Session Item

Uncertainties on the in vivo proton range prevent the realization of the full potential of proton beams. They are typically accounted for by irradiating larger volumes at therapeutic doses using robust optimization or safety margins. This results in considerable healthy tissue exposure, degrading the inherent benefits of proton therapy. Hence, there is an urgent need for tools to verify the proton range in vivo. Recently, we proposed phase-change ultrasound (US) contrast agents as potential in vivo radiation sensors, whereby nanodroplets convert in echogenic microbubbles upon interaction with the proton beam. Previously, we demonstrated detection of the proton range with submillimeter reproducibility in gel phantoms. In this contribution, we provide a first in vivo proof-of-concept of the technology in healthy rats.

Phase-change nanodroplets consisted of a perfluorobutane core and a polyvinyl alcohol shell and were quantified using 19F NMR spectroscopy (Avance II 400, Bruker). Proton irradiations were performed at the Cyclotron Resources Centre in UCLouvain. There, healthy female Sprague-Dawley rats were anaesthetized and intravenously injected with 200 µmol/kg nanodroplets. Afterwards, the animals were positioned in the proton beam, while continuously imaging their liver with low-pressure plane wave US (DiPhAS, Fraunhofer IBMT) as shown in figure 1. Animal 1 was irradiated once with a collimated proton beam (6 mm slit) for 5 Gy at 62 MeV. Animals 2-4 underwent two irradiations of 5 Gy, the first at 49.7 MeV, the second at 62 MeV. Thereafter, animal 4 was injected with an additional 350 µmol/kg nanodroplets and re-irradiated with 5 Gy protons at 62 MeV. Finally, the US images were processed using custom MATLAB algorithms to extract contrast maps.

Figure 1. Proton irradiation setup.

Online US imaging confirmed the ability to (i) trigger droplet vaporization in vivo using proton radiation and (ii) track the contrast generation during irradiation. The irradiations at varying energies illustrated an energy-dependent response, whereby microbubbles are generated much deeper in the animal’s body at higher energies as expected from the larger proton range (figure 2). Finally, increasing the droplet concentration from 200 to 350 µmol/kg, resulted in additional contrast signals, indicating room for improvement in terms of the nanodroplet dosing.

Figure 2. In vivo nanodroplet radiation response in the liver of animal 4. Before the 3rd irradiation, the animal was reinjected with 350 µmol/kg nanodroplets and repositioned. Contrast maps show the empirically thresholded difference between before and after frames.

We demonstrated the energy-dependent radiation response of phase-change nanodroplets for the first time in vivo, highlighting its potential for proton range verification. Future work will be required to verify reproducibility, optimize the nanodroplet concentration and compare the US contrast with a ground truth of the proton range.