Self-fueling ferroptosis-inducing microreactors based on pH-responsive Lipiodol Pickering emulsions enable transarterial ferro-embolization therapy

Lipiodol chemotherapeutic emulsions remain one of the main choices for the treatment of unresectable hepatocellular carcinoma (HCC) via transarterial chemoembolization (TACE). However, the limited stability of Lipiodol chemotherapeutic emulsions would lead to rapid drug diffusion, which would reduce the therapeutic benefit and cause systemic toxicity of administrated chemotherapeutics. Therefore, the development of enhanced Lipiodol-based formulations is of great significance to enable effective and safe TACE treatment. Herein, a stable water-in-oil Lipiodol Pickering emulsion (LPE) stabilized by pH-dissociable calcium carbonate nanoparticles and hemin is prepared and utilized for efficient encapsulation of lipoxygenase (LOX). The obtained LOX-loaded CaCO3&hemin-stabilized LPE (LHCa-LPE) showing greatly improved emulsion stability could work as a pH-responsive and self-fueling microreactor to convert polyunsaturated fatty acids (PUFAs), a main component of Lipiodol, to cytotoxic lipid radicals through the cascading catalytic reaction driven by LOX and hemin, thus inducing ferroptosis of cancer cells. As a result, such LHCa-LPE upon transcatheter embolization can effectively suppress the progression of orthotopic N1S1 HCC in rats. This study highlights a concise strategy to prepare pH-responsive and stable LPE-based self-fueling microreactors, which could serve as bifunctional embolic and ferroptosis-inducing agents to enable proof-of-concept transarterial ferro-embolization therapy of HCC.

Automated summary

This study presents the development of a stable water-in-oil Lipiodol Pickering emulsion (LPE) for efficient encapsulation of lipoxygenase (LOX). The pH-responsive and self-fueling microreactor, LOX-loaded CaCO3&hemin-stabilized LPE (LHCa-LPE), showed greatly improved emulsion stability. By converting polyunsaturated fatty acids (PUFAs) to cytotoxic lipid radicals, this microreactor effectively induced ferroptosis of cancer cells and suppressed the progression of hepatocellular carcinoma (HCC) in rat models. This research provides a concise strategy for the preparation of pH-responsive and stable LPE-based self-fueling microreactors, which can serve as embolic and ferroptosis-inducing agents for transarterial ferro-embolization therapy of HCC.