Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer

Nishant S. Gandhi, Sudhakar Godeshala, Dana Lynn T. Koomoa-Lange, Bhavani Miryala, Kaushal Rege, Mahavir B. Chougule

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number188
JournalPharmaceutical Research
Volume35
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Ethers
Ether
Nanoparticles
Small Interfering RNA
Lung Neoplasms
Cells
Polymers
Genes
Gene Knockdown Techniques
Flow cytometry
Cell proliferation
Cytotoxicity
Surface charge
Sulfhydryl Compounds
Nucleic Acids
Glutathione
Cause of Death
Flow Cytometry
Cell Proliferation
Apoptosis

Keywords

  • bioreducible
  • drug delivery
  • lung cancer
  • mTOR
  • nanomedicine
  • nanoparticles
  • polymer
  • siRNA

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

Gandhi, N. S., Godeshala, S., Koomoa-Lange, D. L. T., Miryala, B., Rege, K., & Chougule, M. B. (2018). Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer. Pharmaceutical Research, 35(10), [188]. https://doi.org/10.1007/s11095-018-2460-z

Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer. / Gandhi, Nishant S.; Godeshala, Sudhakar; Koomoa-Lange, Dana Lynn T.; Miryala, Bhavani; Rege, Kaushal; Chougule, Mahavir B.

In: Pharmaceutical Research, Vol. 35, No. 10, 188, 01.10.2018.

Research output: Contribution to journalArticle

Gandhi, NS, Godeshala, S, Koomoa-Lange, DLT, Miryala, B, Rege, K & Chougule, MB 2018, 'Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer', Pharmaceutical Research, vol. 35, no. 10, 188. https://doi.org/10.1007/s11095-018-2460-z
Gandhi, Nishant S. ; Godeshala, Sudhakar ; Koomoa-Lange, Dana Lynn T. ; Miryala, Bhavani ; Rege, Kaushal ; Chougule, Mahavir B. / Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer. In: Pharmaceutical Research. 2018 ; Vol. 35, No. 10.
@article{b0b05b00816142f785e5a2d7bf8d1b66,
title = "Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer",
abstract = "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.",
keywords = "bioreducible, drug delivery, lung cancer, mTOR, nanomedicine, nanoparticles, polymer, siRNA",
author = "Gandhi, {Nishant S.} and Sudhakar Godeshala and Koomoa-Lange, {Dana Lynn T.} and Bhavani Miryala and Kaushal Rege and Chougule, {Mahavir B.}",
year = "2018",
month = "10",
day = "1",
doi = "10.1007/s11095-018-2460-z",
language = "English (US)",
volume = "35",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York",
number = "10",

}

TY - JOUR

T1 - Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer

AU - Gandhi, Nishant S.

AU - Godeshala, Sudhakar

AU - Koomoa-Lange, Dana Lynn T.

AU - Miryala, Bhavani

AU - Rege, Kaushal

AU - Chougule, Mahavir B.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - bioreducible

KW - drug delivery

KW - lung cancer

KW - mTOR

KW - nanomedicine

KW - nanoparticles

KW - polymer

KW - siRNA

UR - http://www.scopus.com/inward/record.url?scp=85051540992&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051540992&partnerID=8YFLogxK

U2 - 10.1007/s11095-018-2460-z

DO - 10.1007/s11095-018-2460-z

M3 - Article

AN - SCOPUS:85051540992

VL - 35

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 10

M1 - 188

ER -