1384959-15-2Relevant academic research and scientific papers
Synthesis of Poly[ N -(2-hydroxypropyl)methacrylamide] conjugates of inhibitors of the ABC transporter that overcome multidrug resistance in doxorubicin-resistant P388 cells in vitro
?ubr,Sivák,Koziolová,Braunová,Pechar,Strohalm,Kabe?ová,?íhová,Ulbrich,Ková?
, p. 3030 - 3043 (2014)
The effects of novel polymeric therapeutics based on water-soluble N-(2-hydroxypropyl)methacrylamide copolymers (P(HPMA)) bearing the anticancer drug doxorubicin (Dox), an inhibitor of ABC transporters, or both, on the viability and the proliferation of the murine monocytic leukemia cell line P388 (parental cell line) and its doxorubicin-resistant subline P388/MDR were studied in vitro. The inhibitor derivatives 5-methyl-4-oxohexanoyl reversin 121 (MeOHe-R121) and 5-methyl-4-oxohexanoyl ritonavir ester (MeOHe-RIT), showing the highest inhibitory activities, were conjugated to the P(HPMA) via the biodegradable pH-sensitive hydrazone bond, and the ability of these conjugates to block the ATP driven P-glycoprotein (P-gp) efflux pump was tested. The P(HPMA) conjugate P-Ahx-NH-N=MeOHe-R121 showed a dose-dependent increase in the ability to sensitize the P388/MDR cells to Dox from 1.5 to 24μM, and achieved an approximately 50-fold increase in sensitization at 24μM. The P(HPMA) conjugate P-Ahx-NH-N=MeOHe-RIT showed moderate activity at 6μM (～10 times higher sensitization) and increased sensitization by 50-fold at 12μM. The cytostatic activity of the P(HPMA) conjugate P-Ahx-NH-N=MeOHe-R121(Dox) containing Dox and the P-gp inhibitor MeOHe-R121, both bound via hydrazone bonds to the P(HPMA) carrier, was almost 30 times higher than that of the conjugate P-Ahx-NH-N=Dox toward the P388/MDR cells in vitro. A similar result was observed for P-Ahx-NH-N=MeOHe-RIT(Dox), which exhibited almost 10 times higher cytostatic activity than P-Ahx-NH-N=Dox.
Polymer conjugates of acridine-type anticancer drugs with pH-controlled activation
Sedlá?ek, Ond?ej,Hruby, Martin,Studenovsky, Martin,Větvi?ka, David,Svoboda, Jan,Kaňková, Dana,Ková?, Jan,Ulbrich, Karel
experimental part, p. 4056 - 4063 (2012/09/11)
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.
