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Preparation of Neutrally-charged, pH-responsive Polymeric Nanoparticles for Cytosolic siRNA Delivery
Published on: May 2, 2019
A cathepsin B/GSH dual-responsive fluorinated peptide for effective siRNA delivery to cancer cells
Zhen Shi1, Yuhan Yang1, Ziyang Guo1
1Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
Abstract:
Small interfering RNA (siRNA) can be exploited to silence specific genes associated with cancer development, and successful siRNA therapy is highly dependent on the efficiency of the siRNA delivery vector. Herein, a well-designed novel redox- and enzyme-responsive fluorinated polyarginine (PFC-PR) was developed to be used as an anti-cancer siRNA carrier. The multiple guanidine groups could provide positive charges and bind with siRNA efficiently, and further fluorination modification enhanced the interaction with siRNA, resulting in a more stable PFC-PR/siRNA nanocomplex, improving serum tolerance, and promoting cellular uptake and endosome escape. Meanwhile, the PFC-PR was responsive to overexpressed cathepsin B and high levels of glutathione in cancer cells, conferring its ability to enhance siRNA release within cancer cells and making it cancer-targeting. Consequently, PFC-PR showed good biocompatibility and high gene silencing efficiency, which could inhibit cancer cell growth when delivered the siRNA targeting vascular endothelial growth factor, suggesting that it can be potentially used for anti-cancer gene therapy applications.
Insights
A novel fluorinated polyarginine (PFC-PR) effectively delivers small interfering RNA (siRNA) for cancer therapy. This targeted delivery system enhances gene silencing and inhibits cancer cell growth, showing promise for anti-cancer gene therapy.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Gene Therapy
Background:
- Effective delivery of small interfering RNA (siRNA) is crucial for cancer gene therapy.
- Existing siRNA delivery vectors often face challenges with stability, cellular uptake, and targeted release.
- The development of advanced carriers is needed to overcome these limitations in anti-cancer applications.
Purpose of the Study:
- To develop a novel redox- and enzyme-responsive fluorinated polyarginine (PFC-PR) as an anti-cancer siRNA carrier.
- To evaluate the PFC-PR/siRNA nanocomplex for enhanced stability, cellular uptake, and endosomal escape.
- To assess the targeted delivery and gene silencing efficiency of PFC-PR in cancer cells.
Main Methods:
- Synthesis and characterization of a novel fluorinated polyarginine (PFC-PR) material.
- Formation and analysis of PFC-PR/siRNA nanocomplexes, assessing stability and serum tolerance.
- In vitro evaluation of cellular uptake, endosome escape, and gene silencing efficacy using siRNA targeting vascular endothelial growth factor (VEGF).
Main Results:
- The developed PFC-PR demonstrated efficient binding with siRNA, forming stable nanocomplexes with enhanced serum tolerance.
- PFC-PR significantly improved cellular uptake and endosome escape, facilitated by its responsiveness to cancer cell microenvironments (cathepsin B and glutathione).
- PFC-PR/siRNA effectively silenced VEGF, inhibited cancer cell proliferation, and exhibited good biocompatibility.
Conclusions:
- The novel PFC-PR is a promising biocompatible carrier for anti-cancer siRNA delivery.
- Its unique responsive features enable targeted siRNA release and enhanced gene silencing within cancer cells.
- PFC-PR holds potential for developing effective anti-cancer gene therapy strategies.
