Sun Gangqi, Hou Xiaojuan, Zhang Luyao, Zhang Hengyan, Shao Changchun, Li Fengwei, Zong Chen, Li Rong, Shi Junxia, Yang Xue, Zhang Li
Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.
Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China.
Front Oncol. 2022 May 10;12:877982. doi: 10.3389/fonc.2022.877982. eCollection 2022.
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.
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 . 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.
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.
T3-lipo may suppress hepatocarcinogenesis by regulating the inflammatory microenvironment in the liver and reduce the cardiac side effects meanwhile.
肝细胞癌（HCC）是一种炎症相关癌症。肝脏的持续性炎症损伤是介导肝癌发生和发展的重要因素。肝巨噬细胞在炎症微环境中起重要作用，介导肿瘤免疫逃逸、肿瘤生长和转移。先前的研究表明，L-3,5,3-三碘甲状腺原氨酸（T3）可调节炎症；然而，其使用与严重的心脏副作用相关，其在肝癌发生中的作用仍不清楚。在本研究中，我们旨在开发一种具有降低心脏毒性的有效T3递送系统，并探讨其对HCC发生的影响。
采用薄膜水化法制备T3脂质体（T3-lipo），并评估其特性，包括粒径、多分散指数、zeta电位、包封率、载药量、药物释放和稳定性。我们评估了T3-lipo对二乙基亚硝胺（DEN）诱导的大鼠原发性HCC发生的影响，并通过高效液相色谱-质谱法检测了T3和T3-lipo的生物分布。此外，我们通过免疫组织化学和免疫荧光分析、生物芯片分析、实时聚合酶链反应分析和蛋白质印迹分析，探讨了T3-lipo在肝癌发生中的潜在分子机制。
与T3相比，T3-lipo对DEN诱导的大鼠原发性HCC发生具有增强的抑制作用，并减少了心脏副作用。机制上，T3-lipo被肝巨噬细胞吸收，并通过抑制炎症信号通路调节巨噬细胞中炎症细胞因子的分泌。
T3-lipo可能通过调节肝脏炎症微环境抑制肝癌发生，同时减少心脏副作用。
