Redox-responsive biocompatible nanocarriers based on novel heparosan polysaccharides for intracellular anticancer drug delivery

Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine-vitamin E succinate(KSV) micelle system was constructed for intracellular delivery of doxorubicin(DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer(KV) was synthesized as control. DOX-loaded micelles(DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity.

The landscape of UBE2S in hepatocellular carcinoma: Prognostic significance, immuno-oncology feature and drug response

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide.1 E2 ubiquitin conjugating enzymes (UBE2) are potential therapeutic targets in tumors arising from genomic instability and tumor microenvironment (TME).2,3 UBE2S, an important UBE2, has demonstrated strong oncogenic activities in various malignant cancers, including HCC. However, a comprehensive study regarding its role in HCC is still absent, and its association with immunology and drug response of HCC is still unclear. In this study, we conducted a pan-cancer analysis of UBE2S expression and prognosis, carried out enrichment analysis of UBE2S-associated genes, and analyzed association between UBE2S expression and HCC microenvironment, stemness and drug response. Collectively, our results demonstrated that UBE2S expression was significantly increased in multiple types of cancer, including HCC, and harbors prognostic values for HCC. Potential function of UBE2S involves modulation of ubiquitin mediated proteolysis and cell cycle progression. Furthermore, in HCC, UBE2S expression was positively correlated with TME infiltration, microsatellite instability (MSI), DNA methylation, stemness and drug response. These findings highlighted the possible pivotal roles of UBE2S in HCC prognosis, precision immunotherapy and drug response.