Redox-Responsive Nanoparticle-Mediated Systemic RNAi for Effective Cancer Therapy
Xiaoding Xu1,2, Jun Wu1,3, Shuaishuai Liu4
1Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Small (Weinheim an Der Bergstrasse, Germany)
|September 20, 2018
Summary
This study introduces a new biodegradable nanoparticle platform for delivering RNA interference (RNAi) therapeutics. The novel nanoparticles ensure rapid release of small interfering RNA (siRNA) within cancer cells, enhancing gene silencing efficacy.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Therapeutics
Background:
- Biodegradable polymeric nanoparticles (NPs) show promise for systemic delivery of RNA interference (RNAi) therapeutics like small interfering RNA (siRNA) in cancer therapy.
- Inefficient siRNA release from conventional NPs can limit gene silencing efficacy in tumor cells.
Purpose of the Study:
- To develop a biodegradable and redox-responsive nanoparticle (NP) platform for enhanced systemic siRNA delivery and gene silencing in cancer therapy.
- To overcome the limitations of slow siRNA release associated with traditional biodegradable NPs.
Main Methods:
- Development of a biodegradable, redox-responsive NP platform using a poly(disulfide amide) (PDSA)/cationic lipid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell.
- Encapsulation of siRNA in NPs for extracellular stability.
- Utilizing the high glutathione (GSH) concentration in cytoplasm to trigger rapid intracellular siRNA release.
- Screening of PDSA polymers with varying structures and chain lengths to optimize NP performance.
Main Results:
- The optimized NP platform demonstrated long blood circulation and high tumor accumulation.
- Achieved rapid, glutathione (GSH)-triggered intracellular siRNA release.
- Exhibited exceptionally effective gene silencing in tumor cells.
- The NP formulation is scalable and the polymer synthesis is facile.
Conclusions:
- The developed redox-responsive NP platform offers efficient systemic siRNA delivery for cancer therapy.
- Fast intracellular siRNA release mediated by GSH enhances gene silencing efficacy.
- This platform represents a promising tool for RNAi-based cancer treatment, with potential for scale-up.
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