Primary cardiomyocyte-targeted bioreducible polymer for efficient gene delivery to the myocardium.
Primary cardiomyocyte-targeted bioreducible polymer for efficient gene delivery to the myocardium.
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DOI：
10.1016/j.biomaterials.2010.07.025
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发表时间：
2010-11
期刊：
影响因子：
14
通讯作者：
Bull, David A.
中科院分区：
文献类型：
--
作者：
Nam, Hye Y.;McGinn, Arlo;Kim, Pyung-Hwan;Kim, Sung W.;Bull, David A.
利用原代心肌细胞（PCM）特异性肽修饰聚合物开发了一种靶向心肌细胞的Fas siRNA递送系统，具有高转染效率和低细胞毒性。通过噬菌体展示选择原代心肌细胞（PCM）特异性肽，将其偶联到生物可还原的聚半胱胺双丙烯酰胺-二氨基己烷（CBA-DAH） （PCD）上。通过与游离PCM配体的竞争研究和递送到非心肌细胞NIH 3T3成纤维细胞，证实了PCM修饰聚合物对心肌细胞的特异性。游离PCM肽的加入抑制了PCM-聚合物/pDNA复合物的细胞结合和摄取。PCM偶联对H9C2大鼠心肌细胞摄取和转染效率的影响大于NIH 3T3细胞。Fas siRNA/ pcm -聚合物复合物在缺氧条件下大鼠心肌细胞中表现出显著的Fas基因沉默，从而抑制心肌细胞凋亡。这些发现证明了在生物可还原聚合物中添加原代心肌细胞（PCM）特异性肽修饰以靶向递送Fas siRNA以抑制心肌细胞凋亡的效用。
A cardiomyocyte-targeted Fas siRNA delivery system was developed using primary cardiomyocyte (PCM) specific peptide-modified polymers with high transfection efficiency and low cytotoxicity. Primary cardiomyocyte (PCM) specific peptide, selected by phage display, was conjugated to bioreducible poly(cystamine bisacrylamide-diaminohexane, CBA-DAH) (PCD). The specificity of the PCM-modified polymer to cardiomyocytes was confirmed by competition study with free PCM ligand and by delivery to non-cardiomyocyte NIH 3T3 fibroblasts. The cellular binding and uptake of the PCM-polymer/pDNA polyplex was inhibited by addition of free PCM peptide. The impact of PCM conjugation on cellular uptake and transfection efficiency was greater in H9C2 rat cardiomyocytes than in NIH 3T3 cells. Fas siRNA/PCM-polymer polyplexes exhibited significant Fas gene silencing in rat cardiomyocytes under hypoxic conditions, leading to inhibition of cardiomyocyte apoptosis. These findings demonstrate the utility of the addition of a primary cardiomyocyte (PCM) specific peptide modification to a bioreducible polymer for targeted delivery of Fas siRNA to inhibit cardiomyocyte apoptosis.
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