Bentley M D, Roberts M J, Harris J M
Shearwater Polymers, Inc., 2307 Spring Branch Road, Huntsville, Alabama 35801, USA.
J Pharm Sci. 1998 Nov;87(11):1446-9. doi: 10.1021/js980064w.
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.
聚乙二醇（PEG）与药物分子的共价连接可产生具有改变的生物利用度、药代动力学、免疫原性和生物活性的水溶性缀合物。对于带有一个或多个氨基的药物，还原胺化是与PEG缀合的一种潜在有用方法。PEG乙醛已用于此目的，但其在某些条件下易于聚合以及对空气氧化的敏感性在其应用中引起了一些问题。本文展示了一种通过PEG乙醛二乙缩醛水解原位生成PEG乙醛水合物并用于还原胺化的简单可靠制备方法及应用。PEG乙醛二乙缩醛通过在非均相条件下，PEG与氯代二乙缩醛在二氧六环中，在细粉状氢氧化钠存在下反应，以高产率和高纯度制备。PEG乙醛水合物通过在水性酸中水解在溶液中生成。水合物溶液可直接与氰基硼氢化钠一起用于进行还原胺化。我们展示了这些方法在溶菌酶和壳聚糖聚乙二醇化以形成水溶性甲氧基聚乙二醇（mPEG）衍生物和PEG-壳聚糖水凝胶中的应用。
