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

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.