Drug in Drug: A Host–Guest Formulation of Azocalixarene with Hydroxychloroquine for Synergistic Anti‐Inflammation

Abstract

Macrocyclic delivery and therapeutics are two significant topics in supramolecular biomedicine. The functional integration of these topics would open new avenues for treating diseases synergistically. However, these two individual topics have only been occasionally merged, probably because of the lack of functionalized design of macrocyclic host and the lack of efficient recognition between host and guest drugs. Herein, a “drug‐in‐drug” strategy is proposed, in which an active drug is encapsulated by a macrocycle possessing therapeutic activity to form a multifunctional supramolecular active pharmaceutical ingredient. As a proof‐of‐concept, a complex of hydroxychloroquine (HCQ) with sulfonated azocalix[4]arene (HCQ@SAC4A) is prepared to treat rheumatoid arthritis (RA) in a combined fashion. SAC4A is a therapeutic agent that exhibits scavenging capacity for reactive oxygen species and exerts an anti‐inflammatory effect. It is also a hypoxia‐responsive carrier that can deliver HCQ directly to the inflammatory articular cavity. Consequently, HCQ@SAC4A achieves the synergistic anti‐inflammatory effect on both inflamed RAW 264.7 cells and RA rats. This effect is attributed to the temporal and spatial consistency of the two active ingredients of the complex. As a new paradigm for combinational therapy, the drug‐in‐drug strategy advances in easy preparation, mix‐and‐match combination, and precise ratiometric control.

Triple targeting host–guest drug delivery system based on lactose-modified azocalix[4]arene for tumor ablation

“…Design and construction of the triple targeting HGDDS DOX@LacAC4A Azocalixarenes, as an emerging kind of macrocyclic carrier, have attracted considerable attention and have been applied in several hypoxia related diseases. 41,42,[56][57][58][59][60] The azobenzene modification endows azocalixarenes with a deep cavity, which greatly improves the binding abilities of therapeutic agents that decrease the premature dissociation during circulation. 38 Moreover, the azo group is hypoxia-responsive as it can be specifically reduced by azoreductases, which are overexpressed under the hypoxia microenvironment.…”

Preparation and Characterization of Insecticide/Calix[4]arene Complexes and Their Enhanced Insecticidal Activities againstPlutella xylostella

“…For example, avermectin/β-cyclodextrin inclusion complexes were reported to improve the water solubility and insecticidal activity of avermectin while reducing its human cytotoxicity. A β-cyclodextrin-functionalized metal–organic framework was designed for carrying indoxacarb to enhance the insecticidal activity. , In recent years, calixarenes possessing well-defined architecture, easy preparation, low toxicity, and variable physicochemical properties have been constantly used as multifunctional drug carriers. , They can increase the solubility and penetrating ability of drug molecules, thus improving the bioavailability and bioactivity. , However, the applications of calixarenes in the field of pesticide have been limited to the separation, detections, , and fluorescence imaging . To our surprise, the effect of calixarenes on enhancing pesticidal activity has not yet been reported.…”

“…23,24 In recent years, calixarenes possessing well-defined architecture, easy preparation, low toxicity, and variable physicochemical properties have been constantly used as multifunctional drug carriers. 25,26 They can increase the solubility and penetrating ability of drug molecules, thus improving the bioavailability and bioactivity. 27,28 However, the applications of calixarenes in the field of pesticide have been limited to the separation, 29 detections, 30,31 and fluorescence imaging.…”

Enhanced molecular binding affinity toward aromatic dications by anthracene-derived crown ethers in water

“…Progress in the field of supramolecular chemistry has been driven by the need for rationally designed synthetic receptors for applications in self-assembly processes, 1 molecular machines, 2 and functional materials, 3 especially in aqueous environments. 4 In this context, a variety of macrocyclic receptors, including crown ethers, 5 cyclodextrins, 6 calixarenes, 7 and cucurbiturils, 8 have drawn considerable attention in recent decades owing to their strong binding affinities toward a wide range of molecules and organic cations. Moreover, considering water is a unique, ubiquitous solvent in many chemical and biological processes, water-soluble macrocyclic receptors are of particular interest and are widely used as molecular sensors, 9 amphiphilic assemblies, 10 and hydrogels.…”