Paclitaxel delivery systems: the use of amino acid linkers in the conjugation of paclitaxel with carboxymethyldextran to create prodrugs.
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.
Sugahara
Shu-ichi
S
The Second Research Department of Central Technology Laboratory, AsahiKasei Corporation, Fuji, Shizuoka, Japan. sugawara.sb@om.asahi-kasei.co.jp
Kajiki
Masahiro
M
Kuriyama
Hiroshi
H
Kobayashi
To-ru
TR
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
D000596:Amino Acids; D000972:Antineoplastic Agents, Phytogenic; D003911:Dextrans; D004337:Drug Carriers; D011355:Prodrugs; C014392:carboxymethyl dextran; D017239:Paclitaxel