Magnetic Vascular Embolic Agent for Enhanced Radiofrequency Ablation Therapy of Hepatocellular Carcinoma

Magnetic Vascular Embolic Agent for Enhanced Radiofrequency Ablation Therapy of Hepatocellular Carcinoma

Abstract

Radiofrequency ablation (RFA) is clinically adopted to destroy hepatocellular carcinoma, but often struggles to completely ablate large tumors and those with multiple metastatic sites. Vascular embolization has emerged as a crucial method to enhance local therapeutic efficacy. However, most patients fail to benefit from this combined treatment. The effectiveness of RFA combined with vascular embolization can paradoxically worsen anaerobic glycolysis and lactic acid accumulation, which is closely linked to suppressed immune responses. Therefore, strategically combining these treatments and inducing robust antitumor immune responses by eliminating anaerobic glycolysis-related immunosuppression is paramount.

Methods

To address this challenge, we developed a magnetic vascular embolic agent for vascular embolization, assisting RFA and inhibiting lactic acid production, thereby alleviating anaerobic glycolysis-associated immunological inhibition and augmenting the efficacy of combinational therapy. The magnetic vascular embolic agent is constructed by tannic acid (TA) functionalized mesoporous Fe3O4 carrying Zn2+, thrombin, and perfluoropentane (Thrombin-ZnTA-Fe3O4-PFP).

Results

By employing a magnetic targeting strategy with an external ferromagnet, we reduced the toxicity caused by the nonspecific distribution of thrombin and increased tumor-site accumulation of nanoparticles. The prepared Thrombin-ZnTA-Fe3O4-PFP could effectively embolize tumor vessels and enhance the efficacy of RFA. The released Zn2+ significantly attenuated lactic acid production through a ‘Zn-interference’ mechanism triggering NAD+ loss and glycolysis inhibition. The combinational therapy significantly inhibits lactic acid production and reverses its accumulation-related immunosuppressive microenvironment. Moreover, the combination of Thrombin-ZnTA-Fe3O4-PFP and anti-programmed cell death protein-1 antibody (aPD-1) immune checkpoint blockade induced a robust antitumor response against both primary tumors and distant tumors.

Conclusion

The as-prepared Thrombin-ZnTA-Fe3O4-PFP significantly embolizes tumor vessels and enhances the efficacy of RFA. The released Zn2+ inhibits lactic acid production and alleviates the lactic acid-induced immunosuppressive microenvironment. The combinational method can effectively combat orthotopic liver cancer without evident metastasis.

Questions:

1. How effective is the magnetic vascular embolic agent in enhancing the therapeutic efficacy of radiofrequency ablation and vascular embolization for hepatocellular carcinoma?
2. What is the mechanism behind the inhibition of lactic acid production by the released Zn2+ from the magnetic vascular embolic agent, and how does it alleviate the anaerobic glycolysis-associated immunological inhibition?
3. Can the combination of Thrombin-ZnTA-Fe3O4-PFP and anti-programmed cell death protein-1 antibody immune checkpoint blockade be applied to other types of cancer with distant metastases?