Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles
Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles
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DOI：
10.1042/bj20021945
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发表时间：
2003-05-15
影响因子：
4.1
通讯作者：
Wilson, MR
中科院分区：
文献类型：
--
作者：
Jones, RA;Cheung, CY;Wilson, MR
由细胞膜构成的渗透性屏障代表了将亲水性分子递送到细胞中的挑战。我们先前提出，聚（2-烷基丙烯酸）被细胞内吞到酸化的囊泡中，并在那里被低pH触发以破坏膜并将内体/溶酶体的内容物释放到胞质溶胶中。如果这一假设是正确的，这些聚合物可能在药物输送应用中有价值。本文报道了三种聚（2-烷基丙烯酸）的功能比较。在红细胞溶血试验和Lipoplex（脂质体-DNA复合物）试验中比较了聚（2-丙基丙烯酸）（PPAA）、聚（2-乙基丙烯酸）（PEAA）和聚（2-甲基丙烯酸）（PMAA）。我们还直接检查了这些聚合物破坏培养的人细胞中的内体和溶酶体的能力。我们的结果表明：（i）与膜破坏性肽不同，多聚腺苷酸的内体破坏性能力（2-烷基丙烯酸）不一定能从它们在低pH下的溶血活性来预测，（二）PPAA（但不是PEAA或PMAA）有效地促进阳离子脂质复合物的基因转染，和（iii）内吞的聚（2-烷基丙烯酸）由管腔酸化触发，以选择性地破坏内体（而不是溶酶体）并将其内容物释放到胞质溶胶中。这些结果将有助于合理设计未来的内体破坏聚合物的药物输送。
The permeability barrier posed by cell membranes represents a challenge for the delivery of hydrophilic molecules into cells. We previously proposed that poly(2-alkylacrylic acid)s are endocytosed by cells into acidified vesicles and are there triggered by low pH to disrupt membranes and release the contents of endosomes/lysosomes to the cytosol. If this hypothesis is correct, these polymers could be valuable in drug-delivery applications. The present paper reports functional comparisons of a family of three poly(2-alkylacrylic acid)s. Poly(2-propylacrylic acid) (PPAA), poly(2-ethylacrylic acid) (PEAA) and poly(2-methylacrylic acid) (PMAA) were compared in red-blood-cell haemolysis assays and in a lipoplex (liposome-DNA complex) assay. We also directly examined the ability of these polymers to disrupt endosomes and lysosomes in cultured human cells. Our results show that: (i) unlike membrane-disruptive peptides, the endosomal-disruptive ability of poly(2-alkylacrylic acid)s cannot necessarily be predicted from their haemolytic activity at low pH, (ii) PPAA (but not PEAA or PMAA) potently facilitates gene transfection by cationic lipoplexes and (iii) endocytosed poly(2-alkylacrylic acid)s are triggered by luminal acidification to selectively disrupt endosomes (not lysosomes) and release their contents to the cytosol. These results will facilitate the rational design of future endosomal-disrupting polymers for drug delivery.