pH-Responsive reversibly cross-linked micelles by phenol–yne click via curcumin as a drug delivery system in cancer chemotherapy

Abstract

Conventional cross-linked micelles may suffer from low drug loading efficiency, side effects or toxicity of residual cross-linkers and complicated preparation processes of drug-loaded micelles. Herein, pH-sensitive reversibly cross-linked micelles by phenol–yne click via curcumin (Cur) were developed by combining drug loading and cross-linking using poly(ethylene glycol)-b-poly(2-methacrylate ethyl 5-hexynoicate), (mPEG-b-PHEMA-5HA), as a drug delivery system. mPEG-b-PHEMA-5HA was synthesized by ATRP of 2-hydroxyethyl methacrylate (HEMA) using mPEG-Br as a macroinitiator and then by esterification with 5-hexynoic acid. mPEG-b-PHEMA-5HA could form micelles and the micelles could load Cur. Meanwhile, the Cur loaded micelles were readily cross-linked by a phenol–yne click reaction. The cross-linked micelles showed excellent stability after high dilution with water, and turned into smaller micelles under an acid environment (pH 5.0). The cross-linked micelles achieved a higher drug loading of Cur (17.81%, wt%) than the noncross-linked micelles, due to physical entrapment and chemical click reaction. Cur release from the Cur-cross-linked micelles was inhibited under physiological conditions (pH 7.4) but was faster at pH 5.0 in comparison with the noncross-linked micelles. The cross-linked micelles exhibited a superior antitumor activity with a lower IC₅₀ of 4.86 and 9.6 μg mL⁻¹ toward HeLa and 4T1 cells, respectively, resulting from effective internalization by tumor cells. In pharmacokinetics, the cross-linked micelles showed a prolonged circulation time, and thus exhibited more effective inhibition of tumor growth compared to free Cur and Cur loaded noncross-linked micelles in in vivo experiments. Therefore, pH-sensitive reversibly cross-linked micelles via Cur are promising as an antitumor drug delivery system.