期刊
PHARMACEUTICS
卷 14, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14030669
关键词
nanoparticles; miR-155; CXCR4; alcohol-associated liver disease (AALD)
资金
- NIH [R01 AA027695]
- Department of Veterans Affairs BLRD [I01 BX004127, I01 BX000849]
- Nebraska Center for Nanomedicine
- Cognitive Neuroscience of Development & Aging Centers for Biomedical Research Excellence [NIH P30 GM127200, P20 GM130447]
- Fred and Pamela Buffett Cancer Center [NIH P30 CA036727]
- Nebraska Research Initiative
- UNMC Office of the Vice Chancellor for Research
- National Institute for General Medical Science (NIGMS) [INBRE-P20 GM103427, COBRE-P30 GM106397]
- National Cancer Institute (NCI) for The Fred & Pamela Buffett Cancer Center [CA036727]
This study developed dual-functioning nanoparticles for the effective delivery of antifibrotic RNA and CXCR4 inhibitor, which shows promise for improving the treatment of alcohol-associated liver disease. The nanoparticles were able to significantly silence miR-155 expression and reduce liver damage in a model.
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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