Pillar[5]arene pseudo[1]rotaxane-based redox-responsive supramolecular vesicles for controlled drug release

Supramolecular chemotherapy represents an emerging research field, where the construction of new supramolecular amphiphilic assemblies for the targeted release of anticancer drugs in a controlled manner is of great importance although still very challenging. In this work, we construct a unique amphiphilic pillar[5]arene-based pseudo[1]rotaxane (PPR) with a dynamic redox-responsive disulfide bond in the self-included linker and employ it as the hydrophobic core entity followed by the covalent attachment of a biocompatible poly(ethylene glycol) (PEG) polymer as a hydrophilic long arm via a DCC/DMAP-mediated coupling reaction. A number of amphiphilic PPR molecules can self-assemble to form uniform supramolecular vesicles with good colloidal stability in an aqueous solution, which can be disassembled in the presence of a high concentration of glutathione (GSH) resulting from the breakage and exchange of the disulfide bonds in the system. Interestingly, the vesicle system is capable of encapsulating anticancer drug doxorubicin (DOX) with a high loading efficiency to realize controlled drug delivery. Significantly, in vitro experiments reveal that the free vesicles possess non-cytotoxicity while the DOX-loaded vesicles can not only achieve a precise release of DOX but also enhance the efficiency of killing cancer cells such as human lung cancer cell line A549. To the best of our knowledge, this is the first use of pseudo[1]rotaxane-based materials to protect a vulnerable responsive bond in drug delivery systems, which specifically realizes zero premature release of drugs, leaving the healthy cells unharmed, and offers a new possibility for the application of supramolecular amphiphiles and molecular machinery in precise cancer therapy.