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


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.
Greupink
Rick
R
Groningen University Institute for Drug Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.h.greupink@farm.rug.nl
Bakker
Hester I
HI
Reker-Smit
Catharina
C
van Loenen-Weemaes
Anne-miek
AM
Kok
Robbert-Jan
RJ
Meijer
Dirk K F
DK
Beljaars
Leonie
L
Poelstra
Klaas
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003459:Crystallins / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D004337:Drug Carriers; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008360:Mannosephosphates / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009173:Mycophenolic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D003459:Crystallins; D003893:Desmin; D004337:Drug Carriers; D005904:Glial Fibrillary Acidic Protein; D008360:Mannosephosphates; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; C027693:mannose-6-phosphate; D003094:Collagen; D009173:Mycophenolic Acid