Phase-change ultrasound contrast agents for proton range verification: towards anin vivoapplication

Objective.In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a firstin vivoproof-of-concept of this technology.Approach.First, thein vitrobiocompatibility of radiation-sensitive poly(vinyl alcohol) perfluorobutane nanodroplets was investigated using several colorimetric assays. Then,in vivoultrasound contrast was characterized using acoustic droplet vaporization (ADV) and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of thein vivobiocompatibility was performed using ADV and a combination of physiology monitoring and histology.Main results.Nanodroplets were non-toxic over a wide concentration range (