An Antitumor Dual‐Responsive Host‐Guest Supramolecular Polymer Based on Hypoxia‐Cleavable Azocalix[4]arene

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli‐responsive supramolecular polymers (SPs) based on host–guest interactions. Most functional guests, however, fail to manifest stimuli‐responses. Herein, a hypoxia‐responsive dimeric azocalixarene (D‐SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli‐responsive SPs. Since azocalixarenes can also be compatible with stimuli‐responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide‐containing linker to afford a glutathione (GSH)‐responsive ditropic guest (D‐CPT). A unique dual‐responsive SP was obtained by 1 : 1 mixing of D‐SAC4A and D‐CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT‐release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor‐suppressive effects of DSPNs. A host–guest dual‐response supramolecular polymer was prepared based on a dimeric hypoxia‐responsive azocalixrene and GSH‐cleavable CPT dimer (D‐CPT), which further self‐assembles into nanoparticles and exhibits excellent antitumor therapy performance.