Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progression

Li Song; Chunyan Zhu; Qing Shi; Yuhan Xia; Xiayi Liang; Wen Qin; Tao Ye; Biwei Yang; Xin Cao; Jinglin Xia; Kun Zhang

doi:10.1016/j.ebiom.2024.105436

Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progression

EBioMedicine. 2024 Oct 29:109:105436. doi: 10.1016/j.ebiom.2024.105436. Online ahead of print.

Authors

Li Song¹, Chunyan Zhu², Qing Shi³, Yuhan Xia⁴, Xiayi Liang⁵, Wen Qin⁵, Tao Ye⁴, Biwei Yang¹, Xin Cao⁶, Jinglin Xia⁷, Kun Zhang⁸

Affiliations

¹ National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
² Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, Sichuan, China; Department of Stomatology and Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No. 301 Yanchangzhong Road, Shanghai, 200072, China.
³ Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, No. 2, Xuefu Lane, Wenzhou, 325000, Zhejiang, China.
⁴ Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, No. 170, Shensong Road, Shanghai, 200032, China.
⁵ Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, Sichuan, China.
⁶ Institute of Clinical Science, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China. Electronic address: [email protected].
⁷ National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China; Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, No. 2, Xuefu Lane, Wenzhou, 325000, Zhejiang, China. Electronic address: [email protected].
⁸ Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, Sichuan, China. Electronic address: [email protected].

PMID: 39476535
DOI: 10.1016/j.ebiom.2024.105436

Abstract

Background: Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis.

Methods: Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO₂ (HMnO₂). The conditions and capacity of HMnO₂ to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO₂@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO₂@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism.

Findings: The high adhesion and crosslinking of Zein with HMnO₂@DOX impart Zein-HMnO₂@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO₂ decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O₂ release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O₂ release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression.

Interpretation: This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation.

Funding: Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.

Keywords: Glycometabolism; Hepatocellular carcinoma; Hypoxia mitigation; Pro-metastatic microenvironment inhibition; Transcatheter arterial chemoembolization (TACE); Zein-based embolic agents.