Phagocytic macrophages and dendritic cells are desirable targets for potential RNAi (RNA interference) therapeutics because they often mediate pathogenic inflammation and autoimmune responses. We recently engineered a complex 5 component glucan-based encapsulation system for siRNA (small interfering RNA) delivery to phagocytes. In experiments designed to simplify this original formulation, we discovered that the amphipathic peptide Endo-Porter forms stable nanocomplexes with siRNA that can mediate potent gene silencing in multiple cell types. In order to restrict such gene silencing to phagocytes, a method was developed to entrap siRNA–Endo-Porter complexes in glucan shells of 2–4 μm diameter in the absence of other components. The resulting glucan particles containing fluorescently labelled siRNA were readily internalized by macrophages, but not other cell types, and released the labelled siRNA into the macrophage cytoplasm. Intraperitoneal administration of such glucan particles containing siRNA–Endo-Porter complexes to mice caused gene silencing specifically in macrophages that internalized the particles. These results from the present study indicate that specific targeting to phagocytes is mediated by the glucan, whereas Endo-Porter peptide serves both to anchor siRNA within glucan particles and to catalyse escape of siRNA from phagosomes. Thus we have developed a simplified siRNA delivery system that effectively and specifically targets phagocytes in culture or in intact mice.
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Research Article|
May 13 2011
Glucan particles for selective delivery of siRNA to phagocytic cells in mice
Gregory J. Tesz;
Gregory J. Tesz
1
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Myriam Aouadi;
Myriam Aouadi
1
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Matthieu Prot;
Matthieu Prot
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Sarah M. Nicoloro;
Sarah M. Nicoloro
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Emilie Boutet;
Emilie Boutet
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Shinya U. Amano;
Shinya U. Amano
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Anca Goller;
Anca Goller
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Mengxi Wang;
Mengxi Wang
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Chang-An Guo;
Chang-An Guo
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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William E. Salomon;
William E. Salomon
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Joseph V. Virbasius;
Joseph V. Virbasius
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Rebecca A. Baum;
Rebecca A. Baum
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Mark J. O'Connor, Jr;
Mark J. O'Connor, Jr
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Ernesto Soto;
Ernesto Soto
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Gary R. Ostroff;
Gary R. Ostroff
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
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Michael P. Czech
Michael P. Czech
2
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A.
2To whom correspondence should be addressed (email michael.czech@umassmed.edu).
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Publisher: Portland Press Ltd
Received:
February 28 2011
Revision Received:
March 17 2011
Accepted:
March 21 2011
Accepted Manuscript online:
March 21 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 436 (2): 351–362.
Article history
Received:
February 28 2011
Revision Received:
March 17 2011
Accepted:
March 21 2011
Accepted Manuscript online:
March 21 2011
Citation
Gregory J. Tesz, Myriam Aouadi, Matthieu Prot, Sarah M. Nicoloro, Emilie Boutet, Shinya U. Amano, Anca Goller, Mengxi Wang, Chang-An Guo, William E. Salomon, Joseph V. Virbasius, Rebecca A. Baum, Mark J. O'Connor, Ernesto Soto, Gary R. Ostroff, Michael P. Czech; Glucan particles for selective delivery of siRNA to phagocytic cells in mice. Biochem J 1 June 2011; 436 (2): 351–362. doi: https://doi.org/10.1042/BJ20110352
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