This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z=22, to Bismuth, Z=83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation

Gold nanoparticles (GNPs) have shown potential as dose enhancers for radiation therapy. Since damage to the genome affects the viability of a cell, it is generally assumed that GNPs have to localise within the cell nucleus. In practice, however, GNPs tend to localise in the cytoplasm yet still appear to have a dose enhancing effect on the cell. Whether this effect can be attributed to stress-induced biological mechanisms or to physical damage to extra-nuclear cellular targets is still unclear. There is however growing evidence to suggest that the cellular response to radiation can also be influenced by indirect processes induced when the nucleus is not directly targeted by radiation. The mitochondrion in particular may be an effective extra-nuclear radiation target given its many important functional roles in the cell. To more accurately predict the physical effect of radiation within different cell organelles, we measured the full chemical composition of a whole human lymphocytic JURKAT cell as well as two separate organelles; the cell nucleus and the mitochondrion. The experimental measurements found that all three biological materials had similar ionisation energies ~ 70 eV, substantially lower than that of liquid water ~ 78 eV. Monte Carlo simulations for 10 – 50 keV incident photons showed higher energy deposition and ionisation numbers in the cell and organelle materials compared to liquid water. Adding a 1% mass fraction of gold to each material increased the energy deposition by a factor of ~ 1.8 when averaged over all incident photon energies. Simulations of a realistic compartmentalised cell show that the presence of gold in the cytosol increases the energy deposition in the mitochondrial volume more than within the nuclear volume. We find this is due to sub-micron delocalisation of energy by photoelectrons, making the mitochondria a potentially viable indirect radiation target for GNPs that localise to the cytosol.

Gold nanoparticle (GNP) radio-enhancement is a promising technique to increase the dose deposition in a tumor while sparing neighboring healthy tissue. Previous experimental studies showed effects on cell survival and tumor control for keV x-rays but surprisingly also for MV-photons, proton and carbon-ion beams. In a systematic study, we use the Monte Carlo simulation tool TOPAS-nBio to model the GNP radio-enhancement within a cell as a function of GNP concentration, size and clustering for a wide range of energies for photons, protons and, for the first time, carbon-ions. Moreover, we include water radiolysis, which has been recognized as a major pathway of GNP mediated radio-enhancement. At a GNP concentration of 0.5% and a GNP diameter of 10 nm, the dose enhancement ratio was highest for 50 keV x-rays (1.36) and decreased in the orthovoltage (1.04 at 250 keV) and megavoltage range (1.01 at 1 MeV). The dose enhancement linearly increased with GNP concentration and decreased with GNP size and degree of clustering for all radiation modalities. While the highest physical dose enhancement at 5% concentrations was only 1.003 for 10 MeV protons and 1.004 for 100 MeV carbon-ions, we find the number of hydroxyl () altered by 23% and 3% after 1 s at low, clinically-relevant concentrations. For the same concentration and proton-impact, the G-value is most sensitive to the nanoparticle size with 46 times more radical interactions at GNPs for 2 nm than for 50 nm GNP diameter within 1 s. Nanoparticle clustering was found to decrease the number of interactions at GNPs, e.g. for a cluster of 25 GNPs by a factor of 3.4. The changes in G-value correlate to the average distance between the chemical species and the GNPs. While the radiochemistry of GNP-loaded water has yet to be fully understood, this work offers a first relative quantification of radiolysis products for a broad parameter-set.

This study investigates a model cell as a target for low-dose radiation using Monte Carlo simulations. Mono-energetic electrons and photons are used with initial energies between 10 and 50 keV, relevant to out-of-field radiotherapy scenarios where modern treatment modalities expose relatively large amounts of healthy tissue to low-dose radiation, and also to microbeam cell irradiation studies which show the importance of the cytoplasm as a radiation target. The relative proportions of number of ionizations and total energy deposit in the nucleus and cytoplasm are calculated. We show that for a macroscopic dose of no more than 1 Gy only a few hundred ionizations occur in the nucleus volume whereas the number of ionizations in the cytoplasm is over a magnitude larger. We find that the cell geometry can have an appreciable effect on the energy deposit in the cell and can cause a nonlinear increase in energy deposit with cytoplasm density. We also show that changing the nucleus volume has negligible effect on the total energy deposit but alters the relative proportion deposited in the nucleus and cytoplasm; the nucleus volume must increase to approximately the same volume as the cytoplasm before the energy deposit in the nucleus matches that in the cytoplasm. Additionally we find that energy deposited by electrons is generally insensitive to spatial variations in chemical composition, which can be attributed to negligible differences in electron stopping power for cytoplasm and nucleus materials. On the other hand, we find that chemical composition can affect energy deposited by photons due to non-negligible differences in attenuation coefficients. These results are of relevance in considering radiation effects in healthy cells, which tend to have smaller nuclei. Our results further show that the cytoplasm and organelles residing therein can be important targets for low-dose radiation damage in healthy cells and warrant investigation as much as the conventional focus of a high-dose radiation DNA target in tumour cells.

Purpose: This work describes the first live imaging and radiation delivery performed on a prototype 1.0 T inline MRI-Linac system in a rat brain tumor model, which was conducted on 29 January 2019. Methods: A human scale 1.0 T MRI-Linac was adapted to be suitable for animal studies via a specially constructed open 6-channel receiver radiofrequency (RF) coil. A Fischer rat injected with 9L glioma cells in the right hemisphere was imaged and irradiated at day 11 post surgery as part of a larger cohort survival study. The rat was anesthetized and positioned at the iscocenter of the MRI-Linac. Imaging was used to localize the brain and confirm the presence of a tumor following the administration of a gadolinium nanoparticle contrast agent. A single dose of 10 Gy was delivered using a 2.25 cm 9 2.90 cm radiation field covering the whole brain and verified with radiosensitive film in situ. Real-time imaging was used throughout the irradiation period to monitor the animal and target position. Results: The signal-to-noise ratio (SNR) measured in the rat brain was 38. Postcontrast imaging was able to demonstrate a tumor of 5 mm diameter in the upper right hemisphere of the brain approximately 45 min after administration of the nanoparticles. The radiation beam had no impact on SNR and images at the rate of 2 Hz were effective in monitoring both respiration and intrafractional motion. In vivo film dosimetry confirmed the intended dose delivery. The total procedure time was 35 min. Conclusions: We have successfully used MRI guidance to localize and subsequently deliver a radiation field to the whole brain of a rat with a right hemispheric tumor. Real-time imaging during beam on was of sufficient quality to monitor breathing and perform exception gating of the treatment. This represents the first live use of a high field inline MRI-Linac.