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

Abstract

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 drugloaded 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.

Supramolecular gels – a panorama of low-molecular-weight gelators from ancient origins to next-generation technologies

“…Recently, Kieltyka and co-workers explored a dynamic assembly system in which the anticancer drug doxorubicin could be incorporated non-covalently into LMWG assemblies by intercalation, or could react with the gelator scaffold via a bond forming reaction. 316 These outcomes could be tuned based on the dynamics of assembly and the formulation strategy. In the case where the drug became covalently coupled to the gelator framework, a greater degree of sustained release was observed.…”

Fluoride-Ion-Responsive Sol–Gel Transition in an L-Cysteine/AgNO3 System: Self-Assembly Peculiarities and Anticancer Activity

“…In this context, stimuli-responsive gels based on LMWGs could be prospective materials [5]. For instance, gels obtained from Lalanine derivatives [60], hydrazide/benzaldehyde derivatives [61] and small peptide derivatives [62,63] showed potential applications as matrices for the delivery of various…”

Controlled, supramolecular polymer formulation to engineer hydrogels with tunable mechanical and dynamic properties

“…While the Heilshorn lab combined covalent and non‐covalent synthesis on the hydrogel‐level 14 . In addition, the Kieltyka and Eelkema labs showed a covalent versus non‐covalent approach to in‐situ control hydrogel mechanics on the mesoscale 22 …”

“…14 In addition, the Kieltyka and Eelkema labs showed a covalent versus non-covalent approach to in-situ control hydrogel mechanics on the mesoscale. 22 Moving from a combined covalent and non-covalent approach to a fully supramolecular approach, the Stupp lab revealed that their thermodynamically favored peptide amphiphiles (PAs) formed long fibers that promoted cell adhesion and survival, while the metastable PAs assembled into short fibers leading to cell death. 21 The Adams lab reported on the controlled self-assembly of small molecules to yield functional materials: by employing short peptides and pH as a trigger, the gelation process and gel mechanics were tuned.…”