Gillies Elizabeth R, Goodwin Andrew P, Fréchet Jean M J
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Bioconjug Chem. 2004 Nov-Dec;15(6):1254-63. doi: 10.1021/bc049853x.
pH-Sensitive linkages designed to undergo hydrolysis at mildly acidic pH can trigger the release of therapeutics selectively at targets such as tumor and inflammatory tissues and in the endosomes and lysosomes of cells. Acetals have the potential to be used as linkages for a range of alcohol functionalities, and, by altering their chemical structure, it is possible to tune their hydrolysis rate. The syntheses of four conjugates of model drug molecules with PEO using acetals of varying chemical structure are described herein. Primary and secondary alcohols, as well as syn-1,2-diols, were incorporated in the conjugates. The hydrolysis kinetics were investigated by HPLC, and the conjugates had half-lives ranging from less than 1 min to several days at pH 5.0, with slower hydrolysis at pH 7.4 in all cases. These acetal linkages are therefore promising for use in a variety of drug delivery applications ranging from polymer-drug conjugates to pH-sensitive micelles and nanoparticulate systems.
设计用于在弱酸性pH下发生水解的pH敏感连接体，可以在肿瘤和炎症组织以及细胞的内体和溶酶体等靶点处选择性地触发治疗药物的释放。缩醛有潜力用作一系列醇官能团的连接体，并且通过改变其化学结构，可以调节其水解速率。本文描述了使用具有不同化学结构的缩醛合成四种模型药物分子与聚环氧乙烷（PEO）的缀合物。伯醇、仲醇以及顺式-1,2-二醇被引入到缀合物中。通过高效液相色谱法（HPLC）研究了水解动力学，这些缀合物在pH 5.0时的半衰期从不到1分钟到几天不等，在所有情况下，在pH 7.4时水解都较慢。因此，这些缩醛连接体有望用于从聚合物-药物缀合物到pH敏感胶束和纳米颗粒系统等各种药物递送应用中。
