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Enhanced cancer therapeutic efficiency of NO combined with siRNA by caspase-3 responsive polymers
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2021-10-14 , DOI: 10.1016/j.jconrel.2021.10.012
Yi Yan 1 , Cheng-Han Wang 1 , Shi-He Cui 1 , Lin Zhai 1 , Jing Sun 1 , Xiao-Yu Liu 1 , Xin Chen 1 , Yi Sun 1 , Hong-Gang Qian 2 , Xiang Gao 3 , Yi-Da Tang 4 , Yuan-Jun Zhu 1 , Yu-Jie Shi 1 , Qiang Zhang 1 , Jian-Cheng Wang 1
Affiliation  

The combination of nitric oxide (NO) and siRNA is highly desirable for cancer therapy. Here, the furoxans-grafted PEI polymer (FDP) with caspase-3 responsive cleavable DEVD linker was synthesized, and used to bind siRNAs via electrostatic interaction and self-assembled into FDP/siRNA nanoplexes by hydrophobic force. After cellular uptake and lysosomal escape, the FDP/siRNA nanoplexes could achieve GSH-triggered NO release, and then increase the activity of caspase-3. The activated caspase-3 could specifically cleave the DEVD peptide sequence and enhance cell apoptosis. With the cleavage of DEVD peptide sequence, the disassembly of FDP/siRNA nanoplexes was further promoted, thereby resulting in increased siRNAs of ~40% were released at 48 h compared with the caspase-3 non-responsive FDnP/siRNA nanoplexes. By this way, cell apoptosis promotion and cell proliferation inhibition was achieved by siRNA-based downregulation of EGFR protein and the upregulated activity of caspase-3, followed by the enhanced cascade release of NO from FDP/siRNA nanoplexes. Furthermore, in vivo results demonstrated the improved anti-cancer efficiency of FDP/siEGFR nanoplexes without any detectable side effects. Therefore, it is believed that the caspase-3 responsive cleavable furoxans-grafted PEI polymers could provide a potential and efficient enhancement for cancer therapeutic efficiency by the co-delivery of nitric oxide and siRNA.



中文翻译:

通过 caspase-3 响应聚合物提高 NO 与 siRNA 结合的癌症治疗效率

一氧化氮 (NO) 和 siRNA 的组合非常适合癌症治疗。在这里,合成了具有 caspase-3 响应性可切割 DEVD 接头的呋喃类接枝 PEI 聚合物 (FDP),并用于通过以下方式结合 siRNA静电相互作用并通过疏水力自组装成 FDP/siRNA 纳米复合物。在细胞摄取和溶酶体逃逸后,FDP/siRNA纳米复合物可以实现GSH触发的NO释放,进而提高caspase-3的活性。活化的 caspase-3 可以特异性切割 DEVD 肽序列并增强细胞凋亡。随着 DEVD 肽序列的切割,进一步促进了 FDP/siRNA 纳米复合体的分解,从而导致与 caspase-3 非响应性 FDnP/siRNA 纳米复合体相比,在 48 小时释放的 siRNA 增加了约 40%。通过这种方式,细胞凋亡促进和细胞增殖抑制是通过基于 siRNA 的 EGFR 蛋白下调和 caspase-3 活性的上调实现的,然后是 FDP/siRNA 纳米复合体中 NO 的级联释放增强。此外,体内结果证明了 FDP/siEGFR 纳米复合物的抗癌效率提高,没有任何可检测的副作用。因此,据信 caspase-3 响应性可切割呋喃类接枝 PEI 聚合物可通过一氧化氮和 siRNA 的共同递送为癌症治疗效率提供潜在且有效的增强。

更新日期:2021-10-22
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