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

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

Author information

1
Institute of Macromolecular Chemistry, The Czech Academy of Sciences, v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
2
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.
3
Institute of Microbiology, The Czech Academy of Sciences, v.v.i., Vídeňská 1083, 142 20 Prague 4, Czech Republic.
4
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.

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.

KEYWORDS:

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

PMID:
27189135
DOI:
10.1016/j.jconrel.2016.05.036
[Indexed for MEDLINE]

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