Low-molecular-weight hydrogels are attractive scaffolds for drug delivery applications because of their modular and facile preparation starting from inexpensive molecular components. The molecular design of the hydrogelator results in a commitment to a particular release strategy, where either noncovalent or covalent bonding of the drug molecule dictates its rate and mechanism. Herein, we demonstrate an alternative approach using a reaction-coupled gelator to tune drug release in a facile and user-defined manner by altering the reaction pathway of the low-molecular-weight gelator (LMWG) and drug components through an acylhydrazone-bond-forming reaction. We show that an off-the-shelf drug with a reactive handle, doxorubicin, can be covalently bound to the gelator through its ketone moiety when the addition of the aldehyde component is delayed from 0 to 24 h, or noncovalently bound with its addition at 0 h. We also examine the use of an l-histidine methyl ester catalyst to prepare the drug-loaded hydrogels under physiological conditions. Fitting of the drug release profiles with the Korsmeyer-Peppas model corroborates a switch in the mode of release consistent with the reaction pathway taken: increased covalent ligation drives a transition from a Fickian to a semi-Fickian mode in the second stage of release with a decreased rate. Sustained release of doxorubicin from the reaction-coupled hydrogel is further confirmed in an MTT toxicity assay with MCF-7 breast cancer cells. We demonstrate the modularity and ease of the reaction-coupled approach to prepare drug-loaded self-assembled hydrogels in situ with tunable mechanics and drug release profiles that may find eventual applications in macroscale drug delivery.

Researchers investigated the effect of various (bio)polymeric crosslinkers on the self-assembly process of this reaction-coupled hydrazide-aldehyde gelator into hydrogel materials as a model system. They selected duplex DNA, which acted as a stiff, negatively charged rigid rod below its persistence length ideal for the construction of (nano)materials,[38–40] and compared it against a soft, neutral poly(ethylene glycol) (PEG) polymer of comparable size. Aldehyde moieties were specifically incorporated at the terminal ends of the (bio)polymers to introduce them during the self-assembly of the reaction-coupled network composed another set of (bio)polymers. The researchers also examined the effect of these two crosslinkers on the gelation of the reaction-coupled monomers into hydrogels over several length scales and compared their resultant materials properties.