(33f) Injectable Supramolecular Hydrogels with Quasi-Covalent Crosslinking

Introduction: There is great possible benefit to the use of principles from supramolecular chemistry to improve the practice of biomaterials for drug delivery. These materials, characterized by dynamic and reversible crosslink formation and mechanics that are tunable through molecular design, offer a new route to shear-thinning, self-healing hydrogels amenable to routine injection with a myriad number of possible functions. In one interesting approach, an injectable supramolecular hydrogel may have utility in the localized delivery of drug to a precise site, or may even enable localized homing of a systemically administered drug. Pharmaceutical practice suffers from poor regional selectivity in drug action, and materials may play a role in overcoming this by localizing drug action.

Methods: Supramolecular macrocycles were synthesized by retrosynthetic means to access a monofunctional variants bearing a single azide group. In parallel, thermoresponsive PEG-based polymers were synthesized and decorated on both ends with our macrocycles through azide-alkyne cycloaddition “click” chemistry. Oscillating parallel plate rheometry was performed to determine the gelation kinetics, thermoresponsiveness, and shear-thinning self-healing properties of these hydrogels to evaluate injectable use. A suite of model prodrugs was synthesized by conjugating different cyanine dyes to high-affinity guests for the macrocycles. Hydrogels were subcutaneously injected into mice, and model prodrug dyes were then administered systemically. In vivo fluorescence imaging was used to monitor homing of drug to the site of the implanted hydrogel depot. Then, model chemotherapeutics were constructed to interface with this injectable hydrogel homing beacon, for localized chemotherapeutic practice in overcoming tumor burden.

Results: We have developed and scaled a synthetic procedure to create supramolecular macrocycles for click chemistry, enabling gram-scale quantities for orthogonal preparation of hydrogel biomaterials. We next made a PEG-based polymer that undergoes a transition from hydrophobic to hydrophilic around 30 °C. After decorating the ends of this polymer, we achieved thermal gelation of this polymer into three-dimensional percolated hydrogel networks (Figure 1). Oscillating rheometry confirmed a transition from sol to gel upon raising temperatures from ambient (22 °C) to physiologic (37 °C), as well as shear-thinning self-healing behavior common in injectable hydrogels. Thus, the supramolecular interactions underlying polymer crosslinking in this material facilitated dynamic, responsive, and healable properties. We next demonstrated affinity-mediated loading from a suite of near-infrared model prodrugs, with lower affinity guests being displaced by higher affinity guests. Finally, we injected this material subcutaneously into a mouse and administered fluorescent prodrugs systemically. In so doing, we have elucidated the precise monovalent affinity required to overcome physiologic dilution and competition in driving a drug to a depot. This approach extended to demonstrated benefit in tumor prevention in a mouse cancer model.

Conclusions: The creation of thermally gelling hydrogels from dynamic supramolecular interactions affords ideal properties for injectable biomaterial drug depots. The attachment of supramolecular macrocycles on these materials facilitates sites for affinity loading of drugs, even allowing for systemic drug administration and depot filling as well as switching the drug on board the device by tuning affinity. This approach will enable improved drug localization as well as the ability to remote control drug identity and loading in an implanted depot for better spatiotemporal therapy.