Bulmus Volga, Woodward Monica, Lin Lianne, Murthy Niren, Stayton Patrick, Hoffman Allan
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
J Control Release. 2003 Dec 5;93(2):105-20. doi: 10.1016/j.jconrel.2003.06.001.
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 oligonucleotides 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.
在本研究中，我们设计、合成并表征了一种新型的pH响应性聚合物载体，用于增强对酶敏感药物（如反义寡核苷酸、蛋白质和肽）的细胞质递送。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、具有膜破坏作用且带有官能团的三元共聚物，这些官能团可使含硫醇的分子易于共轭。进行了与寡肽或反义寡核苷酸的共轭和/或离子络合，并对其进行了表征。即使在与寡肽和反义寡核苷酸共轭/络合后，低pH值下的溶血活性仍然很高。用小鼠3T3成纤维细胞和人THP-1巨噬细胞样细胞测定，该聚合物无毒性。还在THP-1巨噬细胞样细胞中研究了放射性标记聚合物的摄取以及FITC-ODN的细胞质递送增强情况。
