Sonodynamic therapy: transforming sound into light for hard-to-treat tumours

Sonodynamic therapy (SDT) is an emerging therapeutic modality against hard-to-treat tumours. It involves the use of ultrasound (US) to excite sono-sensitive moieties to produce reactive oxygen species (ROS), which induce tumour cell death. SDT employs the synergetic application of enabling chemicals named sonosensitizers and low-intensity ultrasound. Compared with photodynamic therapy, SDT has the significant advantages of deeper tissue penetration, higher accuracy, and potentially fewer adverse effects if well-designed. There are multiple suggested mechanisms for activating sonosensitizers for SDT, including sonoluminescence, pyrolysis and direct mechanical activation. However, a highly reported mechanism of action and the focus for this review is sonoluminescence (SL). SL is defined as the light generated by catastrophic implosions of oscillating bubbles in a liquid under exposure to ultrasound (US). SL has been shown to interact with sensitising molecules similar to photodynamic therapy to generate ROS. This mechanism involves delocalisation of the excited electron and subsequent transfer from excited sonosensitizers to nearby oxygen molecules (H₂O and O₂) in the surrounding tissues to produce ROS such as superoxides, peroxides, singlet oxygen and hydroxyl radicals. In SDT, both SL and sonosensitizers play a role in generating enough ROS to initiate the observed anticancer effects. These effects have been investigated in in vitro, in vivo and recently applied in clinical settings. There are several questions pertaining to the efficiency and safety of SDT and sonosensitizers for anticancer treatment, especially in hard-to-treat tumours, which are discussed here. Although the application of SDT has rapidly reached the clinical phase, fundamental studies are still needed to address and understand the complex mechanisms involved in the anticancer effect of SDT.