Switching the Mode of Drug Release from a Reaction-Coupled Low-Molecular-Weight Gelator System by Altering Its Reaction Pathway

• Published in: Biomacromolecules 2023-01, Vol.24 (1), p.377-386
• Main Authors: Noteborn, Willem E. M., Vittala, Sandeepa K., Torredemer, Maria Broto, Maity, Chandan, Versluis, Frank, Eelkema, Rienk, Kieltyka, Roxanne E.
• Format: Article
• Language: English
• Subjects: Doxorubicin - pharmacology; Drug Delivery Systems; Drug Liberation; Hydrogels
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.2c01197

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.