title: Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors.
abstract: 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 16h 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.
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Koziolová
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Janoušková
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Cuchalová
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hvězdová
authors.affiliation: Charles University Prague, 2nd Medical Faculty, Department of Pediatric Hematology and Oncology, 150 06 Prague 5, Czech Republic; University Hospital Motol, 150 06 Prague 5, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Hraběta
authors.affiliation: Charles University Prague, 2nd Medical Faculty, Department of Pediatric Hematology and Oncology, 150 06 Prague 5, Czech Republic; University Hospital Motol, 150 06 Prague 5, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Eckschlager
authors.affiliation: Institute of Microbiology, The Czech Academy of Sciences, v.v.i., Vídeňská 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Sivák
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic. Electronic address: subr@imc.cas.cz.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Šubr
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008689:Methacrylates / Q000008:administration & dosage / Q000737:chemistry; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D008689:Methacrylates; D009842:Oligopeptides; C120260:reversin 121; D004317:Doxorubicin; C027260:pirarubicin; D019438:Ritonavir; C032802:hydroxypropyl methacrylate
keywords: Doxorubicin; Multidrug resistance; N-(2-hydroxypropyl)methacrylamide copolymers; Neuroblastoma; P-glycoprotein inhibitors; Pirarubicin; Reversin 121; Ritonavir