title: Paclitaxel delivery systems: the use of amino acid linkers in the conjugation of paclitaxel with carboxymethyldextran to create prodrugs.
abstract: Paclitaxel was bound via its hydroxyl group to carboxymethyldextran (CMDex, 150 kDa) by means of an amino acid linker; the linker was introduced into the 2'- or 7-hydroxyl group of the paclitaxel through an ester bond. These conjugates--CMDex-2'-paclitaxel and CMDex-7-paclitaxel--were designed to be water-soluble with a paclitaxel content between 6-8% (w/w) with a degree of subsititution (DS) of the CM groups at 0.6 per sugar residue. The release of the paclitaxel from the conjugates was influenced by the hydroxyl group (2'- or 7-) of paclitaxel to which the amino acid linker was introduced, and by what amino acid was used as the linker. In mouse plasma incubated at 37 degrees C for 72 h, the most paclitaxel was released using CMDex-paclitaxel conjugate with 2'gly followed by, in descending order, 2'-ala, 2'-leu, 2'-ile, and 7-gly as the amino linkers. Colon 26, a Taxol resistant cancer, was introduced into mice and the conjugates were intravenously administered by bolus injection for a tumor distribution study, and intermittently intravenously administered for a tumor growth regression study. In both studies the highest amount of paclitaxel release was found in the CMDex-2'-gly-paclitaxel followed by CMDex-2'-ala-paclitaxel, CMDex-2'-leu-paclitaxel and paclitaxel. There was a direct correlation between the amount of paclitaxel released and the observed efficacy. CMDex-2'-ile-paclitaxel and CMDex-7-gly-paclitaxel did not show any anti-tumor activity. These results clearly demonstrate that a CMDex-paclitaxel with an appropriate amino acid linker has significant anti-tumor activity against colon 26, and that these anti-tumor effects appear to correlate with the amounts of paclitaxel released in the tumor.
authors.affiliation: The Second Research Department of Central Technology Laboratory, AsahiKasei Corporation, Fuji, Shizuoka, Japan. sugawara.sb@om.asahi-kasei.co.jp
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Sugahara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuriyama
authors.forename: To-ru
authors.initials: TR
authors.lastname: Kobayashi
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy; D003911:Dextrans / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis*; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D000972:Antineoplastic Agents, Phytogenic; D003911:Dextrans; D004337:Drug Carriers; D011355:Prodrugs; C014392:carboxymethyl dextran; D017239:Paclitaxel