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Overcoming Multidrug Resistance in Dox-resistant Neuroblastoma Cell Lines via Treatment With HPMA Copolymer Conjugates Containing Anthracyclines and P-gp Inhibitors

Overcoming Multidrug Resistance in Dox-resistant Neuroblastoma Cell Lines via Treatment With HPMA Copolymer Conjugates Containing Anthracyclines and P-gp Inhibitors

Eva Koziolová, Olga Janoušková, Lucie Cuchalová, Zuzana Hvězdová, Jan Hraběta, Tomáš Eckschlager, Ladislav Sivák, Karel Ulbrich, Tomáš Etrych, Vladimír Šubr

J Control Release. 2016 Jul 10;233:136-46.

PMID: 27189135

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4247630	Reversin 121			Price

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