Emulsifying Lipiodol with pH-sensitive DOX@HmA nanoparticles for hepatocellular carcinoma TACE treatment eliminate metastasis.

Lipiodol-based transcatheter arterial chemoembolization (TACE) is currently the predominant and first-line treatment option recommended by the global standard for unresectable hepatocellular carcinoma (HCC). However, the unstable emulsion of Lipiodol causes a substantial proportion of chemotherapy drugs to enter the circulation system, leading to poor accumulation in cancer tissues and unexpected side effects of chemotherapy drugs. Herein, we emulsified Lipiodol with a pH-sensitive drug delivery system assembled from hexahistidine and zinc ions (HmA) with a super-high loading capacity of doxorubicin (DOX) and a promising ability to penetrate bio-barriers for the effective treatment of HCC by TACE. tests showed that DOX@HmA was comparable to free DOX in killing HCC cells. Impressively, during the in vivo TACE treatment, the anti-tumor efficacy of DOX@HmA was significantly greater than that of free DOX, indicating that DOX@HmA increased the accumulation of DOX in tumor. Emulsifying Lipiodol with pH-sensitive DOX@HmA significantly inhibited cell regeneration and tumor angiogenesis and decreased the systemic side effects of chemotherapy, especially by suppressing pulmonary metastasis in liver VX2 tumors in rabbits by inhibiting epithelial-mesenchymal transition (EMT). Emulsifying tumor microenvironment-responsive drug delivery systems (DDSs) with Lipiodol could be a new strategy for clinical TACE chemotherapy with potentially enhanced HCC treatment.