title: Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells.
abstract: The hallmark of liver fibrosis is an increased extracellular matrix deposition, caused by an activation of hepatic stellate cells (HSC). Therefore, this cell type is an important target for pharmacotherapeutic intervention. Antifibrotic drugs are not efficiently taken up by HSC or may produce unwanted side-effects outside the liver. Cell-specific delivery can provide a solution to these problems, but a specific drug carrier for HSC has not been described until now. The mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II) receptor, which is expressed in particular upon HSC during fibrosis, may serve as a target-receptor for a potential carrier. The aim of the present study was to examine if human serum albumin (HSA) modified with mannose 6-phosphate (M6P) is taken up by HSC in fibrotic livers. A series of M6Px-modified albumins were synthetized: x = 2, 4, 10, and 28. Organ distribution studies were performed to determine total liver uptake. The hepatic uptake of M6Px-HSA increased with increasing M6P density. M6Px-HSA with a low degree of sugar loading (x = 2-10) remained in the plasma and accumulated for 9% +/- 0.5% or less in fibrotic rat livers. An increase in the molar ratio of M6P:HSA to 28:1 caused an increased liver accumulation to 59% +/- 9% of the administered dose. Furthermore, we determined quantitatively the in vivo intrahepatic distribution of M6Px-HSA using double-immunostaining techniques. An increased substitution of M6P was associated with an increased accumulation in HSC; 70% +/- 11% of the intrahepatic staining for M6P28-HSA was found in HSC. We also demonstrate that M6P-modified bovine serum albumin (BSA) accumulates in slices of normal and cirrhotic human livers. After incubation of this neoglycoprotein with human tissue, the protein is found in nonparenchymal liver cells. Because M6P-modified albumins are taken up by HSC in fibrotic livers, this neoglycoprotein can be applied as a selective drug carrier for HSC. This technology may create new opportunities for the pharmacological intervention of liver fibrosis.
authors.affiliation: Groningen Utrecht Institute for Drug Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen, The Netherlands. L.Beljaars@farm.rug.nl
authors.forename: L
authors.initials: L
authors.lastname: Beljaars
authors.forename: G
authors.initials: G
authors.lastname: Molema
authors.forename: B
authors.initials: B
authors.lastname: Weert
authors.forename: H
authors.initials: H
authors.lastname: Bonnema
authors.forename: P
authors.initials: P
authors.lastname: Olinga
authors.forename: G M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
authors.forename: K
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000818:Animals; D004337:Drug Carriers; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008297:Male; D008360:Mannosephosphates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012709:Serum Albumin / Q000187:drug effects* / Q000493:pharmacokinetics; D012710:Serum Albumin, Bovine / Q000187:drug effects / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D004337:Drug Carriers; D008360:Mannosephosphates; D012709:Serum Albumin; D012710:Serum Albumin, Bovine; C027693:mannose-6-phosphate