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.

Capture of Phenylalanine and Phenylalanine-Terminated Peptides Using a Supramolecular Macrocycle for Surface-Enhanced Raman Scattering Detection

“…18 These and other macrocycles serve as host receptors in binding a variety of small molecule guests within the cavity of the macrocycle, with possible applications in affinity-mediated binding and sensing. 19,20 CB[ n ] has particular applicability in SERS techniques as its carbonyl-fringed portal offers affinity for noble metal surfaces, enabling the macrocycle to lay flat with its portal exposed; SERS enhancements of up to 10 9 are thus afforded through formation of NP hostspots. 21 These enhancements give rise to SERS assays with detection capabilities down to 10 −11 M, with even the single molecule regime possible.…”

Facile Engineering of Anti‐Inflammatory Nanotherapies by Host‐Guest Self‐Assembly

“…Host‐guest interactions between drug molecules and cyclodextrin‐containing polymers have been extensively employed to develop various therapeutic delivery systems . According to the above finding, small hydrophobic guest molecules can induce self‐assembly of PEICDs in aqueous solution.…”

Supramolecular nanomaterials based on hollow mesoporous drug carriers and macrocycle-capped CuS nanogates for synergistic chemo-photothermal therapy

“…On the other hand, due to the fascinating properties of high stability 29-31, large loading capacity 32,33, facile functionalization 34-35, and good biocompatibility 36,37, hollow mesoporous silica NPs (HMSNs) have become suitable nanocarriers for enhancing the accumulation at tumor sites via enhanced permeability and retention effect (EPR effect) and improving the therapeutic effect 38-40. We envision, via the marriage of the abovementioned two systems with supramolecular host-guest chemistry as a magpie bridge, new multifunctional supramolecular drug delivery platform comprising efficient PTT entity, anticancer drug carriers with high loading capacity, and multi-stimuli responsive gating functions 41-47 can be constructed to solve the problems and greatly improve the synergistic therapeutic effects with combined chemotherapy and PTT 48-50. Meanwhile, an active targeting strategy by installing folic acid (Fa) ligand 51 in the supramolecular platform as antennas to recognize the over-expressed folate receptor (FR) on tumor cells can also be integrated in the design to improve cell internalization via the route of folate-mediated endocytosis 52,53.…”