Acid-triggered drug release from micelles based on amphiphilic oligo(ethylene glycol)–doxorubicin alternative copolymers

Abstract

We report a facile strategy to synthesize pH-sensitive amphiphilic oligo(ethylene glycol) (OEG)–doxorubicin (DOX) alternative conjugates. Poly[oligo(ethylene glycol) malicate] (POEGM) with numerous pendent hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with malic acid under mild conditions. Then, benzaldehyde groups were introduced into the POEGM backbone via esterification between the pendant hydroxyl groups and 4-formylbenzoic acid. DOX moieties were finally attached to the polymeric backbone via benzoic imine linkages to obtain the OEG–DOX conjugates. Because of the high molecular weight and alternate architecture, this type of amphiphilic OEG–DOX alternative conjugates can form stable micelles in aqueous solution with a high DOX loading content (38.2 wt%) and low critical micelle concentrations (0.021 mg mL⁻¹). Due to the pH-sensitive benzoic imine linkages between the DOX moieties and polymeric backbone, DOX could be rapidly released from the micelles at pH 5.8, whereas only a minimal amount of DOX was released at pH 7.4 under the same conditions. The cytotoxicity assay indicates that the OEG–DOX conjugates show cytotoxic effects to MCF-7 tumor cells, while the corresponding polymer material POEGM–CHO exhibits a great biocompatibility for MCF-7 tumor cells. These pH-sensitive and high drug loading nano-carriers based on the OEG–DOX alternative conjugates provide a promising platform for targeted cancer therapy.