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

IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-11-01 Epub Date: 2024-10-30 DOI:10.1016/j.ebiom.2024.105436
Li Song, Chunyan Zhu, Qing Shi, Yuhan Xia, Xiayi Liang, Wen Qin, Tao Ye, Biwei Yang, Xin Cao, Jinglin Xia, Kun Zhang
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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.

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凝胶栓塞剂可抑制临床 TACE 诱导的促转移微环境,防止肝细胞癌恶化。
背景:目前用于经导管动脉化疗栓塞术(TACE)治疗肝细胞癌(HCC)的栓塞剂存在不稳定性和易渗漏问题,导致残留HCC的TACE疗效打折扣。方法:在此,我们开发了基于Zein的栓塞剂,利用不溶于水但可溶于乙醇的Zein将多柔比星(Doxorubicin,DOX)载入介孔空心二氧化锰(Mesoporous hollow MnO2,HMnO2)。对 HMnO2 产生活性氧(ROS)的条件和能力进行了测定。对 Zein-HMnO2@DOX 进行了机械测试,以评估其作为栓塞剂的潜力。体外实验评估了 Zein-HMnO2@DOX 对 HCC 的影响。建立了皮下 HCC 小鼠模型和兔 VX2 HCC 模型,以研究其抗肿瘤和抗转移功效,并探索其潜在的抗肿瘤机制:研究结果:Zein与HMnO2@DOX的高粘附性和交联性使Zein-HMnO2@DOX具有很强的抗变形和抗冲刷的机械强度。Zein 的凝胶化和 HMnO2 在水和酸性肿瘤微环境中的分解,可使 DOX 持续释放,并通过 Fenton 类反应产生活性氧(ROS)和释放氧气,从而实施 ROS 增强型 TACE。因此,Zein 类栓塞剂在显著抑制原位 HCC 生长方面优于临床使用的脂碘。更重要的是,氧气释放能下调缺氧诱导因子(HIF-1α)、血管内皮生长因子(VEGF)和葡萄糖转运蛋白1(GLUT1),从而重新规划TACE加重的缺氧和促转移微环境,抑制HCC向肺部转移。机理探索发现,这种基于 Zein 的 TACE 药剂会破坏氧化应激、血管生成和糖代谢途径,从而抑制 HCC 的进展:这项创新性工作不仅为HCC提供了一种新的TACE制剂,而且针对临床上常见的TACE术后HCC转移,建立了一种改善TACE加重的缺氧和转移动力的新策略:国家自然科学基金优秀青年科学基金(82022033);国家自然科学基金(82373086、82102761);温州市科技局重大科技创新项目(ZY2021009);上海市青年拔尖人才。
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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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