Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition

Abstract

Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodeling. While MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application due 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 over-expression following a myocardial infarction (MI) significantly reduced MMP activity and attenuated adverse left ventricular remodeling in a porcine model of MI. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.

Preparation and Supramolecular Recognition of Multivalent Peptide–Polysaccharide Conjugates by Cucurbit[8]uril in Hydrogel Formation

“…Examples of their use in the formation of hydrogels through covalent cross-linking lower molecular weight polysaccharide species has shown good promise in recent reports, especially as 3D cell culture scaffolds and implantable drug delivery depots and can be considered strong competitors. 11,12 However, covalently cross-linked hydrogels, although strong, lack the ability to self heal once the network is broken through significant shear strain, and the material strength is dependent on the shortest chain, which experiences the most stress. [13][14][15] These shortcomings are being addressed by employing dynamic 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 and reversible non-covalent interactions as structural cross-links in hydrogels, 16 although introduction of dynamic binding moieties is rarely seen within polysaccharide chemistry, particularly with large molecular weight materials, as they are often difficult to functionalise on account of highly viscous reaction mixtures, large degrees of steric hindrance, and strong hydrogen bonding networks that render many reactive handles such as hydroxyl groups practically inert.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Proteins can be immobilized in a hydrogel using chemical conjugation (Ehrbar et al, 2007). Drug release is dictated by the rate of hydrogel degradation, which can be tuned to be environmentally responsive to enzymes [e.g., MMPs (Purcell et al, 2014)] secreted by, for example, NSPCs (Barkho et al, 2008) or endothelial cells (Rundhaug, 2005).…”

Progress in material design for biomedical applications

“…In the body, supramolecular presentation of bio-signals is exemplified by native extracellular matrix (ECM) interactions, including receptor-ECM interactions and heparin-binding proteins. As such, biomolecule presentation through supramolecular interactions has emerged as a means of controllable delivery (6), including through cyclodextrin-mediated sequestration of small molecules (7) or biomimetic electrostatic protein-matrix interactions (8). Beyond the capacity for single molecule-matrix interactions, the general ECM structure itself is largely the result of self-assembly (e.g., fibrillar structure of collagen) and can be recapitulated, in part, by well-designed synthetic analogs.…”