Tailoring hydrogel degradation and drug release via neighboring amino acid-controlled ester hydrolysis

We present a versatile scheme to rationally modulate the hydrolysis rate of ester bonds in hydrophilic polymer networks via adjacent charged amino acids. As soluble model systems, two cysteine-bearing oligopeptides containing either positively charged arginine (GRCRGGRCRG, termed R-linker) or negatively charged aspartic acid (GDCDGGDCDG, termed D-linker) were linked to monomethoxy PEG-acrylate via Michael-type addition, and the hydrolysis rate of the conjugates was monitored using HPLC. A ca. 6-fold difference in hydrolysis kinetics of the conjugates was determined, positively charged arginine leading to an increased hydrolysis rate (t1/2 of 6.56 days vs. 36.1 days for the R- and D-linker containing conjugates, respectively). As a first step towards utilizing this concept to create tunable matrices for drug delivery and tissue engineering, the above peptides were crosslinked into hybrid hydrogels (R-gels and D-gels) by mixing with 4-arm PEG-acrylate at variable stoichiometric ratios. The physicochemical gel properties were characterized and gel degradation kinetics were quantified by monitoring the gel weight change over time at pH 7.4 and 37 °C. Differences in ester hydrolysis rates of individual chains translated into a ca. 12-fold difference in hydrogel degradation rate (R-gels: t1/2 = 7.53 days, D-gels: t1/2 = 86.6 days). Finally, the gel release kinetics of covalently linked bovine serum albumin (BSA) was also shown to be highly dependent on the charge of adjacent amino acids (R-gels: t1/2 = 3.32 days, D-gels: t1/2 = 32.1 days). With the availability of 20 natural amino acids as building blocks to modulate the chemical environment in close proximity of labile esters, we expect this work will provide a generalizable framework for the engineering of hybrid polymer-co-peptide gels with tunable and predictive degradation and drug release properties.