Optimizing siRNA efficacy through alteration in the target cell-adhesion substrate interaction.
Optimizing siRNA efficacy through alteration in the target cell-adhesion substrate interaction.
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DOI：
10.1002/jbm.a.34202
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发表时间：
2012-10
影响因子：
4.9
通讯作者：
Mooney, David J.
中科院分区：
文献类型：
--
作者：
Khormaee, Sariah;Ali, Omar A.;Chodosh, James;Mooney, David J.
基于siRNA的治疗剂的临床潜力仍然受到将足够的siRNA递送到细胞质中以产生临床相关效果的挑战的阻碍。尽管许多研究都集中在优化这类分子的传递载体上，但对靶细胞对siRNA的反应的微环境影响知之甚少。细胞粘附的基质是可以调节细胞行为的微环境的一个组成部分。在这里，我们测试了调节细胞粘附底物的性质可以改变siRNA功效的假设。具体地，将阳离子脂质复合的siRNA颗粒应用于接种在藻酸盐水凝胶表面上的U251细胞，所述藻酸盐水凝胶表面具有弹性模量和整联蛋白配体RGD密度的系统变化。这些实验揭示在测试的弹性模量范围（53至133kPa）内siRNA介导的eGFP敲低没有变化。然而，藻酸盐生长基质的RGD含量增加8倍导致siRNA敲低功效从25 ± 12%增加至52 ± 10%，沉默增加超过2倍。我们的研究结果确定了细胞粘附底物相互作用的控制作为siRNA蛋白沉默功效的调节剂。
The clinical potential of siRNA based therapeutics remains hindered by the challenge of delivering enough siRNA into the cytoplasm to yield a clinically relevant effect. Although much research has focused on optimizing delivery vehicles for this class of molecules, considerably less is known about the microenvironmental influences on the response of target cells to siRNA. The substrate to which cells adhere is one component of the microenvironment that can modulate cellular behavior. Here, we tested the hypothesis that modulating the properties of cellular adhesion substrates can alter siRNA efficacy. Specifically, cationic lipid complexed siRNA particles were applied to U251 cells seeded on alginate hydrogel surfaces with systematic variation in elastic modulus and integrin ligand RGD density. These experiments revealed no change in siRNA mediated eGFP knockdown over the elastic modulus range tested (53 to 133 kPa). However, an eight-fold increase in RGD content of the alginate growth substrate resulted in an increase in siRNA knockdown efficacy from 25 ± 12% to 52 ± 10%, a more than two fold increase in silencing. Our results identify control of the cell-adhesion substrate interaction as a modulator of siRNA protein silencing efficacy.
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影响因子：
10.8
作者：
Kong, Hyun Joon;Hsiong, Susan;Mooney, David J.
通讯作者：
Mooney, David J.
影响因子：
41.2
作者：
Kong, HJ;Liu, JD;Mooney, DJ
通讯作者：
Mooney, DJ
DOI：
10.1038/nrd2310
发表时间：
2007-06
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
de Fougerolles A;Vornlocher HP;Maraganore J;Lieberman J
通讯作者：
Lieberman J
影响因子：
20.3
作者：
Dao, MA;Hashino, K;Nolta, JA
通讯作者：
Nolta, JA
影响因子：
3.4
作者：
Boontheekul, Tanyarut;Kong, Hyun-Joon;Mooney, David J.
通讯作者：
Mooney, David J.