Development of Cationic Lipid LAH4-L1 siRNA Complexes for Focused Ultrasound Enhanced Tumor Uptake
Shahd Abuhelal1, Miguel N Centelles1, Michael Wright1
1Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, U.K.
Abstract:
RNAi has considerable potential as a cancer therapeutic approach, but effective and efficient delivery of short interfering RNA (siRNA) to tumors remains a major hurdle. It remains a challenge to prepare a functional siRNA complex, target enough dose to the tumor, and stimulate its internalization into tumor cells and its release to the cytoplasm. Here, we show how these key barriers to siRNA delivery can be overcome with a complex─comprising siRNA, cationic lipids, and pH-responsive peptides─that is suited to tumor uptake enhancement via focused ultrasound (FUS). The complex provides effective nucleic acid encapsulation, nuclease protection, and endosomal escape such that gene silencing in cells is substantially more effective than that obtained with either equivalent lipoplexes or commercial reagents. In mice bearing MDA-MB-231 breast cancer xenografts, both lipid and ternary, lipid:peptide:siRNA complexes, prepared with near-infrared fluorescently labeled siRNA, accumulate in tumors following FUS treatments. Therefore, combining a well-designed lipid:peptide:siRNA complex with FUS tumor treatments is a promising route to achieve robust in vivo gene delivery.
Insights
Developing novel complexes of short interfering RNA (siRNA) with lipids and peptides, enhanced by focused ultrasound (FUS), improves cancer gene therapy delivery and effectiveness in preclinical models.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- RNA interference (RNAi) holds significant promise for cancer treatment.
- Effective delivery of short interfering RNA (siRNA) to tumors is a critical challenge.
- Barriers include complex preparation, tumor targeting, cellular internalization, and cytoplasmic release.
Purpose of the Study:
- To overcome key barriers in siRNA delivery for cancer therapy.
- To develop a novel complex for enhanced tumor uptake using focused ultrasound (FUS).
- To evaluate the efficacy of this complex for in vivo gene delivery.
Main Methods:
- Formulation of a ternary complex comprising siRNA, cationic lipids, and pH-responsive peptides.
- Utilized focused ultrasound (FUS) to enhance tumor uptake of the siRNA complex.
- Assessed nucleic acid encapsulation, nuclease protection, and endosomal escape.
- Evaluated gene silencing efficacy in vitro and tumor accumulation in vivo using fluorescently labeled siRNA in breast cancer xenograft models.
Main Results:
- The developed complex demonstrated effective nucleic acid encapsulation, nuclease protection, and endosomal escape.
- Gene silencing in cells was significantly more effective compared to lipoplexes or commercial reagents.
- Lipid and ternary complexes accumulated in tumors following FUS treatment in mice bearing MDA-MB-231 breast cancer xenografts.
Conclusions:
- The novel lipid:peptide:siRNA complex effectively addresses major siRNA delivery hurdles.
- Focused ultrasound (FUS) significantly enhances the accumulation of these complexes in tumors.
- Combining this advanced complex with FUS treatment presents a promising strategy for robust in vivo gene delivery in cancer therapy.
More Related Videos
15:55Long-term Silencing of Intersectin-1s in Mouse Lungs by Repeated Delivery of a Specific siRNA via Cationic Liposomes. Evaluation of Knockdown Effects by Electron Microscopy
Published on: June 21, 2013
08:39Multiplexing Focused Ultrasound Stimulation with Fluorescence Microscopy
Published on: January 7, 2019