Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors

0459478 - ÚMCH 2017 RIV NL eng J - Článek v odborném periodiku
Koziolová, Eva - Janoušková, Olga - Cuchalová, Lucie - Hvězdová, Zuzana - Hraběta, J. - Eckschlager, T. - Sivák, Ladislav - Ulbrich, Karel - Etrych, Tomáš - Šubr, Vladimír
Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors.
Journal of Controlled Release. Roč. 233, 10 July (2016), s. 136-146. ISSN 0168-3659. E-ISSN 1873-4995
Grant CEP: GA ČR(CZ) GAP301/12/1254; GA MŠMT(CZ) LO1507
Institucionální podpora: RVO:61389013 ; RVO:61388971
Klíčová slova: N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors
Kód oboru RIV: CD - Makromolekulární chemie; FD - Onkologie a hematologie (MBU-M)
Impakt faktor: 7.786, rok: 2016

Water-soluble N-(2-hydroxypropyl)methacrylamide copolymer conjugates bearing the anticancer drugs doxorubicin (Dox) or pirarubicin (THP), P-gp inhibitors derived from reversin 121 (REV) or ritonavir (RIT)), or both anticancer drug and P-gp inhibitor were designed and synthesized. All biologically active molecules were attached to the polymer carrier via pH-sensitive spacer enabling controlled release in mild acidic environment modeling endosomes and lysosomes of tumor cells. The cytotoxicity of the conjugates against three sensitive and Dox-resistant neuroblastoma (NB) cell lines, applied alone or in combination, was studied in vitro. All conjugates containing THP displayed higher cytotoxicity against all three Dox-resistant NB cell lines compared with the corresponding Dox-containing conjugates. Furthermore, the cytotoxicity of conjugates containing both drug and P-gp inhibitor was up to 10 times higher than that of the conjugate containing only drug. In general, the polymer-drug conjugates showed higher cytotoxicity when conjugates containing inhibitors were added 8 or 16 h prior to treatment compared with conjugates bearing both the inhibitor and the drug. The difference in cytotoxicity was more pronounced at the 16-h time point. Moreover, higher inhibitor:drug ratios resulted in higher cytotoxicity. The cytotoxicity of the polymer-drug used in combination with polymer P-gp inhibitor was up to 84 times higher than that of the polymer-drug alone.
Trvalý link: http://hdl.handle.net/11104/0259686