Imaging and therapy of liver fibrosis using bioreducible polyethylenimine/siRNA complexes conjugated with N-acetylglucosamine as a targeting moiety

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Title
Imaging and therapy of liver fibrosis using bioreducible polyethylenimine/siRNA complexes conjugated with N-acetylglucosamine as a targeting moiety
Author(s)
Sun Jung Kim; H Ise; E Kim; M Goto; T Akaike; Bong Hyun Chung
Bibliographic Citation
Biomaterials, vol. 34, no. 24, pp. 6504-6514
Publication Year
2013
Abstract
Diagnosis and therapy of early stage liver fibrosis is very important for the treatment of fatal liver diseases. Here, we report on the targeted imaging and therapy of activated hepatic stellate cells (HSCs) and fibrotic liver tissue using N-acetylglucosamine (GlcNAc)- and indocyanine green (ICG)-conjugated PEI/siRNA complexes. The conjugation of a disulfide bond to PEI (PEI-D) was achieved by Michael addition. We modified PEI with N-acetylglucosamine (PEI- D-GlcNAc), which can specifically interact with desmin on activated HSCs, using the EDC coupling method. Confocal microscopic analysis showed that the PEI- D-GlcNAc/siRNA was internalized by HSCs upon interaction with surface desmin. Invitro western blot analysis confirmed that PEI- D-GlcNAc provided strong protein knock-down after transfection with TGFβ1siRNA into HSCs. After a tail vein injection of ICG-conjugated complexes, the PEI- D-GlcNAc-ICG/siRNA complex accumulated to a greater extent in the livers of fibrotic mice than in normal mice over an extended duration. Moreover, immunohistofluorescence analysis confirmed that the PEI- D-GlcNAc-ICG/siRNA complex specifically colocalized with HSCs, which are desmin-positive cells, in fibrotic liver tissues. Invivo TGFβ1siRNA delivery also resulted in superior protein knock-down when using the PEI- D-GlcNAc complex. These results demonstrate that the PEI- D-GlcNAc-ICG/TGFβ1siRNA complex is a useful tool for imaging and treatment of liver fibrosis.
Keyword
DesminImagingLiver fibrosisN-acetylglucosamineSiRNATherapy
ISSN
0142-9612
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.biomaterials.2013.05.013
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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