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.