Spatiotemporal distribution of nanodroplet vaporization in a proton beam using real-time ultrasound imaging for range verification

The potential of proton therapy to improve the conformity of the delivered dose to the tumor volumeis currently limited by range uncertainties. Injectable superheated nanodroplets have recently been proposed forultrasound-basedin vivorange verification, as these vaporize into echogenic microbubbles on proton irradiation.In previous studies, offline ultrasound images of phantoms with dispersed nanodroplets were acquired after irra-diation, relating the induced vaporization profiles to the proton range. However, the aforementioned method didnot enable the counting of individual vaporization events, and offline imaging cannot provide real-time feedback.In this study, we overcame these limitations using high-frame-rate ultrasound imaging with a linear arrayduringproton irradiation of phantoms with dispersed perfluorobutane nanodroplets at 37 ̊C and 50 ̊C. Differentialimage analysis of subsequent frames allowed us to count individual vaporization events and to localize them witha resolution beyond the ultrasound diffraction limit, enabling spatial and temporal quantification of the interac-tion between ionizing radiation and nanodroplets. Vaporization maps were found to accurately correlate withthe stopping distribution of protons (at 50 ̊C) or secondary particles (at both temperatures). Furthermore, a lin-ear relationship between the vaporization count and the number of incoming protons was observed. These resultsindicate the potential of real-time high-frame-rate contrast-enhanced ultrasound imaging for proton range verifi-cation and dosimetry.