HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma.

Abstract

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization.

• Authors: Minjiang Chen, Gaofeng Shu, Xiuling Lv, Xiaoling Xu, Chenying Lu, Enqi Qiao, Shiji Fang, Lin Shen, Nannan Zhang, Jun Wang, Chunmiao Chen, Jingjing Song, Zhuang Liu, Yongzhong Du, Jiansong Ji
• Journal: Biomaterials (Biomaterials) Vol. 284 Pg. 121512 (05 2022) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 35405577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Vascular Endothelial Growth Factor A
• Doxorubicin

Topics

• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Carcinoma, Hepatocellular (metabolism)
• Chemoembolization, Therapeutic
• Doxorubicin (pharmacology, therapeutic use)
• Humans
• Hypoxia (therapy)
• Liver Neoplasms (pathology)
• Microspheres
• Tumor Microenvironment
• Vascular Endothelial Growth Factor A (therapeutic use)