Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Anal Chim Acta. 2010 Feb 5;659(1-2):178-85. doi: 10.1016/j.aca.2009.11.054. Epub 2009 Dec 1.
This work has focused on the rational development of polymers capable of acting as traps of bile salts. Computational modeling was combined with molecular imprinting technology to obtain networks with high affinity for cholate salts in aqueous medium. The screening of a virtual library of 18 monomers, which are commonly used for imprinted networks, identified N-(3-aminopropyl)-methacrylate hydrochloride (APMA.HCl), N,N-diethylamino ethyl methacrylate (DEAEM) and ethyleneglycol methacrylate phosphate (EGMP) as suitable functional monomers with medium-to-high affinity for cholic acid. The polymers were prepared with a fix cholic acid:functional monomer mole ratio of 1:4, but with various cross-linking densities. Compared to polymers prepared without functional monomer, both imprinted and non-imprinted microparticles showed a high capability to remove sodium cholate from aqueous medium. High affinity APMA-based particles even resembled the performance of commercially available cholesterol-lowering granules. The imprinting effect was evident in most of the networks prepared, showing that computational modeling and molecular imprinting can act synergistically to improve the performance of certain polymers. Nevertheless, both the imprinted and non-imprinted networks prepared with the best monomer (APMA.HCl) identified by the modeling demonstrated such high affinity for the template that the imprinting effect was less important. The fitting of adsorption isotherms to the Freundlich model indicated that, in general, imprinting increases the population of high affinity binding sites, except when the affinity of the functional monomer for the target molecule is already very high. The cross-linking density was confirmed as a key parameter that determines the accessibility of the binding points to sodium cholate. Materials prepared with 9% mol APMA and 91% mol cross-linker showed enough affinity to achieve binding levels of up to 0.4 mmol g(-1) (i.e., 170 mg g(-1)) under flow (1 mL min(-1)) of 0.2 mM sodium cholate solution.
这项工作专注于开发能够作为胆汁盐捕集器的聚合物的合理设计。通过计算建模与分子印迹技术相结合，获得了在水介质中对胆酸盐具有高亲和力的网络。对 18 种常用于印迹网络的单体的虚拟文库进行筛选，确定 N-(3-氨丙基)-甲基丙烯盐酸盐（APMA.HCl）、N，N-二乙基氨基乙基甲基丙烯酸酯（DEAEM）和乙二醇甲基丙烯酸磷酸酯（EGMP）为具有中等至高亲和力的合适功能单体与胆酸。聚合物的制备固定胆酸：功能单体摩尔比为 1:4，但交联密度不同。与没有功能单体制备的聚合物相比，印迹和非印迹微球都显示出从水介质中去除胆酸钠的高能力。高亲和力的基于 APMA 的颗粒甚至类似于市售降胆固醇颗粒的性能。在大多数制备的网络中都表现出明显的印迹效应，表明计算建模和分子印迹可以协同作用，提高某些聚合物的性能。然而，通过建模确定的最佳单体（APMA.HCl）制备的印迹和非印迹网络都对模板表现出如此高的亲和力，以至于印迹效应变得不那么重要。吸附等温线对弗伦德利希模型的拟合表明，一般来说，印迹会增加高亲和力结合位点的数量，除非功能单体对目标分子的亲和力已经非常高。交联密度被确认为决定结合点对胆酸钠可及性的关键参数。用 9%摩尔的 APMA 和 91%摩尔的交联剂制备的材料具有足够的亲和力，在以 0.2mM 胆酸钠溶液 1ml/min 的流速下，达到高达 0.4mmol/g（即 170mg/g）的结合水平。
