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Host–guest interactions have been increasingly explored for use in the dynamic physical crosslinking of polymeric precursors to form hydrogel networks. However, the orientation of guest motifs is restricted upon macromolecule conjugation. The implications of such restriction on both the kinetics and thermodynamics of the resulting host–guest supramolecular crosslinks are poorly understood. Herein, guest crosslinking motifs from controlled regioisomers are demonstrated to yield distinct material properties. Moreover, the underlying phenomena point to further unexpected impact of modular guest topology manifest on the molecular scale in both the affinity and dynamics of supramolecular complex formation. 

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. 

The cucurbit[n]uril (CB[ n]) family of macrocycles are known to bind a variety of small molecules with high affinity. These motifs thus have promise in an ever-growing list of trace detection methods. Surface-enhanced Raman scattering (SERS) detection schemes employing CB[ n] motifs exhibit increased sensitivity due to selective concentration of the analyte at the nanoparticle surface, coupled with the ability of CB[ n] to facilitate the formation of well-defined electromagnetic hot spots. Herein, we report a CB[7] SERS assay for quantification of phenylalanine (Phe) and further demonstrate its utility for detecting peptides with an N-terminal Phe. The CB[7]–guest interaction improves the sensitivity 5–25-fold over direct detection of Phe using citrate-capped silver nanoparticle aggregates, enabling use of a portable Raman system. We further illustrate detection of insulin via binding of CB[7] to the N-terminal Phe residue on its B-chain, suggesting a general strategy for detecting Phe-terminated peptides of clinically relevant biomolecules.