Injectable multi-responsive hydrogels cross-linked by responsive macromolecular micelles

Abstract

Injectable multi-responsive hydrogels are very important and exhibit many potential applications in biologically relevant fields. In this work, the preparation of injectable multi-responsive hydrogels at near-physiological conditions and their applications as durg carriers were demonstrated. Diol-capped poly(N, N-dimethylacrylamide)-b-poly(N-isopropylacrylamide) ((OH)2-PDMA-b-PNIPAM) diblock copolymers containing a disulfide linkage on the backbone and N, N-dimethylacrylamide-stat-(2-acrylamidophenylboronic acid) (DMA-stat-2APBA) copolymers were separatedly synthesized. Hydrogels were then prepared by a solution-based mixing of DMA-stat-2APBA with (OH)2-PDMA-b-PNIPAM diblock copolymers in PBS (pH 7.4) solution at a given temperature, i.e. 37 °C. Above the lower critical solution temperature (LCST) of diblock copolymers at around 32 °C, (OH)2-PDMA-b-PNIPAM copolymers self-assembled into core-shell structured macromolecular micelles with numerous diol groups on hydrophilic cornoas. Subsequent complexiation of diols with lateral PBA groups of DMA-stat-2APBA copolymers led to the formation of hydrogels. Due to the integration of a library of responsive units including boronate ester and disulfide DCBs together with thermal responsive PNIPAM blocks within the same system, the as-prepared hydrogels indicated multiple stimuli-responsiveness to pH, temperature, glucose and redox reaction as well as the mechanical field. Such multi-responsive hydrogels could be applied as potential drug carriers. The encapsulation and the stimuli-responsive release of a model drug of Rh B were demonstrated.