Abstract
Targeting myofibroblasts and activated stellate cells in lesion sites of fibrotic tissues is an important approach to treat fibroses. Herein, we focused on targeting the cytoskeletal proteins vimentin, which are reportedly highly expressed on the surface of these cells and have N-acetylglucosamine (GlcNAc)-binding activity. A GlcNAc-bearing polymer synthesized via radical polymerization with a reversible addition-fragmentation chain transfer reagent has been previously found to interact with cell-surface vimentin-expressing cells. We designed a GlcNAc-bearing polymer-conjugated polyethyleneimine (PEI), as the gene carrier to target cell-surface vimentin-expressing cells and specifically deliver nuclear factor-κB decoy oligonucleotides (ODNs) and heat shock protein 47 (HSP47)-small interfering RNA (siRNA) to normal human dermal fibroblasts (NHDFs) that express cell-surface vimentin. The results showed that the expression of tumor necrosis factor-α in lipopolysaccharide-stimulated NHDFs and HSP47 in transforming growth factor-β1-stimulated NHDFs was suppressed by cellular uptake of the GlcNAc-bearing polymer-conjugated PEI/nuclear factor (NF)-κB decoy ODNs and HSP47-siRNA complexes through cell-surface vimentin, respectively. These findings suggest that the effective and specific delivery of ODNs and siRNA for cell-surface vimentin-expressing cells such as myofibroblasts and activated stellate cells can be achieved using GlcNAc-bearing polymer-conjugated PEI. This therapeutic approach could prove advantageous to prevent the promotion of various fibroses.
Highlights
Various tissue fibroses such as liver cirrhosis, pulmonary fibrosis, and hypertensive heart disease are caused by chronic inflammation related to repeated tissue injuries and autoimmune diseases [1].When conventional tissue-repairing systems are disrupted, chronic inflammation is induced and many inflammatory cytokines, chemokines, and growth factors are secreted from immune cells such as leukocytes and macrophages
These fibrotic processes are common to various tissues and organs, and the large numbers of myofibroblasts and activated stellate cells accompanied by abnormal extracellular matrix (ECM) deposition exacerbate fibroses [1,7,8,9,10,11]
We previously discovered the optimal valency of GlcNAc-bearing polymers for binding to cell surface vimentin by using various sized AC-GlcNAcs produced with reversible deactivation radical polymerization (RDRP)
Summary
When conventional tissue-repairing systems are disrupted, chronic inflammation is induced and many inflammatory cytokines, chemokines, and growth factors are secreted from immune cells such as leukocytes and macrophages These cytokines and growth factors stimulate the activation of fibroblasts and stellate cells, inducing their transformation into myofibroblasts and activated stellate cells, respectively [1,2,3]. The accumulation of excess ECM leads to the stiffening of parenchymal tissues, which in turn leads to the destruction of their structural architecture and function [6] These fibrotic processes are common to various tissues and organs, and the large numbers of myofibroblasts and activated stellate cells accompanied by abnormal ECM deposition exacerbate fibroses [1,7,8,9,10,11]. The accurate and early diagnosis of these fibroses is important for tumor prevention and to monitor progression [13]
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