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. 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.
Materials and Methods/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 α-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.
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Abbreviations
- BrdU:
-
bromodeoxy uridine
- HSC:
-
hepatic stellate cell
- MPA:
-
mycophenolic acid
- M6PHSA:
-
mannose-6-phosphate-modified human serum albumin
- M6P/IGF-IIR:
-
mannose-6-phosphate/insulin-like growth factor-II receptor
- PBS:
-
phosphate buffered saline
- Ren2:
-
TGR(mRen2)27 transgenic rats
- α-sma:
-
α-smooth muscle actin
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Acknowledgments
This study was financially supported by the Dutch Foundation for Technical Sciences (STW), grant no GFA.5460. Prof. D.K.F. Meijer is gratefully acknowledged for valuable scientific discussion and review of the manuscript.
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Greupink, R., Bakker, H.I., van Goor, H. et al. Mannose-6-Phosphate/Insulin-Like Growth Factor-II Receptors may Represent a Target for the Selective Delivery of Mycophenolic Acid to Fibrogenic Cells. Pharm Res 23, 1827–1834 (2006). https://doi.org/10.1007/s11095-006-9025-2
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DOI: https://doi.org/10.1007/s11095-006-9025-2