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

  • Biomaterials. 2022 May;284:121512. doi: 10.1016/j.biomaterials.2022.121512.
Minjiang Chen  1 ,  Gaofeng Shu  2 ,  Xiuling Lv  2 ,  Xiaoling Xu  3 ,  Chenying Lu  2 ,  Enqi Qiao  2 ,  Shiji Fang  2 ,  Lin Shen  2 ,  Nannan Zhang  2 ,  Jun Wang  3 ,  Chunmiao Chen  2 ,  Jingjing Song  2 ,  Zhuang Liu  4 ,  Yongzhong Du  5 ,  Jiansong Ji  6
Affiliations
  • 1. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
  • 2. Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
  • 3. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 4. Institute of Functional Nano & Soft Materials (FUNSOM), Key Lab Carbon Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China. Electronic address: [email protected].
  • 5. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address: [email protected].
  • 6. Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. Electronic address: [email protected].
PMID: 35405577 DOI: 10.1016/j.biomaterials.2022.121512
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.

Keywords
Drug-loading microsphere; HIF-2α; Hepatocellular carcinoma; Polyvinyl alcohol; Transcatheter arterial chemoembolization.
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