Azocalixarenes: a scaffold of universal excipients with high efficiency

Excipients are important components of pharmaceutical preparations that affect their quality, safety, and efficacy. Macrocyclic receptors are a family of supramolecular excipients with several advantages, including molecular-level protection, small sizes, fast kinetics of host-guest recognition, and modular construction. With the continuous advances in the medical field, personalized and precision medicine requires the development of excipients with low dosages, integrated modifying effects, universality, and controlled release. To meet these requirements, we have developed a new family of macrocyclic excipients based on calixarenes by integrating their covalent (broad chemical design space) and noncovalent (wide range of substrates) advantages. Accordingly, azocalixarenes (AzoCAs) were designed, showing high binding affinities to a broad spectrum of active pharmaceutical ingredients (APIs), selectivity to interferents, and responsiveness to hypoxic microenvironments. Due to their highly efficient and controllable recognition, AzoCAs serve as low-dose excipients for 30 APIs. Molecular encapsulation by AzoCAs results in the integrated modification of the physicochemical properties of APIs, including solubility, stability, bioavailability, and biocompatibility. Moreover, AzoCAs can be reduced by azoreductases overexpressed in hypoxic microenvironments, leading to the controlled release of APIs. Collectively, AzoCA excipients have broad application prospects for a series of diseases such as enteritis, arthritis, stroke, cancer, bacterial infection and kidney injury, with diverse therapeutic modalities, including chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, boron neutron capture therapy, radiotherapy, fluorescence imaging, and their combinations.