Triple stimuli-responsive supramolecular nanoassembly with mitochondrial targetability for chemophotothermal therapy

Mitochondria play crucial roles in a variety of cellular physiological processes, mitochondria-accumulating drug delivery has drawn pronounced attention in the field of cancer theranostics. Camptothecin (CPT) is a DNA Topoisomerase I inhibitor and exerts a broad-spectrum anticancer profile. Berberine (BBR) is able to perferably enter into cancer cell mitochondria and trigger the cell apoptosis. In this work, CPT and BBR were combined together (CPT-ss-BBR) through GSH-responsible disulfide bond, and then co-assembled with photosensitizer indocyanine green (ICG) into nanodrugs (CPT-ss-BBR/ICG NPs), which was driven through hydrophobic, π-π stacking and especially, electrostatic interactions of anions and cations as found by molecular dynamics simulations and quantum chemistry calculations. Our developed nanodrugs displayed an average size of ~168 nm and showed exceptional instability by irradiation presence, acid condition and high concentration of GSH, thereby eliciting the rapid disassembly and accelerating drug release. The better therapy effect of CPT-ss-BBR/ICG NPs on A549 cells might be attributed to triply stimuli-responsive rapid disassembly, preferable accumulation into mitochondria and combined chemotherapy and photothermal therapy, all of which directly rendered the notable loss of mitochondria membrane potential, high level of reactive oxygen species in cancer cells, accelerated the apoptosis of cancer cells and repressed the growth of tumors.