Radiotherapeutic enhancement using ultrasound-stimulated microbubbles: a critical review

Ultrasound stimulated microbubbles (USMB) are proposed as radioenhancing agents. Acting mechanically, they are attractive because their effects can be localized to the tumor, limiting the potential for normal tissue toxicity. Extensive preclinical research in models of human cancers has demonstrated increased tumor control when USMB are combined with radiotherapy compared with radiation alone, which has led to recent Phase I trials. The leading theory on the radioenhancement mechanism of action (MOA) is that USMB act as vascular disrupting agents, but others are proposed.

Current literature was reviewed with a focus on the role of the tumor vasculature on radiotherapy response, the bioeffects of USMB on the vasculature, and studies of USMB as radioenhancers. Additionally, the possible interplay between USMB as vascular modulators, and radiation-induced anti-tumor immunity, is explored.

Whilst most preclinical evidence compellingly describes the radioenhancement effect, only one study considers the immune cell infiltration post USMB plus radiotherapy, with non-significant findings. Clinical studies demonstrate the safety of USMB. As a monotherapy, USMB can alter tumor immune microenvironments and induce a variety of bioeffects on the vasculature, depending on the stimulatory acoustic parameters. Treatment parameters used to study the effects of USMB alone, and with radiotherapy, vary in the literature making direct comparisons difficult.

Further work exploring USMB for radioenhancement is warranted. Elucidation of the MOA is required to support clinical translation, particularly with a view to optimize treatment parameters.