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标题：Synthesis and Evaluation of Water-Soluble Poly(vinyl alcohol)–paclitaxel Conjugate as a Macromolecular Prodrug
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作者：Atsufumi Kakinoki ; Yoshiharu Kaneo ; Tetsuro Tanaka 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2008
卷号：31
期号：5
页码：963-969
DOI：10.1248/bpb.31.963
出版社：The Pharmaceutical Society of Japan
摘要：Paclitaxel (PTX) is an antitumor agent for the treatment of various human cancers. Cremophor EL^® and ethanol are used to formulate PTX in commercial injection solutions, because of its poor solubility in water. However, these agents cause severe allergic reaction upon intravenous administration. The aim of this study is to synthesize water-soluble macromolecular prodrugs of PTX for enhancing the therapeutic efficacy. Poly(vinyl alcohol) (PVA, 80 kDa), water-soluble synthetic polymer, was used as a drug carrier which is safe and stable in the body. The 2′-hydroxyl group of PTX was reacted with succinic anhydride and then carboxylic group of the succinyl spacer was coupled to PVA via ethylene diamine spacer, resulting the water-soluble prodrug of poly(vinyl alcohol)–paclitaxel conjugate (PVA–SPTX). The solubility of PTX was greatly enhanced by the conjugation to PVA. The release of PTX from the conjugate was accelerated at the neutral to basic conditions in in vitro release experiment. [¹²⁵I]-labeled PVA–SPTX was retained in the blood circulation for several days and was gradually distributed into the tumorous tissue after intravenous injection to the tumor-bearing mice. PVA–SPTX inhibited the growth of sarcoma 180 cells subcutaneously inoculated in mice. It was suggested that the water-solubility of PTX was markedly enhanced by the conjugation to PVA, and PVA–SPTX effectively delivered PTX to the tumorous tissue due to the enhanced permeability and retention (EPR) effect.
关键词：poly(vinyl alcohol);paclitaxel;macromolecular prodrug;cytotoxicity;antitumor activity