ArticleACS omega2022
Conformationally Restricted Dipeptide-Based Nanoparticles for Delivery of siRNA in Experimental Liver Cirrhosis.
Article in ACS omega, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
7 authors.
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Abstract
Liver cirrhosis is a major health problem with multiple associated complications. The presently available drug delivery systems showed moderate site-specific delivery of antifibrotic molecules to the diseased liver; therefore, research on more effective and selective delivery systems in the context of liver cirrhosis remains a necessity in clinical investigation. The aim of the present study was to develop a peptide-based targeted nanocarrier to deliver an oligonucleotide to the hepatic sinusoidal and perivascular regions of the cirrhotic liver. We have synthesized and characterized a conformationally restricted targeted pentapeptide (RΔFRGD), which contains an unnatural amino acid, α,β-dehydrophenylalanine (ΔF). The RΔFRGD self-assembled into spherical nanoparticles (NPs) and was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Next, we investigated the delivery potential of the pentapeptide-based NPs to make a stable complex with a well-established small interference RNA and studied its site-specific delivery in experimental liver cirrhosis. We used siNR4A1 of the orphan nuclear receptor 4A1 (NR4A1), a well-known regulatory checkpoint for controlling liver fibrosis. Peptide NPs and their complex with siNR4A1 showed high biocompatibility against various mammalian cell lines. Hepatic tissue biodistribution analysis illustrated that targeted NPs predominantly accumulated in the cirrhotic liver compared to normal rats, specifically in sinusoidal and perivascular areas. A significant downregulation of the NR4A1 mRNA expression (-70%) andlower levels of the NR4A1/GAPDH ratio (-55%) were observed in the RΔFRGD-siNR4A1 nanocomplex-treated group in comparison to the RΔFRGD-vehicle group (RΔFRGD-Veh) at the gene and protein levels, respectively. In addition,
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