An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis

JOURNAL OF CONTROLLED RELEASE

卷:303

Article

Li, Yanping^1,2  Pu, Shiyun^1,2  Liu, Qinhui¹  Li, Rui^1,2  Zhang, Jinhang^1,2  Wu, Tong^1,2  Chen, Lei^1,2  Li, Hong^1,2  Yang, Xuping^1,2  Zou, Min²  Xiao, Jia³  Xie, Wen^4,5  He, Jinhan^1,2 

[1] Sichuan Univ, West China Hosp, Lab Clin Pharm & Adverse Drug React, Chengdu, Sichuan, Peoples R China

[2] Sichuan Univ, West China Hosp, Dept Pharm, Chengdu, Sichuan, Peoples R China

[3] Jinni Univ, Guangzhou Overseas Chinese Hosp, Inst Clin Sci, Guangzhou, Guangdong, Peoples R China

[4] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA

[5] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA

关键词: Hepatic stellate cells;    Therapeutic agent;    Nanoparticle;    Targeted delivery;   

DOI  :  10.1016/j.jconrel.2019.04.022

来源: Elsevier

【 摘 要 】

Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin alpha v beta 3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to alpha v beta 3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of alpha v beta 3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegibloaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.

【 授权许可】

Free