Multi-stimuli-responsive, liposome-crosslinked poly(ethylene glycol) hydrogels for drug delivery

The development of hybrid hydrogels has been of great interest over recent decades, especially in the field of biomaterials. Such hydrogels provide various opportunities in tissue engineering, drug delivery, and regenerative medicine due to their ability to mimic cellular environments, sequester and release therapeutic agents, and respond to stimuli. Herein we report the synthesis and characterization of an injectable poly(ethylene glycol) hydrogel crosslinked via thiol-maleimide reactions and containing both chemically crosslinked temperature-sensitive liposomes (TSLs) and matrix metalloproteinase-sensitive peptide crosslinks. Rheological studies demonstrate that the hydrogel is mechanically stable and can be synthesized to achieve a range of physically applicable moduli. Experiments characterizing the in situ drug delivery and degradation of these materials indicate that the TSL gel responds to both thermal and enzymatic stimuli in a local environment. Doxorubicin, a widely used anticancer drug, was loaded in the TSLs with a high encapsulation efficiency and the subsequent release was temperature dependent. Finally, TSLs did not compromise viability and proliferation of human and murine fibroblasts, supporting the use of these hydrogel-linked liposomes as a thermo-responsive drug carrier for controlled release.