Design of macromolecular prodrug of cisplatin using dextran with branched galactose units as targeting moieties to hepatoma cells.
We previously reported that a macromolecular prodrug synthesized by immobilizing cisplatin (CDDP) to dextran (Dex) through six-membered chelate-type coordination bond (DCM-Dex/CDDP conjugate) showed a significantly longer half-life in bloodstream and excellent in vivo tumor growth inhibitory effect against mice bearing Colon 26 cancer cells. In this report, to provide DCM-Dex/CDDP conjugate having targetability to hepatoma cells, we designed a new macromolecular prodrug of CDDP using dextran having branched galactose units (Gal4As, four branched galactose residues), DCM-Dex/Gal4A/CDDP conjugate. Galactose was employed as a homing device, because it is well-known that galactose receptors (asialoglycoprotein receptors) were exposed on the surface of liver parenchymal cells. The antennary (branched) structure of Gal4A was designed based on the fact that a saccharide cluster having a branched structure shows highly effective binding with the saccharide receptors, that is a "cluster effect". The apparent affinity constant per galactose residue against RCA120 lectin for dextran carrying Gal4As was higher than that for dextran carrying monomeric galactose residues. Moreover, the DCM-Dex/Gal4A/CDDP conjugate showed cell-specific cytotoxic activity against HepG2 human hepatoma cells in vitro. The cytotoxic activity of the conjugate was inhibited by the addition of galactose and strongly inhibited by the addition of Gal4A. The results suggest that the DCM-Dex/Gal4A/CDDP conjugate having branched galactose units has a higher affinity to hepatoma cells.
Ohya
Y
Y
Department of Applied Chemistry, Faculty of Engineering & High Technology Research Center, Kansai University, Suita, 564-8680, Japan. yohya@ipcku.kansai-u.ac.jp
Oue
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H
Nagatomi
K
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Ouchi
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T
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D002240:Carbohydrate Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry*; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000737:chemistry; D005690:Galactose / Q000737:chemistry; D006801:Humans; D037102:Lectins / Q000737:chemistry; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D037121:Plant Lectins; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D003911:Dextrans; D037102:Lectins; D046911:Macromolecular Substances; D037121:Plant Lectins; D011108:Polymers; D011355:Prodrugs; C017707:Ricinus communis agglutinin-1; D002945:Cisplatin; D005690:Galactose