Proton range verification with ultrasound imaging using injectable radiation sensitive nanodroplets: a feasibility study

Abstract

Technologies enabling in vivo range verification during proton therapy are actively sought as a means to reduce the clinical safety margins currently adopted to avoid tumor underdosage. In this contribution, we applied the semi-empirical theory of radiation-induced vaporization of superheated liquids to coated nanodroplets. Nanodroplets are injectable phase-change contrast agents that can vaporize into highly echogenic microbubbles to provide contrast in ultrasound images. We exposed nanodroplet dispersions in aqueous phantoms to monoenergetic proton beams of varying energies and doses. Ultrasound imaging of the phantoms revealed that radiation-induced droplet vaporization occurred in regions proximal to the proton Bragg peak. A statistically significant increase in contrast was observed in irradiated regions for doses as low as 2 Gy and found to be proportional to the proton fluence. The absence of enhanced response in the vicinity of the Bragg peak, combined with theoretical considerations, suggest that droplet vaporization is induced by high linear energy transfer (LET) recoil ions produced by nuclear reactions with incoming protons. Vaporization profiles were compared to non-elastic cross sections and LET characteristics of oxygen recoils. Shifts between the ultrasound image contrast drop and the expected proton range showed a sub-millimeter reproducibility. These early findings confirm the potential of superheated nanodroplets as a novel tool for proton range verification.

Modulating ultrasound contrast generation from injectable nanodroplets for proton range verification by varying the degree of superheat

“…A first proof-of-concept study was recently performed with nanodroplets made of a 10,12-pentacosadiynoic acid shell encapsulating a liquid decafluorobutane core (PCDA-PFB, boiling point = −2°C), 44 demonstrating radiation-induced vaporization in a proton beam at room temperature (25°C). 25 Moreover, a highly reproducible (<1 mm) relationship between the proton range and the generated ultrasound contrast was observed, thereby disclosing the potential of superheated nanodroplets for ultrasound-guided in vivo range verification. The presence of a shift was explained by the LET threshold for perfluorobutane droplets at 25°C (370 keV/µm) predicted by the thermal spike theory 26 (Fig.…”

“…The PCDA-PFB nanodroplets have an intensity-weighted median diameter of 842 nm AE 12 nm (n = 4) and a polydispersity index of 0.25 AE 0.02. 25…”

“…24 The European Horizon 2020 project "Amphora" recently revisited superheated emulsions as an alternative means to measure the proton range. 25 Superheated emulsions typically comprise micrometer or millimeter-sized drops dispersed in an immiscible aqueous matrix. 26 Owing to the absence of heterogeneous nucleation sites, these droplets can be operated at temperatures above their boiling point, in a metastable superheated state, without vaporizing.…”

“…38 To apply this concept to in vivo noninvasive radiation dosimetry and proton range verification, the aforementioned emulsions were downscaled to phase-change nanodroplets and stabilized by a lipidic shell. 25 This was facilitated by recent developments in the field of ultrasound imaging and therapy, [39][40][41][42] which led to the emergence of several injectable superheated nanodroplet formulations able to provide ultrasound contrast on demand when triggered by acoustic 43,44 or optical 45 sources. A first proof-of-concept study was recently performed with nanodroplets made of a 10,12-pentacosadiynoic acid shell encapsulating a liquid decafluorobutane core (PCDA-PFB, boiling point = −2°C), 44 demonstrating radiation-induced vaporization in a proton beam at room temperature (25°C).…”

A physical unclonable neutron sensor for nuclear arms control inspections

“…In future iterations of our sensors, we envision that smaller sub-micrometer microspheres and drops at potentially higher concentration could be used to achieve even higher degrees of structural and optical complexity 32 . Yet, the entropy of our current neutron-sensitive media already exceeds the original optical PUF design, which employed spheres of diameters ~ 650 μm with density ~ 1400 per cm 3 , by several orders of magnitude 16 .…”