Trafficking microenvironmental pHs of polycationic gene vectors in drug-sensitive and multidrug-resistant MCF7 breast cancer cells.
Trafficking microenvironmental pHs of polycationic gene vectors in drug-sensitive and multidrug-resistant MCF7 breast cancer cells.
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DOI：
10.1016/j.biomaterials.2010.01.001
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发表时间：
2010-04
期刊：
影响因子：
14
通讯作者：
Bae YH
中科院分区：
文献类型：
--
作者：
Kang HC;Samsonova O;Bae YH
虽然多药耐药性（MDR）已经是癌症化疗中的重要问题，但是对各种抗癌生物治疗剂（包括基因）的递送抗性尚未被广泛认为是MDR的性质。本研究旨在通过追踪两种代表性聚合物载体：聚左旋赖氨酸和聚乙烯亚胺的微环境pH值，更好地了解药物敏感细胞和耐药细胞的转染特征。药物敏感的乳腺MCF 7细胞的聚合物转染效率比其对应的耐药MCF 7/ADR-RES细胞高4至7倍。内吞作用后，MCF 7/ADR-RES细胞中的聚合复合物暴露于比MCF 7细胞中的聚合复合物更酸性的微环境中; MDR细胞在内吞作用后的内体/溶酶体中显示出比药物敏感细胞更快的酸化速率（在PLL/pDNA复合物的情况下，转染后0.5小时，MCF 7/ADR-RES细胞的pH约为5.1，而MCF 7细胞的pH约为6.8）。在MCF 7/ADR-RES细胞的酸性亚细胞区室中比在MCF 7细胞中识别出更多的复合物，表明它们缺乏内体逃逸活性。这些发现表明，基于聚合物的基因递送治疗剂的设计应考虑亚细胞区室的pH。
While multidrug resistance (MDR) has been a significant issue in cancer chemotherapy, delivery resistance to various anticancer biotherapeutics, including genes, has not been widely recognized as a property of MDR. This study aims to provide a better understanding of the transfection characteristics of drug-sensitive and drug-resistant cells by tracing microenvironmental pHs of two representative polymer vectors: poly(l-lysine) and polyethyleneimine. Drug-sensitive breast MCF7 cells had four- to seven-times higher polymeric transfection efficiencies than their counterpart drug-resistant MCF7/ADR-RES cells. Polyplexes in MCF7/ADR-RES cells after endocytosis were exposed to a more acidic microenvironment than those in MCF7 cells; the MDR cells show faster acidification rates in endosomes/lysosomes than the drug-sensitive cells after endocytosis (in the case of PLL/pDNA complexes, ~ pH 5.1 for MCF7/ADR-RES cells vs. ~ pH 6.8 for MCF7 cells at 0.5 hr post-transfection). More polyplexes were identified trapped in acidic subcellular compartments of MCF7/ADR-RES cells than in MCF7 cells, suggesting that they lack endosomal escaping activity. These findings demonstrate that the design of polymer-based gene delivery therapeutics should take into account the pH of subcellular compartments.
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影响因子：
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