Calcification-Mediated Dual-Starvation and Immune Activation for Transarterial Chemoembolization
Yanqiao Ren1,2,3, Bo Sun1,2,3, Chao Chen1,2,3
1Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People's Republic of China.
Introduction:
Transarterial chemoembolization (TACE) remains a cornerstone therapy for hepatocellular carcinoma (HCC), but its efficacy is frequently limited by inadequate drug penetration and tumor dissemination.
Methods:
We developed a thermosensitive PND nanogel co-encapsulating tirapazamine (TPZ) and folic acid (FA), TPZ/FA@PND. The system was evaluated for sustained drug release, physiological temperature-triggered sol-gel transition, in vitro antitumor effects under normoxia and hypoxia, calcification induction, biocompatibility, and in vivo therapeutic efficacy in a VX2 tumor-bearing rabbit TACE model.
Results:
TPZ/FA@PND showed sustained release and physiological temperature-triggered gelation. In vitro, TPZ/FA@PND inhibited tumor cell proliferation, migration, and invasion under hypoxia while inducing extracellular calcification, with negligible hemolysis and minimal hepatotoxicity. In vivo, TPZ/FA@PND delivered via TACE achieved complete embolization, induced marginal calcification, reduced metastasis, inhibited VEGF and MMP-9 expression, enhanced CD8+ T-cell infiltration, and promoted systemic antitumor immunity.
Discussion:
This dual-starvation nanogel strategy integrates embolization, calcification-mediated containment, and immune activation, offering a clinically translatable approach to improve the therapeutic efficacy and long-term outcomes of TACE for HCC.
