Design and characterization of matrix metalloproteinase-responsive hydrogels for the treatment of inflammatory skin diseases

Enzyme-responsive hydrogels, formed by step growth photopolymerization of biscysteine peptide linkers with alkene functionalized polyethylene glycol, provide interesting opportunities as biomaterials and drug delivery systems. In this study, we developed stimuli-responsive, specific, and cytocompatible hydrogels for delivery of anti-inflammatory drugs for the treatment of inflammatory skin diseases. We designed peptide linkers with optimized sensitivity towards matrix metalloproteinases, a family of proteolytic en-zymes overexpressed in the extracellular matrix of the skin during inflammation. The peptide linkers were crosslinked with branched 4-arm and 8-arm polyethylene glycols by thiol-norbornene photopoly-merization, leading to the formation of a hydrogel network, in which the anti-inflammatory Janus kinase inhibitor tofacitinib citrate was incorporated. The hydrogels were extensively characterized by physical properties, in vitro release studies, cytocompatibility with fibroblasts, and anti-inflammatory efficacy test-ing in both an atopic dermatitis-like keratinocyte assay and an activated T-cell assay. The drug release was studied after single and multiple-time exposure to matrix metalloproteinase 9 to mimic inflamma-tory flare-ups. Drug release was found to be triggered by matrix metalloproteinase 9 and to depend on type of crosslinker and of the polyethylene glycol polymer, due to differences in architecture and swelling behavior. Moreover, swollen hydrogels showed elastic properties similar to those of extracellular matrix proteins in the dermis. Cell studies revealed limited cytotoxicity when fibroblasts and keratinocytes were exposed to the hydrogels or their enzymatic cleavage products. Taken together, our results suggest multi -arm polyethylene glycol hydrogels as promising matrix metalloproteinase-responsive drug delivery sys-tems, with potential in the treatment of inflammatory skin disease.

Automated summary

This study developed enzyme-responsive hydrogels for the delivery of anti-inflammatory drugs for the treatment of inflammatory skin diseases. The hydrogels were crosslinked with polyethylene glycols using peptide linkers that were sensitive to matrix metalloproteinases. The drug release was triggered by matrix metalloproteinases and depended on the type of crosslinker and polyethylene glycol polymer.