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Preparation of Exosomes for siRNA Delivery to Cancer Cells
Published on: December 5, 2018
Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer
Nishant S Gandhi1,2, Sudhakar Godeshala3, Dana-Lynn T Koomoa-Lange1
1Department of Pharmaceutical Sciences, The Daniel K Inouye College of pharmacy, University of Hawaii at Hilo, Hilo, HI, 96720, USA.
Purpose:
Lung cancer is one of the leading causes of deaths in the United States, but currently available therapies for lung cancer are associated with reduced efficacy and adverse side effects. Small interfering RNA (siRNA) can knock down the expression of specific genes and result in therapeutic efficacy in lung cancer. Recently, mTOR siRNA has been shown to induce apoptosis in NSCLC cell lines but its use is limited due to poor stability in biological conditions.
Methods:
In this study, we modified an aminoglyocisde-derived cationic poly (amino-ether) by introducing a thiol group using Traut's reagent to generate a bio-reducible modified-poly (amino-ether) (mPAE). The mPAE polymer was used to encapsulate mTOR siRNA by nanoprecipitation method, resulting in the formation of stable and bio-reducible nanoparticles (NPs) which possessed an average diameter of 114 nm and a surface charge of approximately +27 mV.
Results:
The mTOR siRNA showed increased release from the mTS-mPAE NPs in the presence of 10 mM glutathione (GSH). The polymeric mTS-mPAE-NPs were also capable of efficient gene knockdown (60 and 64%) in A549 and H460 lung cancer cells, respectively without significant cytotoxicity at 30 μg/ml concentrations. The NPs also showed time-dependent cellular uptake for up to 24 h as determined using flow cytometry. Delivery of the siRNA using these NPs also resulted in significant inhibition of A549 and H460 cell proliferation in vitro, respectively.
Conclusions:
The results demonstrate that the mPAE polymer based NPs show strong potential for siRNA delivery to lung cancer cells. It is anticipated that future modification can help improve the efficacy of nucleic acid delivery, leading to higher inhibition of lung cancer growth in vitro and in vivo.
Insights
This study developed novel nanoparticles for delivering mTOR siRNA to lung cancer cells. These nanoparticles show promise for effective gene knockdown and inhibiting cancer cell growth.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Lung cancer remains a leading cause of death with limited effective therapies.
- Current treatments for lung cancer often have reduced efficacy and adverse side effects.
- Small interfering RNA (siRNA) offers potential for gene knockdown therapy in lung cancer, but its stability is a challenge.
Purpose of the Study:
- To develop a stable and bio-reducible nanoparticle system for delivering mTOR siRNA to lung cancer cells.
- To evaluate the efficacy of modified poly(amino-ether) nanoparticles (mPAE NPs) for siRNA delivery.
- To assess the potential of mPAE NPs in inhibiting lung cancer cell proliferation.
Main Methods:
- A bio-reducible modified-poly(amino-ether) (mPAE) polymer was synthesized by introducing a thiol group.
- mTOR siRNA was encapsulated into mPAE using nanoprecipitation, forming stable nanoparticles (NPs).
- Nanoparticle characterization included size (114 nm), surface charge (+27 mV), and siRNA release in the presence of glutathione (GSH).
Main Results:
- mPAE NPs demonstrated efficient siRNA release in response to GSH.
- The NPs achieved significant gene knockdown (60-64%) in A549 and H460 lung cancer cells without cytotoxicity.
- Flow cytometry confirmed time-dependent cellular uptake of NPs up to 24 hours.
- siRNA delivery via mPAE NPs significantly inhibited lung cancer cell proliferation in vitro.
Conclusions:
- The developed mPAE polymer-based NPs show significant potential for siRNA delivery in lung cancer.
- These nanoparticles effectively deliver siRNA, leading to gene knockdown and reduced cancer cell proliferation.
- Further modifications may enhance nucleic acid delivery efficacy for improved in vitro and in vivo lung cancer inhibition.
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