Imidazole-modified deferasirox encapsulated polymeric micelles as pH-responsive iron-chelating nanocarrier for cancer chemotherapy

Abstract

Deferasirox (Def) is an iron-chelating drug used to reduce iron overload in β-thalassemia patients. After the discovery of its tumor growth inhibition, this drug gained tremendous attention in cancer chemotherapy. Herein, deferasirox and its derivatives including methoxy (mDef) and imidazole-modified (iDef) deferasirox were encapsulated in polymeric micelles. Results showed that the release of deferasirox from polymeric micelles was faster at pH 7.4 (physiological condition) than at pH 4.5 (lysosomal condition). However, the release of mDef was pH-independent where both Def and mDef are not suitable for in vivo applications. Therefore, iDef was synthesized to change the pK_a from 3.7 (carbonyl group of Def) to 6.8 (imidazole group of iDef) without interfering the iron-chelating efficacy. Interestingly, the release rate of imidazole-modified deferasirox was conversed from that of deferasirox where it exhibited slow release at physiological condition and faster release at the lysosomal condition. This release profile showed a pH-response and an ON–OFF release behavior where iDef is encapsulated in micelles during systemic circulation and released inside cancer cells after intracellular endosomes/lysosome. Cytotoxicity of deferasirox and modified deferasirox were also investigated, and it was found that the IC₅₀ against PC-3 and HepG2 cell lines were in the range of micromolar to submicromolar. Flow cytometry analysis confirmed a decrease in the amount of iron inside lysosome when cells were treated by iDef-loaded micelles. Therefore, iDef-loaded micelles have potential application in cancer treatment as a pH-responsive iron-chelating nanocarrier.