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Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
PEGylated DC-Chol/DOPE cationic liposomes containing KSP siRNA as a systemic siRNA delivery Carrier for ovarian
1Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
Abstract:
Although siRNA-mediated downregulation technology has been highly successful in suppressing the expression of any disease-related gene, systemic delivery of siRNA for the clinical applications remains challenging, especially in the use of cancer therapy. DC-Chol/DOPE cationic liposomes as one of the most attractive vehicles for gene delivery have been widely exploited for transfection of siRNA into cells, but complexity of systemic delivery has allowed only their direct injection into local targets due to the formation of aggregations with negatively-charged blood components. Herein, we demonstrate the effects of PEGylation on DC-Chol/DOPE cationic liposomes for systemic siRNA delivery in cancer therapy. In contrast to non-PEGylated DC-Chol/DOPE-siRNA lipoplexes, PEGylated DC-Chol/DOPE-siRNA lipoplexes reduce the excretion by kidneys and scavenging in liver, prolonging the circulation time in vivo, and ultimately increase their preferential tumor accumulation. Therefore, systemic injection of PEGylated DC-Chol/DOPE liposomes loaded with siRNA against kinesin spindle protein (KSP) gene exhibited a high level of target gene silencing at tumor sites and substantial suppression of tumor growth. Furthermore, systemically administered PEGylated lipoplexes did not lead to any activation of innate immune responses in the immunocompetent mice. These results suggest the potential of PEGylated DC-Chol/DOPE liposomes as a systemic delivery carrier for siRNA-mediated cancer therapy.
Insights
PEGylation of DC-Chol/DOPE liposomes enhances systemic delivery of small interfering RNA (siRNA) for cancer therapy. This improved delivery prolongs circulation, increases tumor accumulation, and effectively suppresses tumor growth without immune activation.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- Small interfering RNA (siRNA) holds promise for gene silencing in disease, but systemic delivery for cancer therapy is challenging.
- DC-Chol/DOPE cationic liposomes are effective for siRNA delivery but face limitations in systemic applications due to aggregation with blood components.
- Current methods often restrict lipoplex administration to local injection sites.
Purpose of the Study:
- To investigate the impact of PEGylation on DC-Chol/DOPE cationic liposomes for enhanced systemic siRNA delivery in cancer treatment.
- To evaluate the biodistribution, circulation time, and tumor accumulation of PEGylated versus non-PEGylated lipoplexes.
- To assess the efficacy of PEGylated liposomes in gene silencing, tumor growth suppression, and potential immune responses.
Main Methods:
- Preparation and characterization of PEGylated and non-PEGylated DC-Chol/DOPE-siRNA lipoplexes.
- In vivo studies to assess circulation time, biodistribution (kidney, liver, tumor accumulation), and tumor growth inhibition.
- Evaluation of target gene (kinesin spindle protein - KSP) silencing at tumor sites.
- Assessment of innate immune responses in immunocompetent mice.
Main Results:
- PEGylated DC-Chol/DOPE-siRNA lipoplexes exhibited reduced renal excretion and hepatic scavenging compared to non-PEGylated counterparts.
- PEGylation significantly prolonged in vivo circulation time and enhanced preferential accumulation in tumor tissues.
- Systemic administration of PEGylated liposomes carrying KSP siRNA resulted in effective gene silencing and substantial tumor growth suppression.
- No activation of innate immune responses was observed with systemically administered PEGylated lipoplexes.
Conclusions:
- PEGylation of DC-Chol/DOPE liposomes overcomes systemic delivery challenges for siRNA cancer therapy.
- PEGylated liposomes offer a promising platform for prolonged circulation, targeted tumor delivery, and effective gene silencing.
- These findings highlight the potential of PEGylated DC-Chol/DOPE liposomes as a safe and effective systemic delivery vehicle for siRNA-based cancer treatments.
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