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Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagoni...

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Autores principales: Zhang, Chuhan, Hang, Yu, Tang, Weimin, Sil, Diptesh, Jensen-Smith, Heather C., Bennett, Robert G., McVicker, Benita L., Oupický, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949580/
https://www.ncbi.nlm.nih.gov/pubmed/35336043
http://dx.doi.org/10.3390/pharmaceutics14030669
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author Zhang, Chuhan
Hang, Yu
Tang, Weimin
Sil, Diptesh
Jensen-Smith, Heather C.
Bennett, Robert G.
McVicker, Benita L.
Oupický, David
author_facet Zhang, Chuhan
Hang, Yu
Tang, Weimin
Sil, Diptesh
Jensen-Smith, Heather C.
Bennett, Robert G.
McVicker, Benita L.
Oupický, David
author_sort Zhang, Chuhan
collection PubMed
description Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit the activation of hepatic stellate cells (HSCs) through the CXCL12/CXCR4 axis. The development of dual-functioning nanoparticles for the effective delivery of antifibrotic RNA together with a CXCR4 inhibitor thus promises to improve the treatment of AALD fibrosis. In this study, cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) was synthesized and used to encapsulate anti-miR-155 or non-coding (NC) miRNA in the form of Chol-PCX/miRNA nanoparticles. The results indicate that the nanoparticles induce a significant miR-155 silencing effect both in vitro and in vivo. Treatment with the Chol-PCX/anti-miR-155 particles in a model of moderate alcohol consumption with secondary liver insult resulted in a significant reduction in aminotransferase enzymes as well as collagen content in the liver parenchyma. Overall, our data support the use of Chol-PCX as a carrier for anti-miR-155 for the combined therapeutic inhibition of CXCR4 and miR-155 expression as a way to improve fibrotic damage in the liver.
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spelling pubmed-89495802022-03-26 Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease Zhang, Chuhan Hang, Yu Tang, Weimin Sil, Diptesh Jensen-Smith, Heather C. Bennett, Robert G. McVicker, Benita L. Oupický, David Pharmaceutics Article Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit the activation of hepatic stellate cells (HSCs) through the CXCL12/CXCR4 axis. The development of dual-functioning nanoparticles for the effective delivery of antifibrotic RNA together with a CXCR4 inhibitor thus promises to improve the treatment of AALD fibrosis. In this study, cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) was synthesized and used to encapsulate anti-miR-155 or non-coding (NC) miRNA in the form of Chol-PCX/miRNA nanoparticles. The results indicate that the nanoparticles induce a significant miR-155 silencing effect both in vitro and in vivo. Treatment with the Chol-PCX/anti-miR-155 particles in a model of moderate alcohol consumption with secondary liver insult resulted in a significant reduction in aminotransferase enzymes as well as collagen content in the liver parenchyma. Overall, our data support the use of Chol-PCX as a carrier for anti-miR-155 for the combined therapeutic inhibition of CXCR4 and miR-155 expression as a way to improve fibrotic damage in the liver. MDPI 2022-03-18 /pmc/articles/PMC8949580/ /pubmed/35336043 http://dx.doi.org/10.3390/pharmaceutics14030669 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Chuhan
Hang, Yu
Tang, Weimin
Sil, Diptesh
Jensen-Smith, Heather C.
Bennett, Robert G.
McVicker, Benita L.
Oupický, David
Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title_full Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title_fullStr Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title_full_unstemmed Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title_short Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease
title_sort dually active polycation/mirna nanoparticles for the treatment of fibrosis in alcohol-associated liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949580/
https://www.ncbi.nlm.nih.gov/pubmed/35336043
http://dx.doi.org/10.3390/pharmaceutics14030669
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