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Gene delivery to Her-2+ breast cancer cells using a two-component delivery system to achieve specificity
Max Kullberg1, Ryan McCarthy1, Thomas J Anchordoquy1
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO.
Abstract:
Current liposomal gene delivery systems predominately utilize cationic lipids, which efficiently bind and deliver DNA plasmid, but also result in nonspecific gene expression in lung and liver tissue. To improve specificity, a two-component delivery strategy employing neutral liposomes was used to target breast cancers positive for the human epidermal growth factor receptor 2 (Her-2). The first component consisted of plasmid DNA condensed with cationic polyethylene glycol (PEG) modified polylysine (PL/DNA). The second component was a neutral Her-2 targeting liposome conjugated to the pore-forming protein, Listeriolysin O (LLO). Independently, PL/DNA delivery resulted in low expression of plasmid DNA. However, when PL/DNA and LLO/liposomes co-localized within an endosome, LLO disrupted endosome integrity, leading to cytoplasmic delivery and expression of the plasmid. When used to deliver a plasmid encoding the luciferase gene, this two-component system resulted in gene expression that was 268-fold greater in Her-2 positive cells than in Her-2 negative cells.
From The Clinical Editor:
In this paper a novel two-component gene delivery method is presented using PL/DNA and LLO liposomes, demonstrating strongly significant results in a model system.
Insights
This study introduces a novel two-component gene delivery system using neutral liposomes to target Her-2 positive breast cancers. The system enhances gene expression specificity, significantly improving delivery to target cells.
Area of Science:
- Biotechnology
- Molecular Biology
- Oncology
Background:
- Current liposomal gene delivery systems often cause non-specific gene expression in tissues like the lung and liver.
- There is a need for targeted gene delivery systems to improve specificity and efficacy.
Purpose of the Study:
- To develop and evaluate a two-component gene delivery system for targeting Her-2 positive breast cancers.
- To improve the specificity of gene delivery by utilizing neutral liposomes and a Her-2 targeting strategy.
Main Methods:
- A two-component system was designed: plasmid DNA condensed with cationic polyethylene glycol (PEG) modified polylysine (PL/DNA) and neutral Her-2 targeting liposomes conjugated to Listeriolysin O (LLO).
- The system relies on LLO disrupting endosome integrity for cytoplasmic delivery of the plasmid DNA.
- Gene expression was evaluated using a luciferase reporter plasmid in Her-2 positive and negative cells.
Main Results:
- The two-component system demonstrated significantly enhanced gene delivery compared to PL/DNA alone.
- Gene expression was 268-fold greater in Her-2 positive cells than in Her-2 negative cells, indicating high specificity.
- LLO facilitated endosomal escape, leading to efficient cytoplasmic delivery and gene expression.
Conclusions:
- This novel two-component gene delivery system offers a promising strategy for targeted gene therapy in Her-2 positive breast cancers.
- The system overcomes limitations of non-specific gene expression associated with traditional cationic liposomes.
- The combination of targeted liposomes and endosomolytic agents enhances gene delivery efficiency and specificity.
