Glutathione-depleted and cancer-targeted nanocapsules encapsulating bimetallic oxide nanoparticles for enhanced chemo-sonodynamic therapy

Abstract

Sonodynamic therapy (SDT) has emerged as a promising noninvasive therapeutic modality due to its deep tissue penetration depth. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanocapsules encapsulating oxygen-deficient MnWOx nanoparticles (NPs) and doxorubicin (DOX) were fabricated for chemo-sonodynamic combination therapy against cancer. To achieve cancer-targeted chemo-SDT, PLGA was conjugated to a cancer-targeting biotin through poly(ethylene glycol) (PEG). Biotin-PEG-PLGA (BP-PLGA) nanocapsules encapsulating DOX and hydrophobic MnWOx NPs (BP-PLGA-DOX@MnWOx) exhibited high physiological stability and pH-responsive drug release. The oxygen-deficient MnWOx NPs enabled US-triggered generation of singlet oxygen and hydroxyl radicals owing to their oxygen-deficient structures that prevent electron–hole recombination. Glutathione (GSH) depletion by MnWOx-loaded PLGA nanocapsules was observed in MCF-7 human breast cancer cells, which leads to augmented intracellular ROS levels and sonodynamic effects. Notably, BP-PLGA-DOX@MnWOx greatly improved cellular uptake by breast cancer cells, resulting in efficient intracellular delivery of DOX and MnWOx NPs. As a result, BP-PLGA-DOX@MnWOx exhibited efficient and cancer-targeted cytotoxicity in MCF-7 cells upon US irradiation. This study demonstrates that BP-PLGA-DOX@MnWOx nanocapsules are promising cancer-targeting nanosonosensitizers for efficient chemo-sonodynamic cancer therapy.