Abstract
Human serum albumin (HSA), a non-glycosylated protein, is widely employed as carrier for drug delivery systems. A series of recombinant, mannosylated-HSA mutants (Man-rHSAs: D63N, A320T and D494N) and their triple mutant (TM-rHSA: D63N/A320T/D494N) were prepared, that can be selectively delivered to the liver via mannose receptor (MR) on the liver non-parenchymal cells. A pharmacokinetic analysis of (111)In-Man-rHSAs in mice showed that they were rapidly cleared from the blood circulation, and were largely taken up by the liver rapidly in the order: TM-rHSA>D494N>>A320T=D63N, consistent with their degree of mannosylation. In vivo competition experiments with an excess amount of chemically modified Man-BSA or mannan suggested that the hepatic uptake of TM-rHSA was selectively mediated by MR on Kupffer cells. Lastly, a TM-rHSA-NO conjugate, S-nitrosylated TM-rHSA, effectively delivered NO to the liver and then exhibited a significant inhibitory effect against hepatic ischemia/reperfusion injury model rats, accompanied by the induction of heme oxygenase-1.
2010. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Circular Dichroism
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Disease Models, Animal
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Drug Carriers / chemistry*
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Drug Carriers / pharmacokinetics
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Electrophoresis, Polyacrylamide Gel
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Heme Oxygenase-1 / metabolism
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Humans
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Kupffer Cells / drug effects
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Kupffer Cells / metabolism
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Lectins, C-Type / metabolism*
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Liver / blood supply
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Liver / drug effects*
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Liver / metabolism
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Mannose / chemistry
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Mannose / genetics*
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Mannose / pharmacokinetics
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Mannose Receptor
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Mannose-Binding Lectins / metabolism*
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Mice
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Mice, Inbred Strains
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Nitric Oxide / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Receptors, Cell Surface / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics*
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Recombinant Proteins / pharmacokinetics
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Reperfusion Injury / drug therapy
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Reperfusion Injury / metabolism
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Serum Albumin / chemistry
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Serum Albumin / genetics*
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Serum Albumin / pharmacokinetics
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Tissue Distribution
Substances
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Drug Carriers
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Lectins, C-Type
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Mannose Receptor
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Mannose-Binding Lectins
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Reactive Oxygen Species
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Receptors, Cell Surface
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Recombinant Proteins
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Serum Albumin
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mannose-bovine serum albumin conjugate
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Nitric Oxide
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Heme Oxygenase-1
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Mannose