Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis.
Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis.
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DOI：
10.1016/j.biomaterials.2008.07.047
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发表时间：
2008-11
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：
Kim, Sun Hwa;Jeong, Ji Hoon;Ou, Mei;Yockman, James W.;Kim, Sung Wan;Bull, David A.
利用前列腺素E2（PGE 2）修饰的siRNA复合物（由可还原的聚（酰胺基胺）形成），开发了心肌细胞靶向Fas siRNA递送系统，以抑制心肌细胞凋亡。将PGE 2作为心肌细胞靶向的特异性配体，偶联到正义siRNA的末端（PGE 2-siRNA）。通过1，6-二氨基己烷和胱胺双丙烯酰胺（聚（DAH/CBA））的迈克尔型加聚反应合成的可还原阳离子共聚物使PGE 2-siRNA缀合物紧密缩合以形成直径为100-150 nm的纳米尺寸的聚合复合物。PGE 2-siRNA/poly（DAH/CBA）复合物由于可还原的poly（DAH/CBA）的降解而在胞质还原环境中解复合以释放PGE 2-siRNA。由于PGE 2受体介导的内吞作用，PGE 2-siRNA/poly（DAH/CBA）复合物在大鼠心肌细胞（H9 C2细胞）中的细胞摄取增加。当H9 C2细胞转染针对Fas（缺血诱导凋亡的关键调节因子）的siRNA时，PGE 2-Fas siRNA/poly（DAH/CBA）polyplex递送系统导致Fas基因沉默显著增加，从而抑制心肌细胞凋亡。PGE 2-Fas siRNA/poly（DAH/CBA）复合物在外周血单核细胞中不诱导干扰素-α。这些结果表明，PGE 2-Fas siRNA/poly（DAH/CBA）多聚物制剂可作为心肌细胞靶向的Fas siRNA递送系统用于临床，以抑制心血管疾病中的细胞凋亡。
A cardiomyocyte-targeted Fas siRNA delivery system was developed using prostaglandin E2 (PGE2)-modified siRNA polyplexes formed by a reducible poly(amido amine) to inhibit cardiomyocyte apoptosis. PGE2, which was used as a specific ligand for cardiomyocyte targeting, was conjugated to the terminal-end of the sense siRNA (PGE2-siRNA). The reducible cationic copolymer, synthesized via Michael-type polyaddition of 1,6-diaminohexane and cystamine bis-acrylamide (poly(DAH/CBA)), tightly condensed the PGE2-siRNA conjugate to form nanosize polyplexes having a diameter of 100-150 nm. The PGE2-siRNA/poly(DAH/CBA) polyplexes decomplexed to release PGE2-siRNA in a cytosolic reducing environment due to the degradation of the reducible poly(DAH/CBA). The cellular uptake of the PGE2-siRNA/poly(DAH/CBA) polyplex was increased in rat cardiomyocytes (H9C2 cells) due to PGE2 receptor-mediated endocytosis. When H9C2 cells were transfected with siRNA against Fas, a key regulator of ischemia-induced apoptosis, the PGE2-Fas siRNA/poly(DAH/CBA) polyplex delivery system led to a significant increase in Fas gene silencing, resulting in inhibition of cardiomyocyte apoptosis. The PGE2-Fas siRNA/poly(DAH/CBA) polyplex did not induce interferon-alpha in peripheral blood mononuclear cells. These results suggest that the PGE2-Fas siRNA/poly(DAH/CBA) polyplex formulation may be clinically applicable as a cardiomyocyte-targeted Fas siRNA delivery system to inhibit apoptosis in cardiovascular disease.
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影响因子：
15.9
作者：
GOTTLIEB, RA;BURLESON, KO;ENGLER, RL
通讯作者：
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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