Shengjun Xu1,2,3, Sunbin Ling1,2,3, Qiaonan Shan2,3, Qianwei Ye2,3, Qifan Zhan2,3, Guangjiang Jiang2,3, Jianyong Zhuo2,3, Binhua Pan2,3, Xue Wen4, Tingting Feng5, Haohao Lu6, Xuyong Wei1,2,3, Haiyang Xie3, Shusen Zheng2,3,7, Jiajia Xiang8, Youqing Shen8, Xiao Xu1,2,3. 1. Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310006 China. 2. Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 China. 3. NHC Key Lab of Combined Multi-Organ Transplantation Hangzhou Zhejiang 310003 China. 4. Department of Pathology the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 China. 5. Department of Abdominal Medical Oncology Zhejiang Cancer Hospital Hangzhou Zhejiang 310022 China. 6. Department of Polymer Science and Engineering Zhejiang University Hangzhou Zhejiang 310027 China. 7. Department of Hepatobiliary and Pancreatic Surgery Shulan (Hangzhou) Hospital Hangzhou Zhejiang 310000 China. 8. Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education College of Chemical and Biological Engineering Zhejiang University Hangzhou Zhejiang 310027 China.
Abstract
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.
Resistance to n class="Chemical">sorafenib severely hinpan>ders its effectiveness againpan>st n class="Disease">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.
Authors: Li Liu; Yichen Cao; Charles Chen; Xiaomei Zhang; Angela McNabola; Dean Wilkie; Scott Wilhelm; Mark Lynch; Christopher Carter Journal: Cancer Res Date: 2006-12-15 Impact factor: 12.701
Authors: Jennifer J McCann; Irina A Vasilevskaya; Neermala Poudel Neupane; Ayesha A Shafi; Christopher McNair; Emanuela Dylgjeri; Amy C Mandigo; Matthew J Schiewer; Randy S Schrecengost; Peter Gallagher; Timothy J Stanek; Steven B McMahon; Lisa D Berman-Booty; William F Ostrander; Karen E Knudsen Journal: Cancer Res Date: 2019-11-18 Impact factor: 12.701