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

Abstract

Purpose: Despite the physical benefits of protons over conventional photon radiation in cancer treatment, range uncertainties impede the ability to harness the full potential of proton therapy. While monitoring the proton range in vivo could reduce the currently adopted safety margins, a routinely applicable range verification technique is still lacking. Recently, phase-change nanodroplets were proposed for proton range verification, demonstrating a reproducible relationship between the proton range and generated ultrasound contrast after radiation-induced vaporization at 25°C. In this study, previous findings are extended with proton irradiations at different temperatures, including the physiological temperature of 37°C, for a novel nanodroplet formulation. Moreover, the potential to modulate the linear energy transfer (LET) threshold for vaporization by varying the degree of superheat is investigated, where the aim is to demonstrate vaporization of nanodroplets directly by primary protons. Methods: Perfluorobutane nanodroplets with a shell made of polyvinyl alcohol (PVA-PFB) or 10,12-pentacosadyinoic acid (PCDA-PFB) were dispersed in polyacrylamide hydrogels and irradiated with 62 MeV passively scattered protons at temperatures of 37°C and 50°C. Nanodroplet transition into echogenic microbubbles was assessed using ultrasound imaging (gray value and attenuation analysis) and optical images. The proton range was measured independently and compared to the generated contrast. Results: Nanodroplet design proved crucial to ensure thermal stability, as PVA-shelled nanodroplets dramatically outperformed their PCDA-shelled counterpart. At body temperature, a uniform radiation response proximal to the Bragg peak is attributed to nuclear reaction products interacting with PVA-PFB nanodroplets, with the 50% drop in ultrasound contrast being 0.17 mm AE 0.20 mm 1983

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

“…Nanodroplets with a perfluorobutane core (boiling point À2˚C) and a crosslinked polymeric shell made of polyvinyl alcohol (PVA) were prepared according to the protocol described by Heymans et al (2021). Briefly, gaseous perfluorobutane was injected in an empty vial and liquefied by immersion in liquid nitrogen.…”

“…The resulting nanodroplets were then washed by a two-step centrifugation. Dynamic light scattering measurements yielded intensity-weighted size distributions with a median nanodroplet size of 799 nm and a polydispersity index of 0.3 (Heymans et al 2021). The droplets were dispersed in an aqueous polymer gel, which entrapped their position, to achieve a homogeneous distribution within the phantom.…”

“…The beam currents, total number of protons, irradiation durations and phantom doses are given in Table 1. The radiation dose used at 50˚C was relatively close to the typical dose delivered in a proton therapy session (»2 Gy), while a higher dose was used at 37˚C to account for the fact that at this temperature, nanodroplets are sensitive only to high-LET secondary particles, which are relatively rare (Heymans et al 2021).…”

“…Previous studies of nanodroplet vaporization using a passively scattered proton beam have demonstrated a sub-millimeter reproducibility of the shift between the proton range and vaporization profiles derived from the ultrasound gray value or attenuation coefficient (Carlier et al 2020;Heymans et al 2021). However, offline ultrasound imaging does not enable real-time verification and, potentially, compensation of deviations during treatment delivery.…”

“…Superheated nanodroplets have been introduced as a novel injectable ultrasound contrast agent capable of turning into echogenic microbubbles on controlled energy deposition, for example, acoustic or thermal (Sheeran et al 2012;Shimizu et al 2012;Dove et al 2014;Lin et al 2017;Toumia et al 2019). It was only recently reported that the phase-change mechanism holds for superheated encapsulated nanodroplets irradiated by protons (Carlier et al 2020;Heymans et al 2021). The combination of the longstanding knowledge of radiation-induced nucleation with the recent developments in producing stable, injectable nanodroplets opens the door to ultrasound-based detection and monitoring of ionizing radiation in vivo.…”