SB431542-Loaded Liposomes Alleviate Liver Fibrosis by Suppressing TGF-β Signaling,Molecular Pharmaceutics

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SB431542-Loaded Liposomes Alleviate Liver Fibrosis by Suppressing TGF-β Signaling
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-10-22 , DOI: 10.1021/acs.molpharmaceut.0c00633
Jinhang Zhang _{1,

2} , Rui Li _{1,

2} , Qinhui Liu ₁ , Jian Zhou _{1,

2} , Hui Huang _{1,

2} , Ya Huang _{1,

2} , Zijing Zhang _{1,

2} , Tong Wu _{1,

2} , Qin Tang _{1,

2} , Cuiyuan Huang _{1,

2} , Yingnan Zhao _{1,

2} , Guorong Zhang _{1,

2} , Li Mo ₃ , Yanping Li _{1,

2} , Jinhan He _{1,

2}

Affiliation

Liver fibrosis is a common outcome of most chronic liver diseases, but there is no clinically approved drug for its treatment. Previous studies have reported the potential of SB431542 as an inhibitor of TGF-β signaling in the treatment of liver fibrosis, but it shows poor water solubility and low bioavailability. Here, we improve these characteristics of SB431542 by loading it into liposomes (SB-Lips) with two FDA-approved excipients: soya phosphatidyl S100 and Solutol HS15. In vitro, SB-Lips had stronger inhibitory effects on the proliferation and activation of hepatic stellate cells LX-2 than free SB. After an intravenous injection in a CCl₄-induced liver fibrosis mouse model, SB-Lips accumulated preferentially in the liver, its area under the concentration–time curve was significantly higher than that of free SB431542, and it alleviated hepatic fibrosis significantly more than free drug, which was associated with greater inhibition of TGF-β signaling. Furthermore, SB-Lips did not cause significant injury to other organs. These results suggest that our liposomal system is safe and effective for delivering SB431542 to fibrotic liver.

中文翻译：

装载 SB431542 的脂质体通过抑制 TGF-β 信号传导减轻肝纤维化

肝纤维化是大多数慢性肝病的常见结果，但尚无临床批准的治疗药物。先前的研究报道了 SB431542 作为 TGF-β 信号抑制剂治疗肝纤维化的潜力，但它显示出水溶性差和生物利用度低。在这里，我们通过将 SB431542 加载到脂质体 (SB-Lips) 中来改进 SB431542 的这些特性，其中包含两种 FDA 批准的赋形剂：大豆磷脂酰 S100 和 Solutol HS15。在体外，SB-Lips对肝星状细胞LX-2的增殖和活化的抑制作用强于游离SB。CCl ₄静脉注射后在诱导肝纤维化小鼠模型中，SB-Lips 优先在肝脏中积累，其浓度-时间曲线下面积显着高于游离 SB431542，且对肝纤维化的缓解作用明显大于游离药物，与更大的抑制作用相关TGF-β 信号转导。此外，SB-Lips 不会对其他器官造成显着伤害。这些结果表明，我们的脂质体系统可安全有效地将 SB431542 递送至纤维化肝脏。

更新日期：2020-11-02

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