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Published on: September 12, 2019
Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular
Shengjun Xu1,2,3, Sunbin Ling1,2,3, Qiaonan Shan2,3
1Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310006 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.
Insights
This study introduces a novel nanoplatform (Gal-SLPs) that co-delivers sorafenib and USP22 shRNA to overcome sorafenib resistance in hepatocellular carcinoma (HCC). The nanoplatform effectively reverses cancer stemness and enhances therapeutic outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Sorafenib resistance is a major challenge in hepatocellular carcinoma (HCC) treatment.
- Cancer stemness and multidrug resistance (MDR), influenced by Ubiquitin-specific protease 22 (USP22), contribute significantly to sorafenib resistance.
- Effective strategies to reverse cancer stemness are crucial for advancing HCC therapeutics.
Purpose of the Study:
- To develop a novel nanoplatform for co-delivery of sorafenib and USP22 shRNA to synergistically treat HCC.
- To investigate the mechanism by which the nanoplatform overcomes sorafenib resistance by targeting cancer stemness and MDR.
- To evaluate the in vitro and in vivo efficacy and biosafety of the developed nanoplatform.
Main Methods:
- Development of a galactose-decorated lipopolyplex (Gal-SLP) nanoplatform for targeted co-delivery of sorafenib and USP22 shRNA.
- Sorafenib-induced reactive oxygen species (ROS) cascade to trigger shUSP22 release and subsequent USP22 downregulation.
- Assessment of Gal-SLP effects on HCC cell viability, proliferation, colony formation, and MRP1/glycolysis pathways.
- Evaluation of in vivo antitumor efficacy using a sorafenib-insensitive patient-derived xenograft (PDX) model.
Main Results:
- Gal-SLPs successfully co-delivered sorafenib and shUSP22, leading to suppressed USP22 expression.
- USP22 downregulation by Gal-SLPs reduced MRP1 expression, enhancing intracellular sorafenib accumulation and inhibiting glycolysis.
- Significant inhibition of HCC cell viability, proliferation, and colony formation was observed.
- In vivo studies demonstrated potent antitumor efficiency and good biosafety of Gal-SLPs in a PDX model.
Conclusions:
- The developed Gal-SLP nanoplatform effectively overcomes sorafenib resistance in HCC by targeting cancer stemness and MDR.
- Co-delivery of sorafenib and shUSP22 via Gal-SLPs offers a promising synergistic therapeutic strategy for HCC.
- Gal-SLPs exhibit significant potential for clinical application in treating hepatocellular carcinoma.
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