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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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/3/669 |
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| author | Chuhan Zhang Yu Hang Weimin Tang Diptesh Sil Heather C. Jensen-Smith Robert G. Bennett Benita L. McVicker David Oupický |
| author_facet | Chuhan Zhang Yu Hang Weimin Tang Diptesh Sil Heather C. Jensen-Smith Robert G. Bennett Benita L. McVicker David Oupický |
| author_sort | Chuhan Zhang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T12:57:40Z |
| format | Article |
| id | doaj.art-372bcf1685d943d29308743cd40e5f69 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T12:57:40Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-372bcf1685d943d29308743cd40e5f692023-11-30T21:58:13ZengMDPI AGPharmaceutics1999-49232022-03-0114366910.3390/pharmaceutics14030669Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver DiseaseChuhan Zhang0Yu Hang1Weimin Tang2Diptesh Sil3Heather C. Jensen-Smith4Robert G. Bennett5Benita L. McVicker6David Oupický7Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USACenter for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USACenter for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USACenter for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Cancer Research & Fred and Pamela Buffer Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USACenter for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USAAlcohol-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.https://www.mdpi.com/1999-4923/14/3/669nanoparticlesmiR-155CXCR4alcohol-associated liver disease (AALD) |
| spellingShingle | Chuhan Zhang Yu Hang Weimin Tang Diptesh Sil Heather C. Jensen-Smith Robert G. Bennett Benita L. McVicker David Oupický Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease Pharmaceutics nanoparticles miR-155 CXCR4 alcohol-associated liver disease (AALD) |
| 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 | nanoparticles miR-155 CXCR4 alcohol-associated liver disease (AALD) |
| url | https://www.mdpi.com/1999-4923/14/3/669 |
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