BACKGROUND/AIMS: Hepatic stellate cell (HSC) activation and proliferation are key events in the pathology of liver fibrosis. Inhibiting these parameters, therefore, is a relevant option to treat liver fibrosis pharmacologically. The immunosuppressive drug mycophenolic acid (MPA) has been shown to inhibit proliferation and activation of various types of fibroblasts. In an effort to circumvent the immunosuppression and at the same time enhance this antifibrotic effect, we coupled MPA to the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin and evaluated this conjugate for its specificity and antifibrotic activity. METHODS/ RESULTS: We found that MPA inhibited proliferation of HSC in vitro. The drug coupled to the drug carrier bound specifically to HSC and reduced HSC proliferation in vitro. In vivo studies demonstrated that our conjugate accumulated selectively in the liver with significant uptake in HSC apart from Kupffer and endothelial cells, whereas primary and secondary lymphoid tissues were avoided. Treatment of bile duct-ligated rats with this conjugate reduced hepatic inflammation and hepatic alpha-beta-Crystallin mRNA expression, a marker for HSC activation. CONCLUSIONS: This study shows that targeted delivery of MPA to HSC results in a decrease in HSC activation, making it the first drug that is successfully delivered to this cell type.
BACKGROUND/AIMS: Hepatic stellate cell (HSC) activation and proliferation are key events in the pathology of liver fibrosis. Inhibiting these parameters, therefore, is a relevant option to treat liver fibrosis pharmacologically. The immunosuppressive drug mycophenolic acid (MPA) has been shown to inhibit proliferation and activation of various types of fibroblasts. In an effort to circumvent the immunosuppression and at the same time enhance this antifibrotic effect, we coupled MPA to the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin and evaluated this conjugate for its specificity and antifibrotic activity. METHODS/ RESULTS: We found that MPA inhibited proliferation of HSC in vitro. The drug coupled to the drug carrier bound specifically to HSC and reduced HSC proliferation in vitro. In vivo studies demonstrated that our conjugate accumulated selectively in the liver with significant uptake in HSC apart from Kupffer and endothelial cells, whereas primary and secondary lymphoid tissues were avoided. Treatment of bile duct-ligated rats with this conjugate reduced hepatic inflammation and hepatic alpha-beta-Crystallin mRNA expression, a marker for HSC activation. CONCLUSIONS: This study shows that targeted delivery of MPA to HSC results in a decrease in HSC activation, making it the first drug that is successfully delivered to this cell type.
Authors: Rick Greupink; Hester I Bakker; Harry van Goor; Martin H de Borst; Leonie Beljaars; Klaas Poelstra Journal: Pharm Res Date: 2006-08 Impact factor: 4.200
Authors: Werner I Hagens; Adriana Mattos; Rick Greupink; Alie de Jager-Krikken; Catharina Reker-Smit; Annemiek van Loenen-Weemaes; I Annette S H Gouw; Klaas Poelstra; Leonie Beljaars Journal: Pharm Res Date: 2007-03 Impact factor: 4.200