Targeting of sugar- and charge-modified albumins to fibrotic rat livers: the accessibility of hepatic cells after chronic bile duct ligation.
OBJECTIVE
In normal rat livers, cell-selective delivery of drugs to hepatocytes, endothelial cells and Kupffer cells can be achieved by coupling drugs to lactosaminated human serum albumin (lacHSA), succinylated HSA (sucHSA) and mannosylated HSA (manHSA), respectively. Since fibrosis is associated with increased matrix deposition and sinusoidal capillarization, and since these modified albumins may serve as carriers for anti-fibrotic drugs, we determined the hepatic disposition of these albumins in rats with liver fibrosis.


METHODS
At different time points after bile duct ligation, a bolus dose of either lacHSA, sucHSA or manHSA (fluorescein labelled) was intravenously injected and pharmacokinetic parameters were determined. Organ distributions of the 125I-labelled carriers were assessed in normal and fibrotic rats. In addition, their intrahepatic distributions were determined by immunohistochemical inspection.


RESULTS
In rats with liver fibrosis, the plasma disappearance rate of the three proteins was significantly altered as compared to control rats. A moderately decreased clearance for lacHSA, an increased plasma clearance for manHSA and sucHSA, and an increased volume of distribution for all three proteins was found. Despite these pharmacokinetic alterations, tissue distribution studies still showed selective accumulation of the three modified proteins in livers of diseased animals. Moreover, the intrahepatic distribution of these drug-carriers during fibrosis was similar to distribution in normal livers.


CONCLUSIONS
This study demonstrates that cell-specific delivery of sugar- and charge-modified albumins in fibrotic livers is possible. Despite the increased matrix deposition during fibrosis, the accessibility of the different liver cell types for the carriers was not significantly altered as compared to normal livers. The availability of a complete set of carriers for the different liver cell types provides opportunities for the development of effective therapeutic strategies based on drug targeting.
Beljaars
L
L
Groningen Utrecht Institute for Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. L.Beljaars@farm.rug.nl
Poelstra
K
K
Molema
G
G
Meijer
D K
DK
D000606:Amino Sugars / Q000008:administration & dosage; D000818:Animals; D004337:Drug Carriers; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D008358:Mannose / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000008:administration & dosage / Q000378:metabolism*; D019802:Succinic Acid / Q000008:administration & dosage
D000606:Amino Sugars; D004337:Drug Carriers; D012709:Serum Albumin; C032233:lactosamine; D019802:Succinic Acid; D008358:Mannose