Polymer conjugates of acridine-type anticancer drugs with pH-controlled activation.
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.
Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
Ondřej
O
Sedláček
Martin
M
Hrubý
Martin
M
Studenovský
David
D
Větvička
Jan
J
Svoboda
Dana
D
Kaňková
Jan
J
Kovář
Karel
K
Ulbrich
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D008856:Microscopy, Fluorescence; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007364:Intercalating Agents; D011108:Polymers; D000677:Amsacrine; D014867:Water; C022202:9-anilinoacridine; D004247:DNA; C427203:calf thymus DNA