Development of a Gene Delivery System of Oligonucleotides for Fibroses by Targeting Cell-Surface Vimentin-Expressing Cells with N-Acetylglucosamine-Bearing Polymer-Conjugated Polyethyleneimine
Development of a Gene Delivery System of Oligonucleotides for Fibroses by Targeting Cell-Surface Vimentin-Expressing Cells with N-Acetylglucosamine-Bearing Polymer-Conjugated Polyethyleneimine
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DOI：
10.3390/polym12071508
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发表时间：
2020-07
期刊：
影响因子：
5
通讯作者：
Inu Song;H. Ise
中科院分区：
文献类型：
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作者：
Inu Song;H. Ise
靶向治疗纤维化组织损伤部位的肌成纤维细胞和活化的星状细胞是治疗纤维化的重要途径。在本文中，我们专注于靶向细胞骨架蛋白波形蛋白，据报道，波形蛋白在这些细胞的表面上高度表达，并具有N-乙酰葡糖胺（GlcNAc）结合活性。先前已经发现通过自由基聚合与可逆加成-断裂链转移试剂合成的具有GlcNAc的聚合物与细胞表面波形蛋白表达细胞相互作用。我们设计了一种含有GlcNAc的聚合物偶联聚乙烯亚胺（PEI）作为基因载体，靶向表达细胞表面波形蛋白的细胞，并将核因子-κB诱饵寡核苷酸（ODNs）和热休克蛋白47（HSP 47）-小干扰RNA（siRNA）特异性地递送到表达细胞表面波形蛋白的正常人皮肤成纤维细胞（NHDFs）中。结果显示，细胞通过细胞表面波形蛋白摄取GlcNAc标记的PEI/核因子（NF）-κB decoy ODNs和HSP 47-siRNA复合物，分别抑制了脂多糖刺激的NHDFs中肿瘤坏死因子-α和转化生长因子-β1刺激的NHDFs中HSP 47的表达。这些发现表明，使用带有GlcNAc的聚合物缀合的PEI可以实现ODN和siRNA对细胞表面波形蛋白表达细胞如肌成纤维细胞和活化的星状细胞的有效和特异性递送。这种治疗方法可以证明有利于防止各种纤维化的促进。
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.