Reactive Oxygen Species (ROS)-Degradable Polymeric Nanoplatform for Hypoxia-Targeted Gene Delivery: Unpacking DNA and Reducing Toxicity
Reactive Oxygen Species (ROS)-Degradable Polymeric Nanoplatform for Hypoxia-Targeted Gene Delivery: Unpacking DNA and Reducing Toxicity
复制标题
用于缺氧靶向基因传递的活性氧 (ROS) 可降解聚合物纳米平台：解包 DNA 并降低毒性
DOI：
10.1021/acs.biomac.9b00054
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发表时间：
2019
影响因子：
6.2
通讯作者：
Gu Zhongwei
中科院分区：
文献类型：
--
作者：
Zhang Yuxin;Zhou Jie;Ma Shengnan;He Yiyan;Yang Jun;Gu Zhongwei
智能聚合物作为理想的基因载体，由于其在受到内源性刺激后能有效释放DNA，并能降低细胞毒性而受到越来越多的关注。本文中，刺激响应性、带正电荷和水溶性聚合物（OEI-TKx）通过经由硫代缩酮（TK）键交联低分子量低聚乙烯亚胺（OEI）而容易地工程化，所述硫代缩酮（TK）键将在由缺氧诱导的富含活性氧（ROS）的环境中选择性地裂解。琼脂糖凝胶电泳结果表明，OEI-TKx完全阻滞带负电荷DNA迁移的N/P值大于5。DNA浓缩能力的降低以及粒径、粒径分布和颗粒形态的变化都说明OEI-TKx具有优异的ROS响应性。与PEI/DNA复合物相比，OEI-TKx/DNA复合物具有更低的毒性和更高的基因转染效率。最佳制剂OEI-TKx/DNA复合物（N/P = 40）在细胞摄取曲线方面显示出比PEI/DNA复合物稍好的性能。此外，OEI-TKx/DNA聚合复合物可以像PEI/DNA聚合复合物一样有效地从内体逃逸到胞质溶胶。共聚焦图像证实，OEI-TKx/DNA复合物可以更有效地释放DNA比PEI/DNA复合物，这主要是由于在Hela细胞中的特征性富ROS诱导的硫代缩酮键的有效切割。这些结果表明OEI-TKx可以代表按需刺激响应基因递送平台。
Smart polymers as ideal gene carriers have drawn increasing attentions due to the effective DNA release once triggered by intrinsic stimuli, as well as reduced cytotoxicity. Herein, a stimulus-responsive, positively charged and water-soluble polymer (OEI-TKx) was facilely engineered by cross-linking low molecular weight oligoethylenimine (OEI) via thioketal (TK) linkages that would cleave selectively in reactive oxygen species (ROS)-rich environments induced by hypoxia. Agarose gel electrophoresis assay demonstrated that the threshold N/P ratios for complete retardation of negatively charged DNA migration were above 5 for OEI-TKx. The reduction in DNA-condensing capability and the changes in particle size, size distribution and particle morphology all illustrated that OEI-TKxpossessed excellent ROS responsiveness. OEI-TKx/DNA polyplexes showed lower toxicity and higher gene transfection efficiency compared with PEI/DNA polyplexes. The optimum formulation, OEI-TKx/DNA polyplexes (N/P = 40), showed a little better performance than PEI/DNA polyplexes in cellular uptake profile. Furthermore, OEI-TKx/DNA polyplexes could escape from endosomes to the cytosol as efficiently as PEI/DNA polyplexes. Confocal images confirmed that OEI-TKx/DNA polyplexes could more effectively release DNA than PEI/DNA polyplexes, mainly owing to the valid cleavage of thioketal linkages induced by characteristic rich-ROS in Hela cells. These results suggested that OEI-TKxcould represent an on-demand stimulus-responsive gene delivery platform.