Hypoxia-Responsive Host–Guest Drug Delivery System

Abstract

Conspectus A host–guest drug delivery system (HGDDS) refers to a host–guest complex of an artificial receptor and a therapeutic agent which can dissociate at the lesion site and release the loaded cargo. Macrocyclic receptors are promising drug carriers because of their superior properties, including ease of preparation, precise molecular weight, well-defined molecular structure, and excellent chemical stability. The host–guest loading process is mild, simple, and repeatable. The host–guest formulations can quantitatively load drug because of the exact cavity-loading pattern and quantifiable host–guest binding constant. Host–guest formulations are typically modular, which may be appealing in the context of personalized medicine because the macrocyclic carriers can act as a platform to complex diverse drugs. These lead to good batch reproductivity and excellent application prospects in both scientific research and industry. However, in order to make the HGDDS more suitable for practical application, several demands such as high binding affinity, universal binding to multiple drugs, targeting, and stimuli-responsiveness still need to be considered. The process of hypoxia is linked to several diseases and biological processes, including cancer, acute and chronic diseases, pathogenic microbe infection, and other stress responses. As part of our ongoing research on supramolecular biomaterials based on macrocycles by taking advantage of their recognition and assembly properties, we have developed a hypoxia-responsive HGDDS based on azocalixarenes. These azocalixarenes possess a deepened cavity, resulting in high binding affinities and high encapsulation efficiencies toward therapeutic agents. The azo group is one of the most frequently employed hypoxia-responsive moieties as it can be reduced under hypoxic microenvironments. This property confers the carriers with hypoxia-triggered release due to the remarkable decrease in binding affinities following reduction. The fast release kinetics further facilitates the efficient accumulation of drugs at the lesion site. These azocalixarene-based HGDDSs have been applied in preclinical studies for diagnosis and treatment of several diseases including tumor, bacterial infection, kidney injury, and rheumatoid arthritis. In this Account, we outline our recent efforts in designing and formulating HGDDSs based on azocalixarenes. We first provide a brief introduction of HGDDSs, including their features, the quantitative loading and ratiometric delivery models. Then the molecular design principles and synthesis methods, the strong binding affinity, the drug loading, and the fast hypoxia-response of azocalixarene-based HGDDSs are described. The applications of azocalixarene-based HGDDSs in treating different diseases are followed. Finally, despite the rapid development of azocalixarene-based HGDDSs, there are still several problems that need to be solved both scientifically and in terms of clinical translation. Therefore, we propose perspectives that can be further conducted on HGDDSs.

Expanding the Hydrophobic Cavity Surface of Azocalix[4]arene to Enable Biotin/Avidin Affinity with Controlled Release

“…Our previous works developed a series of phenyl azo units functionalized calixarenes [27] with significantly deepened cavities, such as SAC4A (Figure 1d). These azocalix- [4]arenes exhibited medium-to-strong binding affinities in the range of 10 5 -10 8 M À 1 towards a broad range of hydrophobic guests [28] in aqueous solution.…”

Supramolecular Integration of Multifunctional Nanomaterial by Mannose-Decorated Azocalixarene with Ginsenoside Rb1 for Synergistic Therapy of Rheumatoid Arthritis

“…A calixarene skeleton was selected because of its easy synthesis and modification and inherent ROS scavenging capacity (Figure ). , The azo groups were introduced quantitatively by industrialized diazonium coupling reaction under mild conditions. , Azo modification could deepen the cavity, thereby enhancing the recognition capacity of calix[4]­arene toward drugs by increasing the area of hydrophobic contact and enhancing the hydrophobic effect between host and guest and by maintaining the structural rigidity of the preorganized scaffold of the macrocycle. , Moreover, azo groups provide responsive drug release in the hypoxic inflammatory microenvironment based on its sensitivity to reduction (Figure S1). Azocalix[4]­arene is a modular platform that is adaptable to various drugs and easily further modified.…”

Supramolecular interaction in the action of drug delivery systems

“…Interested readers are encouraged to refer to our previously published reviews on the subject. 133–135…”