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 (t(1/2) 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 degrees C. Differences in ester hydrolysis rates of individual chains translated into a ca. 12-fold difference in hydrogel degradation rate (R-gels: t(1/2) = 7.53 days, D-gels: t(1/2) = 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: t(1/2) = 3.32 days, D-gels: t(1/2) = 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.