A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs
A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs
复制标题
DOI：
10.1016/j.jconrel.2003.06.001
复制
发表时间：
2003-12-05
影响因子：
10.8
通讯作者：
Hoffman, A
中科院分区：
文献类型：
--
作者：
Bulmus, V;Woodward, M;Hoffman, A
在这项研究中，我们设计、合成和表征了一种新型的pH响应型聚合物载体，用于增强酶敏感药物的胞质递送，如反义寡核苷酸、蛋白质和多肽。合成了一种新型功能化单体--丙烯酸吡啶二硫酯，并将其引入由甲基丙烯酸和丙烯酸丁酯组成的两亲共聚物中，得到了一种对谷胱甘肽和pH敏感的膜破坏三元共聚物，这些官能团使含有硫醇的分子能够很容易地连接在一起。与寡肽或反义寡核苷酸进行偶联和/或离子络合，并进行表征。即使在与寡肽和反义寡核苷酸偶联/络合后，低pH值下的溶血活性仍然很高。该聚合物对小鼠3T3成纤维细胞和人THP-1巨噬细胞样细胞均无毒性。在THP-1巨噬细胞样细胞中，还研究了放射性标记聚合物的摄取和FITC-ODN胞浆递送的增强。(C)2003爱思唯尔B.V.保留所有权利。
In this study, we have designed, synthesized and characterized a novel pH-responsive polymeric carrier for the enhanced cytoplasmic delivery of enzyme susceptible drugs, such as antisense oligonucleotides, proteins and peptides. A novel functionalized monomer, pyridyl disulfide acrylate, was synthesized and incorporated into an amphiphilic copolymer consisting of methacrylic acid and butyl acrylate, which resulted in a glutathione- and pH-sensitive, membrane-disruptive terpolymer with functional groups, that allow thiol-containing molecules to be readily conjugated. Conjugation and/or ionic complexation with oligopeptides or antisense oligonticleotides were performed and characterized. Hemolytic activity at low pHs remained high even after the conjugation/complexation with oligopeptides and asODNs. This polymer showed no toxicity, as determined with mouse 3T3 fibroblasts and human THP-1 macrophage-like cells. Uptake of the radiolabeled polymer and enhanced cytoplasmic delivery of FITC-ODN was also studied in THP-1 macrophage-like cells. (C) 2003 Elsevier B.V. All rights reserved.