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连翘酯苷A-透明质酸复合乳源外泌体的制备及其抗肝纤维化作用

Preparation of Phillygenin-Hyaluronic acid composite milk-derived exosomes and its anti-hepatic fibrosis effect.

作者信息

Gong Lihong, Zhou Honglin, Zhang Yafang, Wang Cheng, Fu Ke, Ma Cheng, Li Yunxia

机构信息

State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of StandardizatAion for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.

出版信息

Mater Today Bio. 2023 Sep 16;23:100804. doi: 10.1016/j.mtbio.2023.100804. eCollection 2023 Dec.

DOI:10.1016/j.mtbio.2023.100804
PMID:37753374
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10518489/
Abstract

Liver fibrosis remains a serious problem affecting the health of millions of people worldwide. Hepatic stellate cells (HSCs) are the main effector cells in liver fibrosis and their activation could lead to extracellular matrix deposition, which may aggravate the development of liver fibrosis and inflammation. Previous studies have reported the potential of Phillygenin (PHI) as a hepatoprotective agent to inhibit HSCs activation and fibrosis development. However, the poor water solubility of PHI hinders its clinical application as a potential anti-liver fibrosis therapy. Milk-derived exosomes (mEXO) serve as scalable nanocarriers for delivering chemotherapeutic agents due to their excellent biocompatibility. Here, we developed a PHI-Hyaluronic acid (HA) composite mEXO (PHI-HA-mEXO) drug delivery system, in which DSPE-PEG2000-HA was conjugated to the surface of mEXO to prepare HA-mEXO, and PHI was encapsulated into HA-mEXO to form PHI-HA-mEXO. As a specific receptor for HA, CD44 is frequently over-expressed during liver fibrosis and highly expressed on the surface of activated HSCs (aHSCs). PHI-HA-mEXO can bind to CD44 and enter aHSCs through endocytosis and release PHI. PHI-HA-mEXO drug delivery system can significantly induce aHSCs death without affecting quiescent HSCs (qHSCs) and hepatocytes. Furthermore, we carried out in vitro and in vivo experiments and found that PHI-HA-mEXO could alleviate liver fibrosis through aHSCs-targeted mechanism. In conclusion, the favorable biosafety and superior anti-hepatic fibrosis effects suggest a promising potential of PHI-HA-mEXO in the treatment of hepatic fibrosis. However, detailed pharmokinetics and dose-responsive experiments of PHI-HA-mEXO and the mechanism of mEXO loading drugs are still required before PHI-HA-mEXO can be applied clinically.

摘要

肝纤维化仍然是一个严重的问题，影响着全球数百万人的健康。肝星状细胞（HSCs）是肝纤维化中的主要效应细胞，其激活会导致细胞外基质沉积，这可能会加剧肝纤维化和炎症的发展。先前的研究报道了连翘酯苷（PHI）作为一种肝保护剂具有抑制肝星状细胞激活和纤维化发展的潜力。然而，PHI的水溶性差阻碍了其作为潜在抗肝纤维化疗法的临床应用。牛奶来源的外泌体（mEXO）由于其优异的生物相容性，可作为递送化疗药物的可扩展纳米载体。在此，我们开发了一种PHI-透明质酸（HA）复合mEXO（PHI-HA-mEXO）药物递送系统，其中DSPE-PEG2000-HA与mEXO表面偶联以制备HA-mEXO，并且将PHI封装到HA-mEXO中以形成PHI-HA-mEXO。作为HA的特异性受体，CD44在肝纤维化期间经常过度表达，并在激活的肝星状细胞（aHSCs）表面高度表达。PHI-HA-mEXO可以与CD44结合，并通过内吞作用进入aHSCs并释放PHI。PHI-HA-mEXO药物递送系统可以显著诱导aHSCs死亡，而不影响静止的肝星状细胞（qHSCs）和肝细胞。此外，我们进行了体外和体内实验，发现PHI-HA-mEXO可以通过靶向aHSCs的机制减轻肝纤维化。总之，良好的生物安全性和优异的抗肝纤维化作用表明PHI-HA-mEXO在治疗肝纤维化方面具有广阔的应用前景。然而，在PHI-HA-mEXO能够临床应用之前，仍需要对其进行详细的药代动力学和剂量反应实验以及mEXO载药机制的研究。

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