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

Proton therapy allows the treatment of specific areas and avoids the surrounding tissues. However, this technique has uncertainties in terms of the distal dose fall-off. A promising approach to studying the proton range is the use of nanoparticles as proton-activatable agents that produce detectable signals. For this, we developed an iron oxide nanoparticle doped with Zn (IONP@Zn-cit) with a hydrodynamic size of 10 nm and stability in serum. Cytotoxicity, defined as half of the surveillance, was 100 µg Zn/mL in the U251 cell line. The effect on clonogenic cell death was tested after X-ray irradiation, which suggested a radioprotective effect of these nanoparticles at low concentrations (1-10 µg Zn/mL). To evaluate the production of positron emitters and prompt-gamma signals, IONP@Zn-cit was irradiated with protons, obtaining prompt-gamma signals at the lowest measured concentration (10 mg Zn/mL). Finally, 67Ga-IONP@Zn-cit showed accumulation in the liver and spleen and an accumulation in the tumor tissue of 0.95% ID/g in a mouse model of U251 cells. These results suggest the possibility of using Zn nanoparticles as proton-activatable agents to verify the range by prompt gamma detection and face the challenges of prompt gamma detection in a specific biological situation, opening different avenues to go forward in this field.

Technical note: Measurement of the bunch structure of a clinical proton beam using a SiPM coupled to a plastic scintillator with an optical fiber.

BACKGROUND: Recent proposals of high dose rate plans in protontherapy as well as very short proton bunches may pose problems to current beam monitor systems. There is an increasing demand for real-time proton beam monitoring with high temporal resolution, extended dynamic range and radiation hardness. Plastic scintillators coupled to optical fiber sensors have great potential in this context to become a practical solution towards clinical implementation. PURPOSE: In this work, we evaluate the capabilities of a very compact fast plastic scintillator with an optical fiber readout by a SiPM and electronics sensor which has been used to provide information on the time structure at the nanosecond level of a clinical proton beam. MATERIALS AND METHODS: A 3 × 3 × 3 mm3 plastic scintillator (EJ-232Q Eljen Technology) coupled to a 3 × 3 mm2 SiPM (MicroFJ-SMA-30035, Onsemi) has been characterized with a 70 MeV clinical proton beam accelerated in a Proteus One synchrocyclotron. The signal was read out by a high sampling rate oscilloscope (5 GS/s). By exposing the sensor directly to the proton beam, the time beam profile of individual spots was recorded. RESULTS: Measurements of detector signal have been obtained with a time sampling period of 0.8 ns. Proton bunch period (16 ns), spot (10 µs) and interspot (1 ms) time structures could be observed in the time profile of the detector signal amplitude. From this, the RF frequency of the accelerator has been extracted, which is found to be 64 MHz. CONCLUSIONS: The proposed system was able to measure the fine time structure of a clinical proton accelerator online and with ns time resolution.

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

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.

Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms.

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate "FLASH" irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others they are hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications.