Reductive amination using poly(ethylene glycol) acetaldehyde hydrate generated in situ: Applications to chitosan and lysozyme
Reductive amination using poly(ethylene glycol) acetaldehyde hydrate generated in situ: Applications to chitosan and lysozyme
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DOI：
10.1021/js980064w
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发表时间：
1998-11-01
影响因子：
3.8
通讯作者：
Harris, JM
中科院分区：
文献类型：
--
作者：
Bentley, MD;Roberts, MJ;Harris, JM
聚乙二醇（PEG）与药物分子的共价连接导致水溶性偶联物的生物利用度、药代动力学、免疫原性和生物活性发生改变。对于含有一个或多个氨基的药物，还原性胺化是一种潜在有用的偶联PEG的方法。聚乙二醇乙醛已被用于这一目的，但其在一定条件下易于聚合和对空气氧化的敏感性给其应用带来了一些问题。介绍了一种简单可靠的制备PEG乙醛水合物的方法，并将其应用于PEG乙醛二乙醛水解原位生成的PEG乙醛水合物的还原胺化反应。以聚乙二醇为原料，在细粉状氢氧化钠存在下，在非均相条件下，与氯二乙基缩醛在二恶烷中反应，制备出高收率、高纯度的聚乙二醇乙醛二乙基缩醛。聚乙二醇乙醛水合物是在水溶液中水解生成的。水合物溶液可直接与氰硼氢化钠结合使用，以实现还原性胺化。我们展示了这些方法在溶菌酶和壳聚糖聚乙二醇化中的应用，以形成水溶性甲氧基聚乙二醇（mPEG）衍生物和peg -壳聚糖水凝胶。
Covalent linkage of poly(ethylene glycol) (PEG) to drug molecules results in water-soluble conjugates with altered bioavailability, pharmacokinetics, Immunogenic properties, and biological activities. For drugs bearing one or more amino groups, reductive amination is a potentially useful method for conjugation to PEG. PEG acetaldehyde has been used for this purpose, but its ease of polymerization under certain conditions and its susceptibility to air oxidation have caused some problems in its application. A simple and reliable method for preparation and use in reductive amination of PEG acetaldehyde hydrate generated in situ by hydrolysis of PEG acetaldehyde diethylacetal is demonstrated. PEG acetaldehyde diethylacetal is prepared in high yield and purity by reaction of PEG with chlorodiethylacetal in dioxane in the presence of finely powdered sodium hydroxide under heterogeneous conditions. PEG acetaldehyde hydrate is generated in solution by hydrolysis in aqueous acids. Solutions of the hydrate may be used directly, in conjunction with sodium cyanoborohydride, to effect reductive amination. We demonstrate application of these methods in PEGylation of lysozyme and chitosan to form water-soluble methoxy poly(ethylene glycol) (mPEG) derivatives and PEG-chitosan hydrogels.