Mannose-6-phosphate/insulin-Like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells.

摘要

PURPOSE: 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.