Cationic lipopolymer based siRNA delivery for experimental lung cancer treatment
Remant Kc1, Mohammad Nasrullah2, Gurkirat Sandhu1
1Department of Chemical and Material Engineering, Faculty of Engineering, University of Alberta, Edmonton T6G 2G6, AB, Canada.
Abstract:
Conventional therapeutic approaches often struggle to address "undruggable" or intracellular targets, limiting their effectiveness in treating critical diseases. RNA interference (RNAi), particularly through the delivery of short interfering RNAs (siRNAs), has emerged as a promising alternative. In this study, we evaluated the potential of a series of cationic lipopolymers, including ALL-Fect, Leu-Fect, and Prime-Fect, for delivering siRNAs targeting CDC20, Survivin, and STAT5 in lung cancer cell models. These polymers exhibited strong siRNA binding (BC50: 0.17 ± 0.04 to 1.67 ± 0.31) and dissociation (DC50: 57.9 to 13.6 U/mL) properties, forming nanoparticles with ζ-potential of -15 to +23 mV, and particles sizes of 150 to 400 nm suitable for efficient cellular uptake, achieving over 75 % FAM-positive cell populations in lung cancer cells. Remarkably, these complexes demonstrated significant cell killing effects with specific siRNAs even at a low siRNA concentration (20 nM), with maximal effects observed at a polymer/siRNA ratio of 5:1 ratio and 40 nM siRNA concentration, resulting in over 75 % cell killing. The performance of lipid nanoparticles (LNPs) for the delivery of the specific siRNAs was minimal compared to the lipopolymeric carriers under similar conditions. These findings underscore the potential of lipopolymers as safe and effective non-viral vectors for siRNA-based lung cancer therapeutics.
Insights
Cationic lipopolymers effectively deliver short interfering RNAs (siRNAs) for lung cancer therapy, showing significant cell killing. These non-viral vectors outperform lipid nanoparticles for siRNA delivery.
Area of Science:
- Biotechnology
- Nanomedicine
- Molecular Biology
Background:
- Conventional therapies face challenges with intracellular and "undruggable" targets.
- RNA interference (RNAi) using short interfering RNAs (siRNAs) offers a promising therapeutic alternative.
- Effective delivery of siRNAs remains a critical hurdle in developing RNAi-based treatments.
Purpose of the Study:
- To evaluate cationic lipopolymers (ALL-Fect, Leu-Fect, Prime-Fect) as non-viral vectors for siRNA delivery in lung cancer.
- To assess the physicochemical properties and cellular uptake of lipopolymer-siRNA complexes.
- To determine the therapeutic efficacy of these complexes in killing lung cancer cells.
Main Methods:
- Synthesis and characterization of cationic lipopolymers.
- Formation and analysis of lipopolymer-siRNA nanoparticles (size, ζ-potential, binding/dissociation).
- In vitro evaluation of cellular uptake (FAM-positive cells) and cell killing efficacy in lung cancer models.
Main Results:
- Lipopolymers demonstrated strong siRNA binding and appropriate nanoparticle characteristics for cellular uptake (>75% FAM-positive cells).
- Lipopolymer-siRNA complexes achieved significant lung cancer cell killing (>75%) at low siRNA concentrations (20-40 nM).
- Lipopolymer carriers significantly outperformed lipid nanoparticles (LNPs) in delivering siRNAs under tested conditions.
Conclusions:
- Cationic lipopolymers are effective non-viral vectors for siRNA delivery in lung cancer.
- These lipopolymers show potential as safe and efficient therapeutic agents for siRNA-based lung cancer treatments.
- The study highlights lipopolymers as a superior alternative to LNPs for specific siRNA delivery applications.
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