Song Inu, Ise Hirohiko
Graduate School of Engineering, Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan.
Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan.
Polymers (Basel). 2020 Jul 7;12(7):1508. doi: 10.3390/polym12071508.
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.
靶向纤维化组织损伤部位的肌成纤维细胞和活化星状细胞是治疗纤维化的重要方法。在此，我们重点关注靶向细胞骨架蛋白波形蛋白，据报道这些蛋白在这些细胞表面高度表达且具有N-乙酰葡糖胺（GlcNAc）结合活性。先前已发现通过可逆加成-断裂链转移试剂进行自由基聚合合成的含GlcNAc聚合物可与细胞表面表达波形蛋白的细胞相互作用。我们设计了一种含GlcNAc聚合物共轭的聚乙烯亚胺（PEI），作为基因载体靶向细胞表面表达波形蛋白的细胞，并将核因子-κB诱饵寡核苷酸（ODN）和热休克蛋白47（HSP47）-小干扰RNA（siRNA）特异性递送至表达细胞表面波形蛋白的正常人皮肤成纤维细胞（NHDF）。结果表明，含GlcNAc聚合物共轭的PEI/核因子（NF）-κB诱饵ODN和HSP47-siRNA复合物分别通过细胞表面波形蛋白被细胞摄取后，可抑制脂多糖刺激的NHDF中肿瘤坏死因子-α的表达以及转化生长因子-β1刺激的NHDF中HSP47的表达。这些发现表明，使用含GlcNAc聚合物共轭的PEI可以实现向细胞表面表达波形蛋白的细胞（如肌成纤维细胞和活化星状细胞）有效且特异性地递送ODN和siRNA。这种治疗方法可能有利于预防各种纤维化的进展。
