Copper-Consuming\nNanoplatform for Alleviating Hypoxia\nand Overcoming Resistance to Sonodynamic Therapy of Breast Cancer

Sonodynamic\ntherapy (SDT) is a promising treatment modality for\nbreast cancer; however, its effectiveness is often impeded by the\nhypoxic tumor microenvironment owing to an insufficient oxygen supply\nin the solid tumors. To overcome this challenge, we elaborately developed\na 4T1 tumor-targeted multifunctional nanoagent by integrating both\ndendrimer-structured copper chelating agents and organic sonosensitizers\n(IR820) into a biotin-modified nanoliposome via a microfluidic-assisted\nself-assembly. In particular, the aforementioned copper chelating\nagent was constructed by introducing multiple xanthate groups into\na dendrimer polymer, which showed a significant selectivity for the\nconsumption of the intracellular copper levels. Based on this, the\nnanoliposome-based therapeutic not only disrupted the activity of\nthe mitochondrial complex IV to directly inhibit the tumor cell proliferation\nbut also suppressed the resistance to the SDT via inhibition of the\noxygen consumption for cellular respiration. Both <i>in vitro</i> and <i>in vivo</i> studies confirmed that the designed\nnanoagents exhibit a synergistic tumor inhibition effect of copper\nconsumption and IR820-mediated SDT. Taken together, this approach\nestablishes a proof-of-concept for the construction of a copper-ion-modulated\nnanomedicine to significantly enhance the efficiency of oxygen-dependent\ncancer treatments.