Integrating stimuli–responsive properties in host–guest supramolecular drug delivery systems

Abstract

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.