Spatiotemporal Distribution of Nanodroplet Vaporization in a Proton Beam Using Real-Time Ultrasound Imaging for Range Verification

Abstract

The potential of proton therapy to improve the conformity of the delivered dose to the tumor volume is currently limited by range uncertainties. Injectable superheated nanodroplets have recently been proposed for ultrasound-based in vivo range verification, as these vaporize into echogenic microbubbles on proton irradiation. In previous studies, offline ultrasound images of phantoms with dispersed nanodroplets were acquired after irradiation, relating the induced vaporization profiles to the proton range. However, the aforementioned method did not 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 array during proton irradiation of phantoms with dispersed perfluorobutane nanodroplets at 37˚C and 50˚C. Differential image analysis of subsequent frames allowed us to count individual vaporization events and to localize them with a resolution beyond the ultrasound diffraction limit, enabling spatial and temporal quantification of the interaction between ionizing radiation and nanodroplets. Vaporization maps were found to accurately correlate with the stopping distribution of protons (at 50˚C) or secondary particles (at both temperatures). Furthermore, a linear relationship between the vaporization count and the number of incoming protons was observed. These results indicate the potential of real-time high-frame-rate contrast-enhanced ultrasound imaging for proton range verification and dosimetry.

Acoustic Modulation Enables Proton Detection With Nanodroplets at Body Temperature

“…Both pellets were then recombined and redispersed in 5 ml of Milli-Q water, yielding a droplet concentration in the range 5-50 mM (PFB in water concentration measured with Nuclear Magnetic Resonance spectroscopy). The radiation sensitivity of this nanodroplet formulation has been demonstrated in previous studies [12], [13], [42]. The intensity-weighted mean diameter of this nanodroplet formulation, measured by Dynamic Light Scattering, is 799 nm ± 25 nm, with a polydispersity index of 0.3 [12] (Fig.…”

“…While this choice of tube position also led to a reduction in the number of stopping protons, the ratio of primary protons to secondary particles increased by one order of magnitude. The exact position of the tube with respect to the proton range was measured independently using the technique presented in [13], and the tube was found to be located 6.1 mm behind the position at which 50% of the primary protons have stopped (i.e., the proton range).…”

“…), turning them into echogenic microbubbles [11]. The stochastic distribution of nanodroplet vaporization events can be then acoustically measured, using either offline [12] or online [13] ultrasound imaging, and related to the spatial distribution of charged particles. According to the thermal spike theory, charged particles trigger the vaporization of superheated liquids through homogeneous nucleation [7].…”

Ultrasound-assisted carbon ion dosimetry and range measurement using injectable polymer-shelled phase-change nanodroplets: in vitro study

“…In particular, the aqueous suspensions of PVA/PFB NDs, prepared by pre-condensation of PFB (b.p. − 2 °C) followed by its encapsulation with a crosslinked PVA shell (see Methods) in a sonication-mediated process, have consistently proven to exhibit an exceptional shelf-life and thermal stability even at temperatures highly exceeding 37 °C 26 , 27 , 49 . The additional Laplace pressure exerted by the shell’s surface tension keeps the core in its metastable liquid state in the absence of external stimuli necessary to reach the vaporization conditions (e.g.…”

“…However, proper quantification was hindered by the saturation of the US contrast signal and by multiple scattering of large amount of microbubbles around the Bragg peak. In order to overcome US saturation limitations and extend the linear range to higher doses/concentrations, the US imaging setup could be upgraded into an online high-frame imaging allowing for detecting and tracking the distribution of multiple vaporization events of NDs in real-time during radiation exposure 49 .…”