Ability of polymer-bound P-glycoprotein inhibitor ritonavir to overcome multidrug resistance in various resistant neuroblastoma cell lines

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Abstract

Polymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer–RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer–RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer–DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs.

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