Paclitaxel Delivery Systems : The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Carboxymethyldextran to Create Prodrugs

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概要

• 論文の詳細を見る

• 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 ℃ 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.

• 公益社団法人日本薬学会の論文
• 2002-05-01

著者

• Kobayashi Taketo

  Faculty Of Phamaceutical Sciences Josai University

• Kajiki Masahiro

  The Second Research Department Of Central Technology Laboratory Asahi Kasei Corporation

• Kuriyama H

  National Institute Of Bioscience & Human Technology Agency Of Industrial Science And Technology

• SUGAHARA Shu-ichi

  The Second Research Department of Central Technology Laboratory Asahi Kasei Corporation

• KURIYAMA Hiroshi

  Institute for Life Science Research, Asahi Kasei Corporation

• KOBAYASHI To-ru

  Institute for Life Science Research, Asahi Kasei Corporation

• Sugahara Shuichi

  The Second Research Department Of Central Technology Laboratory Asahi Kasei Corporation

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