摘要：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 °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.
关键词：paclitaxel (Taxol®);carboxymethyldextran;anti-tumor effect;linker;polymeric drug
