Self-motivated supramolecular combination chemotherapy for overcoming drug resistance based on acid-activated competition of host–guest interactions

In this work, we propose a nanoparticle-based strategy of self-motivated supramolecular combination chemotherapy that carries drugs stably and releases them actively in the acidic tumor microenvironment to overcome the drug resistance of cancer cells. This self-motivated nanoparticle consists of a cucurbit [7]uril-containing polymer (PCB)-based core, in which the oxaliplatin and a mitochondria-targeting cytotoxic peptide with an N-terminal phenylalanine are stably loaded through host–guest interactions, and a polymeric protection shell containing acid-activated competitors for releasing drugs. In the acidic tumor environment, the protected aminomethyl phenylalanine moieties on the polymer shell were recovered with a remarkable increase in the binding constant toward cucurbit[7]uril, which competitively replaced and released the combination drugs in PCB. With the synergistic effect of released mitochondria-targeting cytotoxic peptides that effectively inhibited the energy-dependent drug efflux, this self-motivated nanoparticle augmented the anticancer activity of oxaliplatin against drug-resistant cells. This strategy of self-motivated supramolecular combination chemotherapy provides a new method for efficient combination of chemical drugs and bioactive peptides with on-demand drug release, and opens a great prospect for supramolecular chemotherapy toward overcoming the drug resistance of cancers.