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Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation.

ABSTRACT: Liver fibrosis currently represents a global health problem without effective pharmacotherapeutic strategies. The clinical translation of polydatin, a promising natural anti-fibrotic drug candidate with broad anti-inflammatory and antioxidant capabilities, remains a major challenge due to its limited water solubility and tissue absorption. Herein, a polydatin-loaded micelle (PD-MC) based on reactive oxygen species (ROS) and pH dual-sensitive block polymer PEG-P(PBEM-co-DPA) is developed. The micelle exerts great potential in improving the biocompatibility of polydatin and shows highly efficient liver-targeted drug release in response to the fibrotic microenvironment. Both in vitro and in vivo studies demonstrate that PD-MC can significantly suppress inflammatory response and oxidative stress, reduce hepatocyte apoptosis, and avert activation of macrophages and hepatic stellate cells. More excitingly, the blank micelle itself promotes the hepatic ROS consumption at the pathologic site to provide anti-inflammatory benefits. These favorable therapeutic virtues of targeting multiple cell types endow PD-MC with remarkable efficacy with minimal side effects in liver fibrosis treatment. Thus, PD-MC holds great potential to push forward the clinical application of polydatin in pharmacotherapeutic approaches against liver fibrosis.

SUBMITTER: Lin L

PROVIDER: S-EPMC7140994 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation.

Lin Liteng L Gong Hengye H Li Rui R Huang Jingjun J Cai Mingyue M Lan Tian T Huang Wensou W Guo Yongjian Y Zhou Zhimei Z An Yongcheng Y Chen Zhiwei Z Liang Licong L Wang Yong Y Shuai Xintao X Zhu Kangshun K

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200214 7

Liver fibrosis currently represents a global health problem without effective pharmacotherapeutic strategies. The clinical translation of polydatin, a promising natural anti-fibrotic drug candidate with broad anti-inflammatory and antioxidant capabilities, remains a major challenge due to its limited water solubility and tissue absorption. Herein, a polydatin-loaded micelle (PD-MC) based on reactive oxygen species (ROS) and pH dual-sensitive block polymer PEG-P(PBEM-<i>co</i>-DPA) is developed. ...[more]

PMID: 32274310

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Project description:Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.

Dataset Information

Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation.

Publications

Nanodrug with ROS and pH Dual-Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation.

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