Mechanistic insights and basis for real-time monitoring and closed-loop feedback control in sonodynamic therapy for glioblastoma.

Sonodynamic therapy (SDT) involves the administration of otherwise inactive agents that can be activated by acoustic energy ('sonosensitizers') to impart therapeutic effects. SDT is a treatment of significant clinical interest in glioblastoma, a highly aggressive brain tumor, due to the known uptake and conversion of the clinically approved fluorescence guided surgery agent, 5-aminolevulinic acid (5-ALA). Building evidence suggests acoustic energy may activate the converted product of 5-ALA, protoporphyrin IX. Despite ongoing clinical trials using 5-ALA-based SDT demonstrating treatment safety, feasibility, and potential efficacy, the precise underlying tumoricidal mechanisms of SDT remain unknown. Additionally, the ability to monitor SDT effects during treatments remains underexplored. Here we synthesize existing evidence regarding mechanisms behind the antitumoral effects of SDT, including various SDT agents studied in their capacity to generate reactive oxygen species that result in intrinsic apoptotic pathway activation, sonomechanical effects that result in cellular damage, pyrolytic and sonoluminescent reactions, and immunological activation. Additionally, we discuss the opportunities for in situ, real-time monitoring of SDT and related effects to enable safe, reproducible, and prescriptive treatments. Specifically, we explore the potential utility of magnetic resonance (MR) based monitoring tools including MR thermometry and MR acoustic radiation force imaging, and acoustic emissions feedback monitoring.