Dexime: A Selectively Enzyme-Degradable Hydrogel for Protein Therapeutic Release.

Abstract

Hydrogels are of great interest for the delivery of protein therapeutics as they obviate the denaturing shear forces and/or organic solvents common to other delivery systems. Dextrin, a polysaccharide derived from starch, has been largely ignored in the design of hydrogels, yet is biodegradable and can be modified to allow in situ gelation after injection by click-crosslinking. Herein, dextrin is modified with either ketone or aldehyde moieties and then click-crosslinked with poly(ethylene glycol)-tetraoxyamine to form dextrin-oxime (dexime) hydrogels. The rheological and mechanical properties are tunable by changing formulation parameters such as total dextrin weight percentage (wt.%) and pH. The hydrogels are injectable through a 30G needle, selectively degradable via α-amylase, yet stable and minimally swelling in the presence of other enzymes, including hyaluronidase and chondroitinase ABC (ChASE). The presence of low amounts of α-amylase in many fluids and tissues of the body allow for the slow degradation of dexime with minimal swelling. Dexime is particularly useful for local delivery of ChASE: an enzyme that degrades the aggregate scar formed after injury in the central nervous system. Dexime is cytocompatible and releases active ChASE both in vitro and in vivo as evidenced by chondroitin sulphate proteoglycan degradation in the spinal cord.