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

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

  • J Control Release. 2019 Jun 10;303:77-90. doi: 10.1016/j.jconrel.2019.04.022.
Yanping Li 1,  Shiyun Pu 1,  Qinhui Liu 2,  Rui Li 1,  Jinhang Zhang 1,  Tong Wu 1,  Lei Chen 1,  Hong Li 1,  Xuping Yang 1,  Min Zou 3,  Jia Xiao 4,  Wen Xie 5,  Jinhan He 6
Affiliations

Affiliations

  • 1 Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China.
  • 2 Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China.
  • 3 Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China.
  • 4 Institute of Clinical Science, Guangzhou Overseas Chinese Hospital, Jinan University, Guangzhou, China.
  • 5 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wex6@pitt.edu.
  • 6 Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China. Electronic address: jinhanhe@scu.edu.cn.
PMID: 31004666 DOI: 10.1016/j.jconrel.2019.04.022
Abstract

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 αvβ3. Thus we established sterically stable liposomes that contain the cyclic Peptides (cRGDyK) with a high affinity to αvβ3 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 αvβ3. 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 vismodegib-loaded 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.

Keywords

Hepatic stellate cells; Nanoparticle; Targeted delivery; Therapeutic agent.

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