Photo‐ and pH‐ Dual‐Responsive β‐Cyclodextrin‐Based Supramolecular Prodrug Complex Self‐Assemblies for Programmed Drug Delivery

: Despite the fact that progress has been made in the application of supramolecular prodrug self-assemblies to enhance the functionality of drug-delivery systems, corresponding research on multi-responsive supramolecular prodrug self-assemblies for programmed drug delivery is still limited. In this paper, the synthesis and self-assembly behavior of supramolecular prodrug complexes (SPCs) with β-cyclodextrin-acylhydrazone-doxorubicin (β-CD-hydrazone-DOX) and the targeting of azobenzene-terminated poly[2-(dimethylamino)ethyl methacrylate] (Azo-PDMA-FA) as a building block were investigated. The obtained SPCs could also form self-assemblies on the basis of their amphiphilic nature. Next, SPC-based multi-compartment vesicles and complex micelles, which were confirmed by transmission electron microscopy and dynamic/static light scattering, were obtained with good reversibility under alternative visible light or UV irradiation. Furthermore, three-stage programmed drug-delivery behavior was observed from dual-responsive SPC-based self-assemblies by utilizing UV and pH stimuli. Specifically, the SPCs first self-assembled into multicompartmental vesicles, which was accompanied by a slow release of DOX. Next, UV-light irradiation induced the dissociation of β-CD/Azo, which led to morphology transition and a slight increase in the rate of release of DOX. Upon transferring the self-assemblies to phosphate-buffer solution (pH 5.0), the release rates increased notably as a result of the broken acylhydrazone bond. Finally, basic cell experiments further demonstrated that the SPC-based self-assemblies could be internalized into cancer cells, which suggests their promise for applications in cancer therapy.