Cucurbit[7]uril (CB[7]) macrocycles exhibit a broad range of host–guest binding affinity. Attaching pendant CB[7] and complementary guests on 8-arm PEG macromers affords supramolecular hydrogels with cross-link affinity spanning more than 5 orders of magnitude (1.5 × 107 to 5.4 × 1012 M–1) without changing network topology. Cross-link affinity translates directly to bulk dynamic properties; hydrogels with high-affinity cross-linking behave like covalent gels with limited ability to relax or self-heal. Cross-link affinity furthermore dictates the release rate of encapsulated macromolecules, as well as cell infiltration and material clearance in vivo. This work thus informs a role for affinity in dictating supramolecular hydrogel properties by quantifying and isolating this feature over an unprecedented range.
Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization, yet often deliver considerably less than 1% of an administered drug to a desired site in the body. We report on an alternative targeting paradigm using pendant guest motifs to direct molecules to sites distinguished by a hydrogel bearing a high density of a complementary cucurbituril supramolecular host. Host–guest affinity ( K eq ) of 10 12 M –1 serves to spatially localize ∼4% of a model small molecule within hours of its administration in mice. These high-affinity interactions furthermore ensure long-lasting retention of the model compound at the site of interest, and the site can be serially targeted upon repeated dosing. This supramolecular homing axis extends the localization of small molecule payloads beyond injectable hydrogels, enabling targeting of modified biomaterials. This approach also has promising therapeutic utility, improving efficacy of a guest-modified chemotherapeutic agent in a tumor model.
Host-guest motifs are likely the most recognizable manifestation of supramolecular chemistry. These complexes are characterized by the organization of small molecules on the basis of preferential association of a guest within the portal of a host. In the context of their therapeutic use, the primary application of these complexes has been as excipients which enhance the solubility or improve the stability of drug formulations, primarily in a vial. However, there may be opportunities to go significantly beyond such a role and leverage key features of the affinity, specificity, and dynamics of the interaction itself toward “smarter” therapeutic designs. One approach in this regard would seek stimuli-responsive host-guest recognition, wherein a complex forms in a manner that is sensitive to, or can be governed by, externally applied triggers, disease-specific proteins and analytes, or the presence of a competing guest. This review will highlight the general and phenomenological design considerations governing host-guest recognition and the specific types of chemistry which have been used and are available for different applications. Finally, a discussion of the molecular engineering and design approaches which enable sensitivity to a variety of different stimuli are highlighted. Ultimately, these molecular-scale approaches offer an assortment of new chemistry and material design tools toward improving precision in drug delivery.
Host−guest physical cross-linking has been used to prepare supramolecular hydrogels for various biomedical applications. More recent efforts to endow these materials with stimuli-responsivity offers an opportunity to precisely tune their function for a target use. In the context of light-responsive materials, azobenzenes are one prevailing motif. Here, an asymmetric azobenzene was explored for its ability to form homoternary complexes with the cucurbit[8]uril macrocycle, exhibiting an affinity (K eq ) of 6.21 × 10 10 M −2 for sequential binding, though having negative cooperativity. Copolymers were first prepared from different and tunable ratios of NIPAM and DMAEA, and DMAEA groups were then postsynthetically modified with this asymmetric azobenzene. Upon macrocycle addition, these polymers formed supramolecular hydrogels; relaxation dynamics increased with temperature due to temperature-dependent affinity reduction for the ternary complex. Application of UV light disrupted the supramolecular motif through azobenzene photoisomerization, prompting a gel-to-sol transition in the hydrogel. Excitingly, within several minutes at room temperature, thermal relaxation of azobenzene to its trans state afforded rapid hydrogel recovery. By revealing this supramolecular motif and employing facile means for its attachment onto pre-synthesized polymers, the approach described here may further enable stimuli-directed control of supramolecular hydrogels for a number of applications.
Hydrogels prepared from supramolecular cross-linking motifs are appealing for use as biomaterials and drug delivery technologies. The inclusion of macromolecules (e.g., protein therapeutics) in these materials is relevant to many of their intended uses. However, the impact of dynamic network cross-linking on macromolecule diffusion must be better understood. Here, hydrogel networks with identical topology but disparate cross-link dynamics are explored. These materials are prepared from cross-linking with host–guest complexes of the cucurbit[7]uril (CB[7]) macrocycle and two guests of different affinity. Rheology confirms differences in bulk material dynamics arising from differences in cross-link thermodynamics. Fluorescence recovery after photobleaching (FRAP) provides insight into macromolecule diffusion as a function of probe molecular weight and hydrogel network dynamics. Together, both rheology and FRAP enable the estimation of the mean network mesh size, which is then related to the solute hydrodynamic diameters to further understand macromolecule diffusion. Interestingly, the thermodynamics of host–guest cross-linking are correlated with a marked deviation from classical diffusion behavior for higher molecular weight probes, yielding solute aggregation in high-affinity networks. These studies offer insights into fundamental macromolecular transport phenomena as they relate to the association dynamics of supramolecular networks. Translation of these materials from in vitro to in vivo is also assessed by bulk release of an encapsulated macromolecule. Contradictory in vitro to in vivo results with inverse relationships in release between the two hydrogels underscores the caution demanded when translating supramolecular biomaterials into application.
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