Document Detail

Characteristics of the hepatic stellate cell-selective carrier mannose 6-phosphate modified albumin (M6P(28)-HSA).
MedLine Citation:
PMID:  11589768     Owner:  NLM     Status:  MEDLINE    
BACKGROUND/AIMS: Drug targeting to hepatic stellate cells (HSC) may improve the pharmacological effects of antifibrotic drugs. Recently, albumin substituted with 28 mannose 6-phosphate moieties (M6P(28)-HSA) was found to distribute selectively to HSC in fibrotic rat livers. To assess whether this albumin can be used as a carrier for intracellular drug delivery, we explored the cellular handling of M6P(28)-HSA in HSC. METHODS/RESULTS: Application of competitive substrates for the M6P/IGFII receptor or other receptors showed that the binding of M6P-HSA to the M6P/IGFII receptor is specific. Binding was strong to activated HSC, but not to quiescent HSC. Furthermore, M6P(28)-HSA was extensively internalized by these cells. Using monensin, a specific inhibitor of the lysosomal pathway, proof was obtained that M6P-HSA is endocytosed via this route. The experiments performed with tissue slices, prepared from rat and human livers, revealed a specific binding and uptake of M6P(28)-HSA in both normal and cirrhotic livers. In livers from cirrhotic patients, HSC contributed predominantly to the uptake of this neoglycoprotein. CONCLUSIONS: Based on our in vivo data demonstrating the HSC-selectivity and on our in vitro data demonstrating binding and rapid internalization in activated HSC, we conclude that M6P(28)-HSA is applicable as a stellate cell-selective carrier for antifibrotic drugs that act intracellularly. This may have implications for the design of new strategies for the treatment of liver fibrosis.
L Beljaars; P Olinga; G Molema; P de Bleser; A Geerts; G M Groothuis; D K Meijer; K Poelstra
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Liver     Volume:  21     ISSN:  0106-9543     ISO Abbreviation:  Liver     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-08     Completed Date:  2001-10-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8200939     Medline TA:  Liver     Country:  Denmark    
Other Details:
Languages:  eng     Pagination:  320-8     Citation Subset:  IM    
Groningen University Institute for Drug Exploration, Groningen, The Netherlands.
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MeSH Terms
Cells, Cultured
Culture Techniques
Drug Carriers / pharmacokinetics*
Hepatocytes / metabolism*
Iodine Radioisotopes
Liver Cirrhosis, Experimental / drug therapy,  metabolism*
Mannosephosphates / pharmacokinetics*
Rats, Wistar
Serum Albumin / pharmacokinetics*
Reg. No./Substance:
0/Drug Carriers; 0/Iodine Radioisotopes; 0/Mannosephosphates; 0/Serum Albumin; 3672-15-9/mannose-6-phosphate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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