Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
27189135
DOI
10.1016/j.jconrel.2016.05.036
PII: S0168-3659(16)30316-9
Knihovny.cz E-resources
- Keywords
- Doxorubicin, Multidrug resistance, N-(2-hydroxypropyl)methacrylamide copolymers, Neuroblastoma, P-glycoprotein inhibitors, Pirarubicin, Reversin 121, Ritonavir,
- MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Doxorubicin administration & dosage analogs & derivatives chemistry pharmacology MeSH
- Humans MeSH
- Methacrylates administration & dosage chemistry MeSH
- Drug Resistance, Multiple drug effects MeSH
- Cell Line, Tumor MeSH
- Neuroblastoma genetics metabolism MeSH
- Oligopeptides administration & dosage chemistry pharmacology MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors genetics metabolism MeSH
- Antibiotics, Antineoplastic administration & dosage chemistry pharmacology MeSH
- Ritonavir administration & dosage chemistry pharmacology MeSH
- Drug Liberation MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Browser
- Methacrylates MeSH
- Oligopeptides MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 MeSH
- pirarubicin MeSH Browser
- Antibiotics, Antineoplastic MeSH
- reversin 121 MeSH Browser
- Ritonavir MeSH
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.
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