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The temporal and quantitative control of the cargo release is a challenging issue in the application of hydrogels for cancer therapy. Here, we report hyaluronic acid hydrogel-based depot that provides ultrasound-triggered thermal elevation and on-demand cargo release. The hyaluronic acid hydrogel was developed by employing the gold cluster as a sonothermal crosslinker which was grown on the cargo to prevent its undesired leakage until ultrasound-induced dissociation. The results demonstrated that, in the presence of ultrasound at 30 W, the hyaluronic acid hydrogel significantly increased the temperature to 53.7 °C, leading to dissociation of gold clusters and subsequent cargo release. In addition, the prepared hydrogel exhibited appropriate mechanical properties and superior biostability as an injectable hydrogel for in vivo applications.

Glutathione (GSH), a tripeptide abundant in the cancer cells, inhibits the cytotoxic effect of reactive oxygen species (ROS) and is associated with anti-apoptosis, thus facilitating tumor growth. Here, we report GSH-depleting carboxymethyl dextran nanocomposites for chemo-sonodynamic therapy for cancer. The nanocomposite is composed of the TiO2-based core as the sonosensitizer, MnO2 coat as the GSH-consuming chemosensitizer, and carboxymethyl dextran as the hydrophilic shell. The in vitro cell experiments demonstrated that, when taken up by the cancer cells, the nanocomposites can deplete intracellular GSH by reducing MnO2 to Mn2+ which induces intracellular ROS production. Upon exposure to ultrasound, the nanocomposites effectively generated cytotoxic singlet oxygen at the intracellular level, remarkably enhancing the cytotoxicity to cancer cells. Notably, chemo-sonodynamic activity of the nanocomposites induced apoptosis as well as necrosis of cancer cells, implying their high potential as the anticancer therapeutics.

Sonodynamic therapy has received increasing attention for cancer treatments as an alternative to photodynamic therapy. However, its clinical applications have been limited by the lack of a sonosensitizer that is capable of producing sufficient amounts of reactive oxygen species (ROS) in response to ultrasound (US) exposure. Herein, PEGylated mesoporous silica-titania nanoparticles (P-MSTNs) are prepared and used as US-responsive nanocarriers for cancer sonotheranostics. Perfluorohexane (PFH), which is chosen as the gas precursor, is physically encapsulated into P-MSTNs using the oil-in-water emulsion method. Owing to the vaporization of the gas precursor, PFH@P-MSTNs (137 nm in diameter) exhibit a strong photoacoustic signal in vivo for at least 6 h. Compared to P-MSTNs, PFH@P-MSTNs generate significantly higher amounts of ROS due to the nanobubble-induced cavitation in the presence of US. When systemically administered to tumor-bearing mice, PFH@P-MSTNs effectively accumulate in the tumor site due to the passive targeting mechanism. Consequently, PFH@P-MSTNs show much higher antitumor efficacy than P-MSTNs due to the enhanced cavitation-mediated ROS generation in response to US exposure. It is considered that PFH@P-MSTNs may hold significant potential for cancer sonotheranostics.