Synthesis and pharmacokinetics of a new liver-specific carrier, glycosylated carboxymethyl-dextran, and its application to drug targeting

To develop a new carrier system for hepatic targeting, carboxymethyl-dextran (CMD) was modified with galactose and mannose residues (Gal-CMD, Man-CMD), and their disposition characteristics were studied in mice using 14C-labeled dextran. At a dose of 1 mg/kg, i.v.-injected Gal-CMD and Man-CMD rapidl...

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Bibliographic Details
Published in:Pharmaceutical research 1993-09, Vol.10 (9), p.1253-1261
Main Authors: NISHIKAWA, M, KAMIJO, A, FUJITA, T, TAKAKURA, Y, SEZAKI, H, HASHIDA, M
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Carbohydrate Sequence
Chemical Phenomena
Chemistry, Physical
Cytarabine - administration & dosage
Cytarabine - pharmacokinetics
Dextrans - chemical synthesis
Dextrans - chemistry
Dextrans - pharmacokinetics
Drug Carriers
Galactose - chemistry
General pharmacology
Half-Life
Indium Radioisotopes
Liver - metabolism
Male
Mannose - chemistry
Medical sciences
Mice
Mice, Inbred Strains
Molecular Sequence Data
Molecular Weight
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Tissue Distribution
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Summary:To develop a new carrier system for hepatic targeting, carboxymethyl-dextran (CMD) was modified with galactose and mannose residues (Gal-CMD, Man-CMD), and their disposition characteristics were studied in mice using 14C-labeled dextran. At a dose of 1 mg/kg, i.v.-injected Gal-CMD and Man-CMD rapidly accumulated in the liver parenchymal and nonparenchymal cells, respectively, because of their preferential uptake via carbohydrate receptors in these cells. Pharmacokinetic analysis revealed that their uptake rates were sufficiently large for selective drug targeting. Targeting of cytosine beta-D-arabinoside (araC) was studied using Gal-CMD as a specific carrier to the hepatocytes. From the conjugate of araC with Gal-CMD, araC was released with a half-life of 36 hr in phosphate buffer (pH 7.4) and 23 hr in plasma. An in vivo biodistribution study demonstrated a disposition profile of the conjugated araC similar to that of the carrier, and selective delivery to hepatocytes of up to 80% of the dose was achieved. These findings suggest that glycosylated CMDs are carriers with a high affinity to liver parenchymal or nonparenchymal cells without any affinity to other tissues.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1018949109004