Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell

• Published in: Journal of hepatology Vol. 43; no. 5; pp. 884 - 892
• Main Authors: Greupink, Rick, Bakker, Hester I., Reker-Smit, Catharina, van Loenen-Weemaes, Anne-miek, Kok, Robbert-Jan, Meijer, Dirk K.F., Beljaars, Leonie, Poelstra, Klaas
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.11.2005; Elsevier
• Subjects: Activation of hepatic stellate cells; Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Proliferation - drug effects; Collagen - metabolism; Crystallins - genetics; Crystallins - metabolism; Delivery. Postpartum. Lactation; Desmin - metabolism; Drug Carriers; Drug targeting; Fibrosis - drug therapy; Fibrosis - pathology; Glial Fibrillary Acidic Protein - metabolism; Gynecology. Andrology. Obstetrics; Hepatic stellate cell; Hepatocytes - cytology; Hepatocytes - drug effects; Humans; Immunomodulators; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver fibrosis; Male; Mannosephosphates - chemistry; Mannosephosphates - metabolism; Medical sciences; Molecular Structure; Mycophenolic acid; Mycophenolic Acid - chemistry; Mycophenolic Acid - metabolism; Mycophenolic Acid - pharmacology; Mycophenolic Acid - therapeutic use; Pharmacology. Drug treatments; Proliferation of hepatic stellate cells; Protein Isoforms - genetics; Protein Isoforms - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Tissue Distribution; Mycophenolic acid; DAB; Activation of hepatic stellate cells; M6P-HSA-MPA; Liver fibrosis; M6P-HSA; Hep; KC; Drug targeting; HSC; Hepatic stellate cell; Proliferation of hepatic stellate cells; EC; MPA; Spider cell; Immunomodulator; Antibiotic; Liver; Antiviral; Delivery; Immunosuppressive agent
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2005.04.014

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. 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 α-β-Crystallin mRNA expression, a marker for HSC activation. 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.