Redox-responsive polymer inhibits macrophages uptake for effective intracellular gene delivery and enhanced cancer therapy
Redox-responsive polymer inhibits macrophages uptake for effective intracellular gene delivery and enhanced cancer therapy
复制标题
氧化还原反应聚合物可抑制巨噬细胞的摄取，从而有效地进行细胞内基因传递并增强癌症治疗。
DOI：
10.1016/j.colsurfb.2018.12.016
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发表时间：
2019-03-01
影响因子：
5.8
通讯作者：
Hu, Fuqiang
中科院分区：
文献类型：
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作者：
Wen, Lijuan;Hu, Yingwen;Hu, Fuqiang
具有刺激响应性释放方式的先进基因递送载体的开发是肿瘤治疗的期望，因为它们可以响应靶位点的特异性刺激而通过其结构变化来专一地释放治疗基因。此外，巨噬细胞与药物递送系统（DDS）之间的相互作用严重损害DDS的治疗效率，因此巨噬细胞摄取抑制将在一定程度上提高肿瘤细胞对DDS的胞内摄取。本文中，开发了用于有效癌症治疗的聚乙二醇化氧化还原响应基因递送系统。PEG修饰的类糖脂聚合物（P-CSSO）与p53静电作用形成P-CSSO/p53复合物，在10 mM谷胱甘肽（GSH）水平下，P-CSSO/p53复合物的氧化还原敏感性增强，二硫键被降解，质粒从P-CSSO中释放的速率是无反应平台（P-CSO-SA）的2.29倍。聚乙二醇修饰可显著减弱巨噬细胞对P-CSSO的摄取，但增强P-CSSO在体内外肿瘤细胞中的蓄积。P-CSSO/p53复合物的抑瘤率（77.1%）明显高于CSSO/p53复合物的抑瘤率（69.9%），而P-CSSO-SA/p53复合物的抑瘤率（59.2%）和Lipofectamine（TM）2000/p53复合物的抑瘤率（52.0%）明显高于CSSO/p53复合物。目前的研究表明，肿瘤微环境敏感和巨噬细胞摄取抑制P-CSSO/p53是一个强大的体内基因递送系统，用于增强抗癌治疗。
The development of advanced gene delivery carriers with stimuli-responsive release manner for tumor therapeutics is desirable, since they can exclusively release the therapeutic gene via their structural changes in response to the specific stimuli of the target site. Moreover, interactions between macrophages and drug delivery systems (DDSs) seriously impair the treatment efficiency of DDSs, thus macrophages uptake inhibition would to some extent improve the intracellular uptake of DDSs in tumor cells. Herein, a PEGylated redox-responsive gene delivery system was developed for effective cancer therapy. PEG modified glycolipid-like polymer (P-CSSO) was electrostatic interacted with p53 to form P-CSSO/p53 complexes, which exhibited an enhanced redox sensitivity in that the disulfide bond was degraded and the rate the plasmid released from P-CSSO was 2.29-fold that of nonresponsive platform (P-CSO-SA) in 10 mM levels of glutathione (GSH). PEGylation could significantly weaken macrophages uptake, while enhance the accumulation of P-CSSO in tumor cells both in vitro and in vivo. Compared with nonresponsive complexes (P-CSO-SA/p53) (59.2%) and Lipofectamine (TM) 2000/p53 complexes (52.0%), the tumor inhibition rate of P-CSSO/p53 complexes (77.1%) significantly increased, which was higher than CSSO/p53 complexes (69.9%). The present study indicates that tumor microenvironment sensitive and macrophages uptake suppressive P-CSSO/p53 is a powerful in vivo gene delivery system for enhanced anticancer therapy.