Mannose-6-phosphate/insulin-Like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells.
OBJECTIVE
The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively deliver drugs to these cells.


METHODS
We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.


RESULTS
M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.


CONCLUSIONS
M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA.
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. rick_greupink@hotmail.com
Bakker
Hester I
HI
van Goor
Harry
H
de Borst
Martin H
MH
Beljaars
Leonie
L
Poelstra
Klaas
K
D016475:3T3 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003135:Common Bile Duct / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008026:Ligation; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D008360:Mannosephosphates / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000903:Antibiotics, Antineoplastic; D008360:Mannosephosphates; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D004247:DNA; D009173:Mycophenolic Acid