3,5,3'-Triiodothyronine-Loaded Liposomes Inhibit Hepatocarcinogenesis Via Inflammation-Associated Macrophages

Gangqi Sun; Xiaojuan Hou; Luyao Zhang; Hengyan Zhang; Changchun Shao; Fengwei Li; Chen Zong; Rong Li; Junxia Shi; Xue Yang; Li Zhang

doi:10.3389/fonc.2022.877982

3,5,3'-Triiodothyronine-Loaded Liposomes Inhibit Hepatocarcinogenesis Via Inflammation-Associated Macrophages

Front Oncol. 2022 May 10:12:877982. doi: 10.3389/fonc.2022.877982. eCollection 2022.

Authors

Gangqi Sun^{1

2}, Xiaojuan Hou^{3

4}, Luyao Zhang^{2

5}, Hengyan Zhang², Changchun Shao⁶, Fengwei Li⁷, Chen Zong^{3

4}, Rong Li⁸, Junxia Shi^{3

4}, Xue Yang^{3

4}, Li Zhang^{1

2}

Affiliations

¹ Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.
² Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China.
³ Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.
⁴ Department of Tumor Immunity and Metabolism,The National Center for Liver Cancer, Shanghai, China.
⁵ School of Pharmacy, Anhui Medical University, Hefei, China.
⁶ Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁷ Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁸ Laboratory Zone, Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Naval Medical University, Shanghai, China.

Abstract

Background: Hepatocellular carcinoma (HCC) is inflammation-related cancer. Persistent inflammatory injury of the liver is an important factor mediating the occurrence and development of liver cancer. Hepatic macrophages play an important role in the inflammatory microenvironment, which mediates tumor immune escape, tumor growth, and metastasis. Previous studies have suggested that L-3,5,3-triiodothyronine (T3) can regulate inflammation; however, its use is associated with serious cardiac side effects, and its role in hepatocarcinogenesis remains unclear. In this study, we aimed to develop an effective T3 delivery system with reduced cardiac toxicity and to explore its effects on HCC occurrence.

Methods: T3 liposomes (T3-lipo) were prepared using the thin-film hydration method, and their characteristics, including particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading, drug release, and stability, were evaluated in vitro. We assessed the effect of T3-lipo on hepatocarcinogenesis in diethylnitrosamine (DEN)-induced primary HCC in rats and examined the biodistribution of T3 and T3-lipo by high-performance liquid chromatography-mass spectrometry. Furthermore, we explored the potential molecular mechanism of T3-lipo in hepatocarcinogenesis by immunohistochemistry and immunofluorescence analyses, Bio-Plex assays, real-time polymerase chain reaction analysis, and Western blotting assays.

Results: Compared with T3, T3-lipo had an enhanced inhibitory effect on hepatocarcinogenesis and reduced cardiac side effects in DEN-induced primary HCC in rats. Mechanistically, T3-lipo were absorbed by hepatic macrophages and regulated the secretion of inflammatory cytokines in macrophages by inhibiting inflammatory signaling pathways.

Conclusions: T3-lipo may suppress hepatocarcinogenesis by regulating the inflammatory microenvironment in the liver and reduce the cardiac side effects meanwhile.

Keywords: 3,5,3′-triiodothyronine; hepatocarcinogenesis; inflammation; liposome; macrophage.