Rational design of composition and activity correlations for pH-responsive and glutathione-reactive polymer therapeutics.
Rational design of composition and activity correlations for pH-responsive and glutathione-reactive polymer therapeutics.
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pH 响应性和谷胱甘肽反应性聚合物治疗剂的成分和活性相关性的合理设计。
DOI：
10.1016/j.jconrel.2005.01.009
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Stayton,PatrickS
中科院分区：
文献类型：
--
作者：
El-Sayed,MohamedEH;Hoffman,AllanS;Stayton,PatrickS
酶敏感药物的有限细胞质递送仍然是在细胞内区室中起作用的蛋白质和核酸疗法的开发所面临的重大挑战。“智能”pH响应性、膜去稳定化聚合物提供了一种新的方法来穿梭治疗分子通过内体膜并进入靶细胞的细胞质。本报告描述了使用的功能化单体，吡啶基二硫化物丙烯酸酯（PDSA），开发pH响应，膜去稳定，谷胱甘肽反应性聚合物与几个pH响应和疏水单体共聚。载体的活性被描述为（a）增加取代到pH响应性单体上的疏水烷基的长度和（B）引入疏水单体如丙烯酸丁酯（BA）对新聚合物组合物的pH敏感性和膜去稳定活性的函数。不同聚合物组合物的膜去稳定化活性作为pH和聚合物浓度的函数使用红细胞（RBC）溶血测定来评估。溶血的结果表明，在聚合物主链的疏水特性的增加，导致在pH值的敏感性和增加的膜去稳定活性的转变。结果表明，所观察到的溶血活性和pH敏感性曲线可以在与增强大分子治疗剂的细胞质递送所需的性质相匹配的范围内设计。
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-responsive, membrane-destabilizing polymers present a new approach to shuttling therapeutic molecules past the endosomal membrane and into the cytoplasm of targeted cells. This report describes the use of a functionalized monomer, pyridyl disulfide acrylate (PDSA), to develop pH-responsive, membrane-destabilizing, and glutathione-reactive polymers by copolymerization with several pH-responsive and hydrophobic monomers. The activity of the carriers is described as a function of (a) increasing the length of the hydrophobic alkyl group substituted onto the pH-responsive monomer and (b) the incorporation of 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 cell (RBC) hemolysis assay. Hemolysis results show that the increase in the hydrophobic character of the polymer backbone results in a shift in the pH sensitivities 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 enhancing the cytoplasmic delivery of macromolecular therapeutic.