Polymer conjugates of acridine-type anticancer drugs with pH-controlled activation

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• 作者：Ond艡ej Sedlá ; 膷ek^a ; Martin Hrubý ; ^a ; ^{mhruby@centrum.cz} ; Martin Studenovský ; ^a ; David V臎tvi膷ka^b ; ^c ; Jan Svoboda^d ; Dana Ka艌ková ; ^a ; Jan Ková ; 艡^e ; Karel Ulbrich^a
• 关键词：Drug delivery systems ; Cancer therapy ; Controlled release ; Acridines ; Hydrazone
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 July, 2012
• 卷：20
• 期：13
• 页码：4056-4063
• 文件大小：715 K

摘要

Acridines are potent DNA-intercalating anticancer agents with high in vivo anticancer effectiveness, but also severe side effects. We synthesized five 9-anilinoacridine-type drugs and their conjugates with biocompatible water-soluble hydrazide polymer carrier. All of the synthesized acridine drugs retained their in vitro antiproliferative properties. Their polymer conjugates were sufficiently stable at pH 7.4 (model of pH in blood plasma) while releasing free drugs at pH 5.0 (model of pH in endosomes). After internalization of the conjugates, the free drugs were released and are visible in cell nuclei by fluorescence microscopy. Their intercalation ability was proven using a competitive ethidium bromide displacement assay.