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

J Control Release. 2016 Jul 10:233:136-46. doi: 10.1016/j.jconrel.2016.05.036. Epub 2016 May 14.


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.

Keywords: Doxorubicin; Multidrug resistance; N-(2-hydroxypropyl)methacrylamide copolymers; Neuroblastoma; P-glycoprotein inhibitors; Pirarubicin; Reversin 121; Ritonavir.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / administration & dosage*
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology
  • Drug Liberation
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Methacrylates / administration & dosage
  • Methacrylates / chemistry
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Oligopeptides / administration & dosage
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Ritonavir / administration & dosage
  • Ritonavir / chemistry
  • Ritonavir / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Methacrylates
  • Oligopeptides
  • reversin 121
  • Doxorubicin
  • pirarubicin
  • Ritonavir
  • hydroxypropyl methacrylate