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

Greupink, A., Bakker, H., van Goor, H., de Borst, M. H., Beljaars, L. & Poelstra, K., Aug-2006, In : Pharmaceutical Research. 23, 8, p. 1827-1834 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1827-1834
Number of pages8
JournalPharmaceutical Research
Volume23
Issue number8
Publication statusPublished - Aug-2006

    Keywords

  • drug targeting, liver fibrosis, mycophenolic acid, TGR(mRen2)27 rats, vascular lesions, HEPATIC STELLATE CELLS, HUMAN ENDOTHELIAL-CELLS, MANNOSE 6-PHOSPHATE, AXIS COMPONENTS, FACTOR-BETA, RAT, MOFETIL, ACTIVATION, LIVER, ATHEROSCLEROSIS

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