期刊
ACS APPLIED MATERIALS & INTERFACES
卷 11, 期 18, 页码 16296-16310出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.9b02016
关键词
endosomal escape; MDR; codelivery; siRNA delivery; pH sensitive; redox sensitive
资金
- National Natural Science Foundation of China [81573372]
- Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University [ZQN2014A03]
The enhanced endo-lysosomal sequestration still remains a big challenge in overcoming multidrug resistance (MDR). Herein, a dual-responsive polyplex with effective endo-lysosomal escape based on methoxypoly(ethylene glycol)-polylactide-polyhistidine-ss-oligoethylenimine (mPEG-b-PLA-PHis-ssOEI) was developed for codelivering MDR1 siRNA and doxorubicin (DOX). The polyplex showed good encapsulation of DOX and siRNA as well as triggered payload release in response to pH/redox stimuli because of the PHis protonation and the disulfide bond cleavage. The polyplex at an N/P ratio of 7 demonstrated a much higher payload delivery efficiency, MDR1 gene silence efficiency, cytotoxicity against MCF-7/ADR cell, and stronger MCF-7/ADR tumor growth inhibition than the polyplexes at higher N/P ratios. This was attributed to the stronger electrostatic attraction between siRNA and OEIs at higher N/P ratios that suppressed the release of MDR1 siRNA and OEIs, which played a dominant role in overcoming payload endo-lysosomal sequestration by the OEI-induced membrane permeabilization effect. Consequently, the polyplex with effective endo-lysosomal escape provides a rational approach for codelivery of siRNAs and chemotherapy agents for MDR reversal.
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