Characteristics of the hepatic stellate cell-selective carrier mannose 6-phosphate modified albumin (M6P(28)-HSA).
OBJECTIVE
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.


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.
Beljaars
L
L
Groningen University Institute for Drug Exploration, Groningen, The Netherlands. L.Beljaars@farm.rug.nl
Olinga
P
P
Molema
G
G
de Bleser
P
P
Geerts
A
A
Groothuis
G M
GM
Meijer
D K
DK
Poelstra
K
K
D000818:Animals; D002478:Cells, Cultured; D046508:Culture Techniques; D004337:Drug Carriers / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008360:Mannosephosphates / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000493:pharmacokinetics*
D004337:Drug Carriers; D007457:Iodine Radioisotopes; D008360:Mannosephosphates; D012709:Serum Albumin; C027693:mannose-6-phosphate