Double pH-responsive supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases and acetalated dextran for drug delivery

Abstract

A double pH-responsive supramolecular copolymer micelle was successfully developed, which was based on complementary multiple hydrogen bonds of nucleobases and acetalated dextran. The thymine-terminated poly(ethylene glycol) (T-PEG-T) and adenine-terminated acetalated dextran (AcDEX-A) were synthesized and used to construct supramolecular amphiphilic triblock copolymer AcDEX-A:T-PEG-T:A-AcDEX, which could be further self-assembled into supramolecular micelles in water. These micelles were stable at pH 7.4, but disruptive at pH 5.0 due to the double pH-sensitivity of hydrogen bonds within the copolymer backbones and the hydrolysis of the acetalated dextran. The hydroxyl coverage of Ac-DEX had an important effect on the critical micelle concentration (CMC) and particle size of AcDEX-A:T-PEG-T:A-AcDEX micelles, which were observed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In addition, turbidometry was utilized to evaluate the effect of pH-responsivity of AcDEX-A:T-PEG-T:A-AcDEX micelles and these supramolecular micelles were completely decomposed at pH 5.0. Cytotoxicity evaluation showed good biocompatibility of these micelles, and doxorubicin (DOX) was encapsulated into supramolecular micelles as a model drug. The in vitro drug release profile showed that the DOX release speed at pH 5.0 could be adjusted by changing the hydroxyl coverage of Ac-DEX. Meanwhile, DOX-loaded supramolecular micelles could be efficiently internalized into cancer cells and showed similar inhibition of proliferation of the Hela cell as free DOX. This work provided a new method for enabling a rapid intracellular release of drugs by using double pH-sensitive hydrogen bonds and acetalated dextran, which would have the potential to be applied in controlled drug delivery.