Nanotechnology-enabled sonodynamic therapy against malignant tumors

Abstract

Sonodynamic therapy (SDT) is an emerging approach for malignant tumor treatment, offering high precision, deep tissue penetration, and minimal side effects. The rapid advancements in nanotechnology, particularly in cancer treatment, have enhanced the efficacy and targeting specificity of SDT. Combining sonodynamic therapy with nanotechnology offers a promising direction for future cancer treatments. In this review, we first systematically discussed the anti-tumor mechanism of SDT and then summarized the common nanotechnology-related sonosensitizers and their recent applications. Subsequently, nanotechnology-related therapies derived using the SDT mechanism were elaborated. Finally, the role of nanomaterials in SDT combined therapy was also introduced.

Fig. 1. (A) Schematic illustration of the possible anticancer mechanism of ROS in SDT. ROS play a key role in the process of cell apoptosis. ROS can lead to apoptosis through calcium overload, cytC release and lipid oxidation. In addition, they can also cause cell death by regulating apoptosis-related gene expression, tumor angiogenesis and loss of MMP. (B) The comparison between SDT and PDT. Reproduced from ref. with permission from John Wiley & Sons, copyright 2016.

Fig. 2. Schematic illustration of the possible mechanism of SDT. US can induce cavitation implosion and further lead to cell death through mechanical damage, SL and the pyrolysis process. Furthermore, US can directly activate the sonosensitizer to produce singlet oxygen leading to cell death.

Fig. 3. Microbubble interactions with ultrasound. Inertial cavitation events at a high mechanical index, causing disruption of the endothelial lining. At lower US pressures, volumetric oscillations of the microbubble can stretch or distend the blood vessel.

Fig. 4. CDT-enhanced SDT of PEG–TiO_1+x NRs. (A) Schematic illustration of using HTiO₂ NPs as the sonosensitizer for efficient tumor SDT and (B) relative viabilities of HUVECs and 4T1 cells after being incubated with different concentrations of PEG–TiO_1+x NRs; (C) relative viabilities of 4T1 cells incubated with H₂O₂ at different concentrations and treated with PEG–TiO_1+x NRs (50 µg mL⁻¹); (D) relative viabilities of 4T1 cells incubated with PEG–TiO_1+x NRs and treated with US irradiation and H₂O₂ (50 µM) + US irradiation (40 kHz, 5 min). “Reproduced from ref. with permission from American Chemical Society, copyright 2020.” (E) Schematic illustration of using HTiO₂ NPs as the sonosensitizer for efficient tumor SDT. (F) Changes in tumor volume for each treatment group. (G) Bright-field images of tumor vasculature after SDT with US. Reproduced from ref. with permission from Springer Nature, copyright 2016.

Fig. 5. Schematic illustration of the possible mechanism of microbubble-augmented SDT. The MBs can circulate within the blood vessels and accumulate in tumor tissues. These MBs can produce sono-luminescence emission and undergo a pyrolysis reaction through the cavitation effect and further induce the generation of toxic ROS and singlet oxygen from loaded organic sonosensitizer molecules upon US irradiation, which cause the death of cancer cells afterwards. Reproduced from ref. with permission from John Wiley & Sons, copyright 2016.

Fig. 6. (A) The synthetic procedure for GOD@CaCO₃–Fe₃O₄ particles and schematic illustration of the sequential catalytic-therapeutic mechanism of GOD@CaCO₃–Fe₃O₄ particles. (B) Tumor volumes of mice in different groups within 12 days of treatments. (C) Cytotoxicity profiles of A549 cells incubated with GOD@CaCO3–Fe₃O₄ or CaCO₃–Fe₃O₄ particles. Reproduced from ref. with permission from Elsevier, copyright 2019. (D) Schematic illustration of the synthetic procedure and hypoxia-responsive copper metal–organic framework nanosystem for improved cancer therapy. (E) XPS spectra of Cu-MOF. (F) Cell viability of NHDF cells and MCF-7 cells incubated with Cu-MOF/Ce6 at different concentrations (10, 20, 50 100 µg mL⁻¹). (G) Relative tumor volumes and (H) body weight of mice that received different treatments. Reproduced from ref. with permission from Elsevier, copyright 2020. Illustration of (I) self‐assembly of amphiphilic Janus Au–MnO NPs into functional vesicles and (J) their sequential US and GSH‐induced disassembly into small JNPs with deep tumor penetration for synergistic SDT/CDT. (K) Images of ultrathin sections of MCF-7 cells treated with JNP Ve, JNP Ve with US, and JNP Ve with US and GSH decomposition. (L) Tumor volume curves in the different groups. The mice were treated on days 1, 3, 5, and 7. (M) The viability of cells treated with different concentrations of JNP Ve with or without US irradiation. Reproduced from ref. with permission from John Wiley & Sons, copyright 2020.

Yunxi Huang

Junjie Liu