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Self‐Activated Cascade‐Responsive Sorafenib and USP22 shRNA Co‐Delivery System for Synergetic Hepatocellular Carcinoma Therapy
Author(s) -
Xu Shengjun,
Ling Sunbin,
Shan Qiaonan,
Ye Qianwei,
Zhan Qifan,
Jiang Guangjiang,
Zhuo Jianyong,
Pan Binhua,
Wen Xue,
Feng Tingting,
Lu Haohao,
Wei Xuyong,
Xie Haiyang,
Zheng Shusen,
Xiang Jiajia,
Shen Youqing,
Xu Xiao
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202003042
Subject(s) - sorafenib , hepatocellular carcinoma , cancer research , small hairpin rna , multiple drug resistance , downregulation and upregulation , in vivo , medicine , chemistry , pharmacology , drug resistance , biology , apoptosis , biochemistry , microbiology and biotechnology , gene knockdown , gene
Resistance to sorafenib severely hinders its effectiveness against hepatocellular carcinoma (HCC). Cancer stemness is closely connected with resistance to sorafenib. Methods for reversing the cancer stemness remains one of the largest concerns in research and the lack of such methods obstructs current HCC therapeutics. Ubiquitin‐specific protease 22 (USP22) is reported to play a pivotal role in HCC stemness and multidrug resistance (MDR). Herein, a galactose‐decorated lipopolyplex (Gal‐SLP) is developed as an HCC‐targeting self‐activated cascade‐responsive nanoplatform to co‐delivery sorafenib and USP22 shRNA (shUSP22) for synergetic HCC therapy. Sorafenib, entrapped in the Gal‐SLPs, induced a reactive oxygen species (ROS) cascade and triggered rapid shUSP22 release. Thus, Gal‐SLPs dramatically suppressed the expression of USP22. The downregulation of USP22 suppresses multidrug resistance‐associated protein 1 (MRP1) to induce intracellular sorafenib accumulation and hampers glycolysis of HCC cells. As a result, Gal‐SLPs efficiently inhibit the viability, proliferation, and colony formation of HCC cells. A sorafenib‐insensitive patient‐derived xenograft (PDX) model is established and adopted to evaluate in vivo antitumor effect of Gal‐SLPs. Gal‐SLPs exhibit potent antitumor efficiency and biosafety. Therefore, Gal‐SLPs are expected to have great potential in the clinical treatment of HCC.

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