In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification

Abstract

Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including 18O, 68Zn or 63Cu, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of 18O-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (18F) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough 18O into a living organism to produce a detectable signal from 18F after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of 18F (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific 18F activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by 18O from infused 18-W, and evidenced an entrapment of 59% for specific activity of 18F after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate 18O in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. 18F produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients.

Radiochromic film dosimetry for protons up to 10 MeV with EBT2, EBT3 and unlaminated EBT3 films

“…In preparation for radiobiology experiments (España et al 2021) at the 10 MeV proton beam (waterequivalent range of 1.2 mm) of CMAM (https://cmam.uam.es/en) Cockroft-Walton tandem electrostatic accelerator (Enguita et al 2004), we have investigated an accurate dosimetry protocol for low-energy proton beams. Radiochromic films (RCF) are a standard, widely used method of passive dosimetry (Niroomand-Rad et al 2020) presenting near tissue equivalence and very high spatial resolution (Devic et al 2016).…”

Zinc-Doped Iron Oxide Nanoparticles as a Proton-Activatable Agent for Dose Range Verification in Proton Therapy

“…However, these isotopes are produced by nuclear interactions along the proton beam path with a relatively high energy production threshold, implying that they will not be formed near the Bragg peak [11]. As a result, an alternative methodology has been proposed that consists of using contrast agents [12][13][14][15][16][17] and external media that facilitate the production of detectable activity closer to the Bragg peak. One of the proposed materials is zinc, which leads to the production of isotopes such as 66 Ga and 68 Ga via proton-induced reactions [12].…”

Blocking Studies to Evaluate Receptor-Specific Radioligand Binding in the CAM Model by PET and MR Imaging

“…Based on own previous studies and data from other groups, the model appears suitable for efficient initial in vivo screening of the biodistribution of novel radiolabeled compounds prior to the evaluation in small animals [ 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. However, testing for target specificity of a radiolabeled tracer by blocking studies has not yet been demonstrated in the CAM model.…”