National Medical Center & National Clinical Research Center for Interventional Medicine, Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
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.
EBioMedicine. 2024 Nov;109:105436. doi: 10.1016/j.ebiom.2024.105436. Epub 2024 Oct 30.
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.
Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO (HMnO). The conditions and capacity of HMnO to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO@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.
The high adhesion and crosslinking of Zein with HMnO@DOX impart Zein-HMnO@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO 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 O release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O 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.
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.
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.
目前，经导管动脉化疗栓塞术（TACE）治疗肝细胞癌（HCC）中使用的栓塞剂不稳定且容易泄漏，从而降低了 HCC 的 TACE 疗效。此外，临床 TACE 加重了缺氧和促转移的微环境，导致 HCC 患者预后不良。
本研究开发了基于玉米醇溶蛋白的栓塞剂，利用不溶于水但溶于乙醇的玉米醇溶蛋白包裹载多柔比星（DOX）的介孔中空 MnO（HMnO）。对 HMnO 生成活性氧（ROS）的条件和能力进行了检测。对 Zein-HMnO@DOX 的机械性能进行了评估，以评估其作为栓塞剂的潜力。进行了体外实验以评估 Zein-HMnO@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疗效，并探讨其潜在的抗肿瘤机制。
玉米醇溶蛋白与 HMnO@DOX 的高粘附性和交联性赋予了 Zein-HMnO@DOX 强大的机械强度，使其能够抵抗变形和洗脱。玉米醇溶蛋白凝胶化和 HMnO 在水和酸性肿瘤微环境中的分解分别使 DOX 持续释放和 Fenton 样反应产生活性氧（ROS）和 O 释放，从而执行 ROS 增强的 TACE。因此，基于玉米醇溶蛋白的栓塞剂优于临床使用的碘油，可显著抑制原位 HCC 的生长。更重要的是，O 释放下调缺氧诱导因子（HIF-1α）、血管内皮生长因子（VEGF）和葡萄糖转运蛋白 1（GLUT1），从而重新编程 TACE 加重的缺氧和促转移微环境，抑制 HCC 向肺部转移。机制探索表明，这种基于玉米醇溶蛋白的 TACE 制剂破坏了氧化应激、血管生成和糖代谢途径，从而抑制了 HCC 的进展。
这项创新性工作不仅为 HCC 提供了一种新的 TACE 药物，而且还建立了一种新的策略来改善 TACE 加重的缺氧和转移动力，以防止 HCC 在 TACE 手术后的常见转移。
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（Grant No. 82373086, 82102761）；温州市科技局重大科技创新项目（Grant No. ZY2021009）；上海青年拔尖人才。
