A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs

被引：224

作者：

Bulmus, V ^{[1
]}

Woodward, M ^{[1
]}

Lin, L ^{[1
]}

Murthy, N ^{[1
]}

Stayton, P ^{[1
]}

Hoffman, A ^{[1
]}

机构：

[1] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

来源：

JOURNAL OF CONTROLLED RELEASE | 2003年 / 93卷 / 02期

关键词：

pH-sensitive polymer; glutathione; polymer conjugates; cytoplasmic delivery; endosomal membrane disruption;

D O I：

10.1016/j.jconrel.2003.06.001

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：105 / 120

页数：16

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