Supramolecular Drug-Drug Complex Vesicles Enable Sequential Drug Release For Enhanced Combination Therapy (Vol 12, Pg 27940, 2020)

Drug-drug self-delivery systems serving as both carriers and cargos have been explored as advanced combination chemotherapy strategies to overcome the limitations of traditional single-drug chemotherapy. However, most known drug-drug self-delivery systems may cause a rapid increase in drug concentration when the single covalent bond is broken, thus leading to high toxicity to organs and low therapeutic efficiency against tumours. To address the above problem, in this study, a novel supramolecular drug-drug complex (SDDC) simultaneously containing both covalent and non-covalent bonds was proposed to realize the sequential release of two drugs in tumour cells for enhanced combination therapy. The SDDC could self-assemble into uniform bilayered supramolecular vesicles (SVs) with a remarkable drug loading capacity and stable drug transport. Notably, the SVs with controlled sequential release ability in tumour cells exhibited a superior synergistic effect and significantly improved therapeutic efficiency with reduced toxicity in in vivo antitumour activity and histological analyses in comparison with either individual free drugs or a mixture of two free drugs. Therefore, this study combining the advantages of non-covalent interactions with the dynamic nature and stable covalent bonds opens a new way for cancer therapy.