Enhanced cancer therapeutic efficiency of NO combined with siRNA by caspase-3 responsive polymers

• DOI: 10.1016/j.jconrel.2021.10.012
• Publication Date: 2021-10-15T01:35:57Z
• Authors: Yi Yan; Cheng-Han Wang; Shi-He Cui; Lin Zhai; Jing Sun; Xiao-Yu Liu; Xin Chen; Yi Sun; Hong-Gang Qian; Xiang Gao; Yi-Da Tang; Yuan-Jun Zhu; Yu-Jie Shi; Qiang Zhang; Jian-Cheng Wang
• Keywords: 0301 basic medicine; 03 medical and health sciences; Caspase 3; Polymers; Neoplasms; Humans; RNA, Small Interfering; Nitric Oxide; 3. Good health

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.