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.

Radical Production with Pulsed Beams: Understanding the Transition to FLASH.

Ultra-high dose rate (UHDR) irradiation regimes have the potential to spare normal tissue while keeping equivalent tumoricidal capacity than conventional dose rate radiotherapy (CONV-RT). This has been called the FLASH effect. In this work, we present a new simulation framework aiming to study the production of radical species in water and biological media under different irradiation patterns. The chemical stage (heterogeneous phase) is based on a nonlinear reaction-diffusion model, implemented in GPU. After the first 1 µs, no further radical diffusion is assumed, and radical evolution may be simulated over long periods of hundreds of seconds. Our approach was first validated against previous results in the literature and then employed to assess the influence of different temporal microstructures of dose deposition in the expected biological damage. The variation of the Normal Tissue Complication Probability (NTCP), assuming the model of Labarbe et al., where the integral of the peroxyl radical concentration over time (AUC-ROO) is taken as surrogate for biological damage, is presented for different intra-pulse dose rate and pulse frequency configurations, relevant in the clinical scenario. These simulations yield that overall, mean dose rate and the dose per pulse are the best predictors of biological effects at UHDR.

Feasibility study of a SiPM-fiber detector for non-invasive measurement of arterial input function for preclinical and clinical positron emission tomography.

Pharmacokinetic positron emission tomography (PET) studies rely on the measurement of the arterial input function (AIF), which represents the time-activity curve of the radiotracer concentration in the blood plasma. Traditionally, obtaining the AIF requires invasive procedures, such as arterial catheterization, which can be challenging, time-consuming, and associated with potential risks. Therefore, the development of non-invasive techniques for AIF measurement is highly desirable. This study presents a detector for the non-invasive measurement of the AIF in PET studies. The detector is based on the combination of scintillation fibers and silicon photomultipliers (SiPMs) which leads to a very compact and rugged device. The feasibility of the detector was assessed through Monte Carlo simulations conducted on mouse tail and human wrist anatomies studying relevant parameters such as energy spectrum, detector efficiency and minimum detectable activity (MDA). The simulations involved the use of 18F and 68Ga isotopes, which exhibit significantly different positron ranges. In addition, several prototypes were built in order to study the different components of the detector including the scintillation fiber, the coating of the fiber, the SiPMs, and the operating configuration. Finally, the simulations were compared with experimental measurements conducted using a tube filled with both 18F and 68Ga to validate the obtained results. The MDA achieved for both anatomies (approximately 1000 kBq/mL for mice and 1 kBq/mL for humans) falls below the peak radiotracer concentrations typically found in PET studies, affirming the feasibility of conducting non-invasive AIF measurements with the fiber detector. The sensitivity for measurements with a tube filled with 18F (68Ga) was 1.2 (2.07) cps/(kBq/mL), while for simulations, it was 2.81 (6.23) cps/(kBq/mL). Further studies are needed to validate these results in pharmacokinetic PET studies.

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.

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

Passive dosimetry with radiochromic films is widely used in proton radiotherapy, both in clinical and scientific environments, thanks to its simplicity, high spatial resolution and dose-rate independence. However, film under-response for low-energy protons, the so-called linear-energy transfer (LET) quenching, must be accounted and corrected for. We perform a meta-analysis on existing film under-response data with EBT, EBT2 and EBT3 GAFchromic™ films and provide a common framework to integrate it, based on the calculation of dose-averaged LET in the active layer of the films. We also report on direct measurements with the 10 MeV proton beam at the Center for Microanalysis of Materials (CMAM) for EBT2, EBT3 and unlaminated EBT3 films, focusing on the 20-80 keVµm-1LET range, where previous data was scarce. Measured film relative efficiency (RE) values are in agreement with previously reported data from the literature. A model on film RE constructed with combined literature and own experimental values in the 5-80 keVµm-1LET range is presented, supporting the hypothesis of a linear decrease of RE with LET, with no remarkable differences between the three types of films analyzed.

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.