Orally delivered thioketal nanoparticles loaded with TNF-α–siRNA target inflammation and inhibit gene expression in the intestines (original) (raw)

Nature Materials volume 9, pages 923–928 (2010)Cite this article

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Abstract

Small interfering RNAs (siRNAs) directed against proinflammatory cytokines have the potential to treat numerous diseases associated with intestinal inflammation1; however, the side-effects caused by the systemic depletion of cytokines2,3,4 demands that the delivery of cytokine-targeted siRNAs be localized to diseased intestinal tissues. Although various delivery vehicles have been developed to orally deliver therapeutics to intestinal tissue5,6,7, none of these strategies has demonstrated the ability to protect siRNA from the harsh environment of the gastrointestinal tract and target its delivery to inflamed intestinal tissue. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally delivered siRNA to sites of intestinal inflammation, and thus inhibit gene expression in inflamed intestinal tissue. TKNs are formulated from a polymer, poly-(1,4-phenyleneacetone dimethylene thioketal), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation8,9,10. Using a murine model of ulcerative colitis, we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α) diminish TNF-α messenger RNA levels in the colon and protect mice from ulcerative colitis.

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Acknowledgements

This project was financially supported by the Georgia Tech/Emory Center for the Engineering of Living Tissues (funded by NSF-EEC-9731643) (N.M.), NSF-BES-0546962 Career Award (N.M.), NIH UO1 HL80711-01 (N.M.), NIH R21 EB006418 (N.M.), NIH RO1 HL096796-01 (N.M.), NIH RO1-DK-071594 (D.M.) and NIH RO1-DK-064711 (S.V.S.). D.S.W. is supported by the Center for Drug Design, Development and Delivery at the Georgia Institute of Technology and the NIH Cellular and Tissue Engineering Training Grant T32 GM08433. G.D. is supported by a research fellowship award from the Crohn’s Colitis Foundation of America.

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Author notes

  1. D. Scott Wilson and Guillaume Dalmasso: These authors contributed equally to this work

Authors and Affiliations

  1. School of Chemical and Bimolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia, 30332, USA
    D. Scott Wilson
  2. Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, 30322, USA
    Guillaume Dalmasso, Lixin Wang, Shanthi V. Sitaraman & Didier Merlin
  3. Veterans Affairs Medical Center, Decatur, Georgia, 30033, USA
    Didier Merlin
  4. The Wallace H. Coulter Department of Biomedical Engineering and The Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, 30332, USA
    Niren Murthy

Authors

  1. D. Scott Wilson
  2. Guillaume Dalmasso
  3. Lixin Wang
  4. Shanthi V. Sitaraman
  5. Didier Merlin
  6. Niren Murthy

Contributions

D.S.W. synthesized and characterized PPADT; formulated particles; designed, carried out and analysed experiments; and wrote the manuscript. G.D. designed, carried out and analysed experiments; and proof read the manuscript. L.W. carried out experiments. S.V.S. supervised the project. D.M. designed experiments; supervised the project; and proof read the manuscript. N.M. designed the synthetic strategy used to synthesize PPADT; supervised the project; and contributed to the writing of the manuscript.

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Correspondence toDidier Merlin or Niren Murthy.

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The authors declare no competing financial interests.

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Wilson, D., Dalmasso, G., Wang, L. et al. Orally delivered thioketal nanoparticles loaded with TNF-α–siRNA target inflammation and inhibit gene expression in the intestines.Nature Mater 9, 923–928 (2010). https://doi.org/10.1038/nmat2859

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