Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progressionResearch in context
Li Song,
Chunyan Zhu,
Qing Shi,
Yuhan Xia,
Xiayi Liang,
Wen Qin,
Tao Ye,
Biwei Yang,
Xin Cao,
Jinglin Xia,
Kun Zhang
Affiliations
Li Song
National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
Chunyan Zhu
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
Qing Shi
Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, No. 2, Xuefu Lane, Wenzhou, 325000, Zhejiang, China
Yuhan Xia
Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, No. 170, Shensong Road, Shanghai, 200032, China
Xiayi Liang
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
Wen Qin
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
Tao Ye
Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, No. 170, Shensong Road, Shanghai, 200032, China
Biwei Yang
National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
Xin Cao
Institute of Clinical Science, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China; Corresponding author.
Jinglin Xia
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; Corresponding author. National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
Kun Zhang
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; Corresponding author.
Summary: 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.
