application.
Insights
Liposome-complexed adenoviral vectors delivering endostatin show promise for treating advanced cancers by enhancing gene delivery and reducing immune response. This novel approach effectively targets CAR-negative ovarian cancer cells, inhibiting tumor growth and angiogenesis.
Area of Science:
- Oncology
- Gene Therapy
- Nanomedicine
Background:
- Adenoviral vectors for cancer gene therapy face limitations due to host immune responses and low coxsackie-adenovirus receptor (CAR) expression.
- Liposome complexation offers a strategy to overcome these barriers, improving gene delivery and reducing immunogenicity.
Purpose of the Study:
- To investigate the antitumor effects of PEG-PE cationic liposome-encapsulated recombinant human endostatin adenovirus (Ad-hEndo) in CAR-negative ovarian cancer.
- To assess the safety, efficacy, and mechanism of action of this novel gene delivery system.
Main Methods:
- Electron microscopy confirmed efficient encapsulation of adenoviral vectors within PEG-PE cationic liposomes.
- In vivo studies involved intravenous administration of Ad-hEndo/liposomes in immunocompetent mice and a human ovarian cancer model.
- Analysis included assessment of transfection efficiency, antibody response, tumor growth, micro-vessel density, and apoptosis.
Main Results:
- Liposome encapsulation facilitated CAR-independent adenovector transduction and enhanced transfection efficiency.
- Prolonged systemic administration in mice did not elicit a significant antibody response.
- Ad-hEndo/liposomes demonstrated well-tolerated systemic administration, marked tumor growth suppression, reduced angiogenesis, and increased tumor cell apoptosis in ovarian cancer models.
Conclusions:
- PEG-PE cationic liposome-encapsulated Ad-hE (Ad-hE/Lipo) offers a viable intravenous delivery method for gene therapy targeting angiogenesis.
- This approach shows significant potential for clinical application in treating advanced cancers, particularly ovarian cancer.
