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HER2/neu Oncogene Silencing in a Breast Cancer Cell Model Using Cationic Lipid-Based Delivery Systems
Adhika Balgobind1, Aliscia Daniels1, Mario Ariatti1
1Nano-Gene and Drug Delivery Laboratory, Discipline of Biochemistry, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa.
Abstract:
The overexpression of the human epidermal growth factor 2 (HER2/neu) oncogene is predictive of adverse breast cancer prognosis. Silencing the HER2/neu overexpression using siRNA may be an effective treatment strategy. Major requirements for siRNA-based therapy are safe, stable, and efficient delivery systems to channel siRNA into target cells. This study assessed the efficacy of cationic lipid-based systems for the delivery of siRNA. Cationic liposomes were formulated with equimolar ratios of the respective cholesteryl cytofectins, 3β-N-(N', N'-dimethylaminopropyl)-carbamoyl cholesterol (Chol-T) or N, N-dimethylaminopropylaminylsuccinylcholesterylformylhydrazide (MS09), with the neutral helper lipid, dioleoylphosphatidylethanolamine (DOPE), with and without a polyethylene glycol stabilizer. All cationic liposomes efficiently bound, compacted, and protected the therapeutic siRNA against nuclease degradation. Liposomes and siRNA lipoplexes were spherical, <200 nm in size, with moderate particle size distributions (PDI < 0.4). The siRNA lipoplexes exhibited minimal dose-dependent cytotoxicity and effective HER2/neu siRNA transfection in the HER2/neu overexpressing SKBR-3 cells. The non-PEGylated Chol-T-siRNA lipoplexes induced the highest HER2/neu silencing at the mRNA (10000-fold decrease) and protein levels (>111.6-fold decrease), surpassing that of commercially available Lipofectamine 3000 (4.1-fold reduction in mRNA expression). These cationic liposomes are suitable carriers of HER2/neu siRNA for gene silencing in breast cancer.
Insights
Cationic liposomes effectively deliver small interfering RNA (siRNA) to silence human epidermal growth factor 2 (HER2/neu) in breast cancer cells. This novel delivery system shows promise for targeted cancer therapy, outperforming commercial options.
Area of Science:
- Biotechnology
- Nanotechnology
- Oncology
Background:
- Overexpression of the human epidermal growth factor 2 (HER2/neu) oncogene is linked to poor breast cancer prognosis.
- Small interfering RNA (siRNA) offers a potential strategy for HER2/neu silencing.
- Effective delivery systems are crucial for siRNA-based cancer therapies.
Purpose of the Study:
- To evaluate cationic lipid-based systems for siRNA delivery targeting HER2/neu.
- To assess the safety, stability, and efficiency of these liposomal formulations.
- To compare the efficacy of novel lipoplexes with a commercial transfection agent.
Main Methods:
- Formulation of cationic liposomes using cholesteryl cytofectins (Chol-T or MS09) and dioleoylphosphatidylethanolamine (DOPE), with or without polyethylene glycol (PEG).
- Characterization of liposomes and siRNA lipoplexes for size, particle distribution, and nuclease protection.
- Assessment of siRNA transfection efficiency and HER2/neu gene silencing in HER2/neu-overexpressing SKBR-3 cells.
Main Results:
- Cationic liposomes effectively bound, compacted, and protected siRNA from degradation.
- Liposomes and lipoplexes were spherical, <200 nm, with PDI < 0.4.
- Non-PEGylated Chol-T-siRNA lipoplexes achieved significant HER2/neu mRNA (10,000-fold decrease) and protein (>111.6-fold decrease) silencing, outperforming Lipofectamine 3000.
Conclusions:
- Cationic liposomes are suitable and efficient carriers for HER2/neu siRNA delivery.
- These liposomal systems demonstrate potential for targeted gene silencing in breast cancer treatment.
- The developed lipoplexes offer a promising alternative to existing siRNA delivery methods.
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