Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China.
Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China.
Mol Pharm. 2020 Nov 2;17(11):4152-4162. doi: 10.1021/acs.molpharmaceut.0c00633. Epub 2020 Oct 22.
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. , 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 CCl-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.
肝纤维化是大多数慢性肝病的常见后果，但目前尚无临床批准的药物可用于治疗。先前的研究报告称，SB431542 作为 TGF-β信号通路抑制剂在肝纤维化治疗中具有潜力，但它的水溶性差，生物利用度低。在这里，我们使用两种 FDA 批准的辅料：大豆磷脂 S100 和 Solutol HS15 将 SB431542 载入脂质体（SB-Lips）中，从而改善了 SB431542 的这些特性。与游离 SB 相比，SB-Lips 对肝星状细胞 LX-2 的增殖和活化具有更强的抑制作用。在 CCl 诱导的肝纤维化小鼠模型中静脉注射后，SB-Lips 优先在肝脏中积累，其浓度-时间曲线下面积明显高于游离 SB431542，并且比游离药物更显著地缓解了肝纤维化，这与对 TGF-β信号的更大抑制作用有关。此外，SB-Lips 未对其他器官造成明显损伤。这些结果表明，我们的脂质体系统安全有效，可将 SB431542 递送至纤维化肝脏。
