Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition

Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodelling. Although MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application owing to the dose-limiting side effects following systemic administration of the drugs. Here, we describe the synthesis of a polysaccharide-based hydrogel that can be locally injected into tissues and releases a recombinant tissue inhibitor of MMPs (rTIMP-3) in response to MMP activity. Specifically, rTIMP-3 is sequestered in the hydrogels through electrostatic interactions and is released as crosslinks are degraded by active MMPs. Targeted delivery of the hydrogel/rTIMP-3 construct to regions of MMP overexpression following a myocardial infarction significantly reduced MMP activity and attenuated adverse left ventricular remodelling in a porcine model of myocardial infarction. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel. Excessive activity of matrix metalloproteinases (MMPs) occurs in many diseases; however, the systemic administration of MMP inhibitors can cause undesirable, off-target effects and hence, clinical translation has been hampered. Now, injectable polysaccharide-based hydrogels are shown to enable the localized delivery of an inhibitor of MMP following the hydrogels’ degradation in response to MMP activity. This targeted approach shows efficacy in a myocardial infarction model in large animals.