Supramolecular Chemotherapy: Noncovalent Bond Synergy of Cucurbit[7]uril against Human Colorectal Tumor Cells

Supramolecular chemotherapy has drawn increasing interest due to its ability to improve the efficiency of antitumor drugs and fewer associated toxic side effects. In this study, the smart supramolecular cargo, the doxorubicin-ZnO-cucurbit[7]uril (CDZ) nanocomplex, was constructed through ion-dipole interactions between cucurbit[7]uril {CB[7]} and doxorubicin-ZnO (dox-ZnO). The binding affinity of CB[7] and dox-ZnO was determined to be 10⁴ M^-1 by isothermal titration calorimetry. Importantly, spermine had a stronger binding affinity (10⁶ M^-1) with CB[7] than dox-ZnO through host-guest interactions. In the tumor microenvironment, spermine disassembled the CDZ nanocomplex, and dox was released from the nanocomplex by XRD, UV-visible spectra, and contact angle analysis. Compared to the single drug dox, the CDZ nanocomplex was demonstrated to possess higher activity of killing colorectal tumor cells by confocal laser scanning microscopy and cytotoxicity, which could be attributed to spermine concentration, spermine synthase, free radical damage, and G₁ cell cycle arrest. Overall, the supramolecular delivery of dox can enhance the inhibition of human colorectal tumor cell proliferation and reduce cytotoxicity in human myocardial cells through the noncovalent bond synergy of {CB[7]}.