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

Qing Shi; Xingxing Zhang; Minmin Wu; Yuhan Xia; Yating Pan; Jialu Weng; Na Li; Xingjie Zan; Jinglin Xia

doi:10.1016/j.mtbio.2023.100873

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

Mater Today Bio. 2023 Nov 29:23:100873. doi: 10.1016/j.mtbio.2023.100873. eCollection 2023 Dec.

Authors

Qing Shi¹, Xingxing Zhang^{1

2}, Minmin Wu¹, Yuhan Xia¹, Yating Pan¹, Jialu Weng¹, Na Li^{1

3}, Xingjie Zan^{1

3}, Jinglin Xia^{1

4

5}

Affiliations

¹ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
² Shanghai University of Medicine ＆ Health Sciences Affiliated Sixth People＇s Hospital South Compus, Shanghai, 201499, China.
³ Wenzhou Institute, Wenzhou Key Laboratory of Perioperative Medicine, University of Chinese Academy of Sciences, Wenzhou, 325001, China.
⁴ Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
⁵ National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.

Abstract

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. In vitro 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.

Keywords: Doxorubicin; Hexahistidine-metal; Liver cancer; Transcatheter arterial chemoembolization; pH-sensitive nanoparticles.