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

Abstract

Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets' response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification.

Figure 1

C-ions exposure experiment of PVA/PFB NDs entrapped in PAM tissue-mimicking phantoms and filled in PMMA containers: (a) Representative scheme of the C-ions irradiation setup; (b) Offline US imaging setup of PVA/PFB NDs phantoms pre- and post-irradiation at 7.5 MHz frequency and mechanical index MI = 0.1 (the probe is positioned on top of the phantom); (c) Depiction of the imaging scan of the phantoms along the Y axis of the PMMA container (green arrow), and of the acoustic window considered for each image (the red line indicates extent of the lateral length of the acoustic window, i.e. 3 cm). The center of the probe was aligned with the middle of the internal length of the phantom container (red triangle and yellow mark), i.e. parallel to the beam direction. The green marks indicate the probe positioning for a phantom scan through the y axis (acquisition of 3 ROIs).

Figure 2

Ultrasound images of PVA/PFB NDs dispersed in PAM phantom (4 × 10⁶ ND/ml) before (a) and after (b) exposure to 312 MeV/u C-ions (4 Gy dose, 180 mm range). Corresponding images for a control phantom with dispersed PVA/PFB NDs before (c) and after (d) incubation at 37 °C (i.e. without irradiation). US images of control phantom made of pure PAM without NDs before (e) and after (f) at identical irradiation conditions. The images are acquired at 7.5 MHz with MI = 0.1. The yellow arrows indicate the beam entrance side, The red triangles indicate the US focal depth. (g) Oil immersion optical microscopy image of PVA/PFB NDs (objective 60 ×). (h) Size distribution of the nanodroplets by intensity-weighted dynamic light scattering.

Figure 3

Dose effect of C-ions (312 MeV/u, 180 mm range) on the triggered vaporization of PVA/PFB NDs @ 37 °C: (a) Top-view photographs of independent phantoms of NDs dispersed in PAM (4 × 10⁶ NDs/ml) post-irradiation at doses between 0.1 and 4 Gy (the red scale bars correspond to 10 mm); (b) corresponding depth-resolved US images (7.5 MHz, MI = 0.1) of the NDs phantoms at each dose, the yellow arrow indicates the C-ions beam’ entrance side (scale bars are 5 mm); (c) Comparison of the average grayscale value profiles of the US images at different doses as a function of the distance traveled by C-ions (beam depth), the shaded areas correspond to the standard deviation (n = 6). (d) Variation of the FWHM of grayscale peaks as a function of the received C-ions dose (the red line is a dose–response fit function). (e) Evaluation of the peaks integrals from the average grayscale profiles as a function of C-ions dose. The inset shows the linear regression fits in the intervals of 0.1–1 Gy (green) and 0.1–2 Gy (red).

Figure 4

(a) US images (@7.5 MHz; MI = 0.1) of phantoms (nanodroplets concentration:1.7 × 10⁶–8.4 × 10⁶ NDs/ml) post 1 Gy C-ions exposure (312 MeV/u, 180 mm); (b) Average grayscale value profiles of PVA/PFB NDs phantoms at the different NDs concentrations. The inset plot represents average grey value peak-width (i.e. NDs vaporization signal) as a function of NDs concentration; (c) US images of PVA/PFB NDs phantoms pre- and post-irradiation @ 37 °C with C-ion beam range of 50 mm (150.7 MeV/u, 1 Gy, 4 × 10⁶ ND/ml); (d) Mean derived vaporization profiles from independent phantoms (orange) compared to the pre-irradiation grayscale signal (black). The shaded areas represent the standard deviation (n = 6).

Figure 5

(a) US image of SOBP C-ions irradiation of a PVA/PFB PAM phantom @37 °C (1 Gy, 4 × 10⁶ ND/ml, 312 MeV/u, 180 mm); the yellow arrow indicates the beam enteance side. (b) Comparison between SOBP and pristine Bragg peak irradiation of NDs post 1 Gy exposure. The shaded areas represent the standard deviations, n = 6).

Figure 6

Overlay of the PVA/PFB NDs vaporization profile post 1 Gy C-ions exposure @37 °C and the measured Bragg curve: (a) for a beam range of 50 mm and (b) for a beam range of 180 mm.