The effect of the linker on the hydrolysis rate of drug-linked ester bonds
The effect of the linker on the hydrolysis rate of drug-linked ester bonds
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DOI：
10.1016/j.jconrel.2003.12.009
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发表时间：
2004-03-05
影响因子：
10.8
通讯作者：
Hubbell, JA
中科院分区：
文献类型：
--
作者：
Schoenmakers, RG;van de Wetering, P;Hubbell, JA
调整含有硫化物的连接体的长度可以将药物连接的酯键的水解值调整到适合一周给药一次的值。通过硫醇和丙烯酰胺的共轭加成反应，将紫杉醇模型药物用可水解性连接物偶联到聚乙二醇大分子单体上。大分子单体分三步合成，平均总收率为70%。通过改变连接基的长度，将药物的释放半衰期从4.2+/-0.1天增加到14.0+/-0.2天。这些大分子单体分别与3-磺酰丙酰基或4-磺酰基布比林基链接物进行自由基光聚合，得到了含Drug的水凝胶。药物从这些水凝胶中释放的趋势与药物从可溶聚合物-药物结合物中释放的趋势相似。所采用的合成方法不涉及在药物和聚合物之间的最终结合中使用偶联剂，排除潜在有毒残留物的存在。这种偶联方法相对简单，几乎适用于任何含羟基的药物。(C)2004爱思唯尔B.V.保留所有权利。
Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2 +/- 0.1 to 14.0 +/- 0.2 days. Drugcontaining hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylburyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs. (C) 2004 Elsevier B.V. All rights reserved.