Sustained release hypoxia-activated prodrug-loaded BSA nanoparticles enhance transarterial chemoembolization against hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but facing the problem of low therapeutic effect. Conventional TACE formulations contain Lipiodol (LP) and chemotherapeutic agents characterized by burst release due to the unstable emulsion. Herein, we developed a novel TACE system by inducing bovine serum albumin (BSA) loaded hypoxia-activated prodrug (tirapazamine, TPZ) nanoparticle (BSA) for sustained drug release. In the rabbit VX2 liver cancer model, TACE treatment induced a long-term hypoxic tumor microenvironment as demonstrated by increased expression of HIF-1α in the tumor. BSA nanoparticles combined with LP greatly enhanced the anti-tumor effects of the TACE treatment. Compared to conventional TACE treatment, BSA nanoparticle-based TACE therapy more significantly delayed tumor progression and inhibited the metastases in the lungs. The effects could be partially mediated by the rebuilt immune responses, as BSA nanoparticle can served as an immunogenic cell death (ICD) inducer. Collectively, our results suggest that BSA nanoparticle-based TACE therapy could be a promising strategy to improve clinical outcomes for patients with HCC and provide a preclinical rationale for evaluating TPZ therapy in clinical studies.