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Long-Circulating Liposomal Delivery System Targeting at PDGFR-β Enhances the Therapeutic Effect of IFN-α on Hepatic Fibrosis

[ Vol. 23 , Issue. 20 ]

Author(s):

Qinghua Li*, Qi Yu, Jing Ju, Tiangeng You*, Zhiqiang Yan, Xiangli Nan, Jie Zhong and Jing E. Zhou   Pages 3034 - 3046 ( 13 )

Abstract:


Background: In this study, we developed a drug of IFN-α combined with pPB-SSLs, which specifically target at platelet-derived growth factor receptor-β (PDGFR-β).

Aim: The aim of this study is to improve the limitations of IFN-α including insufficient drug concentration for the target cells and side-effects causing serious concerns in treatment of hepatic fibrosis.

Methods: We constructed the targeted stable liposomes (SSLs) that not only increase the half-life period of IFN- α, but also can deliver IFN-α to hepatic stellate cells (HSCs). Subsequently, the anti-hepatic-fibrosis effect of pPB-SSL-IFN-α was evaluated both in vitro and in vivo. Immunofluorescent assay showed that the pPB-SSL particles were able to be easily taken up by 3T3 cells. The cellular distribution experiment demonstrated that most of the pPB-SSL-IFN-α would accumulate around the fibroblast, and the cell would be invaded by pPB-SSLIFN- α.

Results: The pPB-SSL-IFN-α showed an entrapment efficiency of 39.73 ± 5.21% for IFN-α and the particles reached nanoscale level. It showed more significant alleviated performance for hepatic fibrosis than IFN-α. Both in vitro and in vivo, the pPB-SSL-IFN-α could contribute to reduction or inhibition in the expression of TGF-β1 and α-SMA even cleavage of caspase-3. Moreover, it was found that the pPB-SSL-IFN-α induced the apoptosis of 3T3 cells by inhibiting the expression of TGF-β1 as well as α-SMA. Under observation for fibrotic liver of mice treated with pPB-SSL-IFN-α, the semiquantitative score for collagen I, TGF-β1 and α-SMA were all inferior to the control group and those treated with PEG-IFN-α, SSL-IFN-α or IFN-α. In addition, pPB-SSL-IFN-α has been detected to down-regulate the expression of TNF-α and IL-1β in comparison with model group (P<0.01). And the phosphorylations of JAK1 and STAT1 were enhanced by pPB-SSL-IFN-αin comparison with model groups (P < 0.01).

Conclusion: All results of our present research indicated that the pPB-SSL-IFN-α might be an alternative antiliver fibrotic drug and the synthetic method may offer a new access to the anti-hepatic fibrosis research and development.

Keywords:

Interferon-α, long-circulating liposomes, drug delivery, target, PDGFβR, hepatic fibrosis.

Affiliation:

Department of Hepatopancreatobiliary and Gastroenterology, Shanghai East Hospital, Tongji University, 1800 Yuntai Road, Pudong New District, Shanghai 200123, Department of Hepatopancreatobiliary and Gastroenterology, Shanghai East Hospital, Tongji University, 1800 Yuntai Road, Shanghai 200123, Department of Biochemistry and Molecular Biology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, Department of Hepatopancreatobiliary and Gastroenterology, Shanghai East Hospital, Tongji University, 1800 Yuntai Road, Pudong New District, Shanghai 200123, Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, 3663 Zhongshan Road (N), Shanghai 200062, Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, 3663 Zhongshan Road (N), Shanghai 200062, Department of Hepatopancreatobiliary and Gastroenterology, Shanghai East Hospital, Tongji University, 1800 Yuntai Road, Shanghai 200123, Institute of Biomedical Engineering and Technology, School of Chemistry and Molecular Engineering, East China Normal University, 3663 Zhongshan Road (N), Shanghai 200062



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