Rational design of composition and activity correlations for pH-sensitive and glutathione-reactive polymer therapeutics
Rational design of composition and activity correlations for pH-sensitive and glutathione-reactive polymer therapeutics
复制标题
DOI：
10.1016/j.jconrel.2004.08.032
复制
发表时间：
2005-01-03
影响因子：
10.8
通讯作者：
Stayton, PS
中科院分区：
文献类型：
--
作者：
El-Sayed, MEH;Hoffman, AS;Stayton, PS
酶敏感药物的有限胞质递送仍然是发展作用于细胞内隔室的蛋白质和核酸疗法面临的重大挑战。“智能”pH敏感、膜不稳定的聚合物提供了一种诱人的方法，将治疗分子穿透内膜进入靶细胞的细胞质。本文介绍了一种新型功能化单体--吡二硫基丙烯酸酯(PDSA)与几种pH敏感疏水单体的共聚反应，制备了pH敏感、膜不稳定和谷胱甘肽反应性聚合物。载体的活性被描述为(A)增加pH敏感单体上取代的疏水烷基长度的影响和(B)加入疏水单体如丙烯酸丁酯(BA)对新聚合物组合物的pH敏感性和膜不稳定活性的影响的函数。用红细胞溶血试验评价了不同聚合物组成的膜不稳定活性与pH和聚合物浓度的关系。溶血结果表明，聚合物主链疏水性的增加导致了pH敏感曲线的移动和膜的不稳定活性的增加。结果表明，观察到的溶血活性和pH敏感性曲线可以在一定范围内设计，以匹配药物载体所需的性质，以增强治疗货物的细胞质输送。(C)2004爱思唯尔B.V.保留所有权利。
Limited cytoplasmic delivery of enzyme-susceptible drugs remains a significant challenge facing the development of protein and nucleic acid therapies that act in intracellular compartments. "Smart" pH-sensitive, membrane-destabilizing polymers present an attractive approach to shuttle therapeutic molecules past the endosomal membrane and into the cytoplasm of targeted cells. This report describes the use of a new functionalized monomer, pyridyl disulfide acrylate (PDSA), to develop pH-sensitive, membrane-destabilizing, and glutathione-reactive polymers by copolymerization with several pH-sensitive and hydrophobic monomers. The activity of the carriers is described as a function of (a) the influence of increasing the length of the hydrophobic alkyl group substituted onto the pH-sensitive monomer and (b) of the effect of incorporating a hydrophobic monomer such as butyl acrylate (BA) on the pH sensitivity and membrane-destabilizing activity of new polymer compositions. The membrane-destabilizing activity of different polymer compositions was evaluated as a function of pH and polymer concentration using the red blood cells (RBC) hemolysis assay. Hemolysis results show that the increase in the hydrophobic character of polymer backbone results in a shift in the pH sensitivity profile and an increase in the membrane-destabilizing activity. Results show that the observed hemolytic activities and pH sensitivity profiles could be designed across a range that matches the properties needed for drug carriers to enhance the cytoplasmic delivery of therapeutic cargos. (c) 2004 Elsevier B.V. All rights reserved.