Radiobiological impact of gadolinium neutron capture from proton therapy and alternative neutron sources using TOPAS-nBio.

PURPOSE: A multi-scale investigation of the biological properties of gadolinium neutron capture (GdNC) therapy with applications in particle therapy is conducted using the TOPAS Monte Carlo (MC) simulation code. The simulation results are used to quantify the amount of gadolinium dose enhancement produced as a result of the secondary neutron production from proton therapy scaled by measured data. MATERIALS AND METHODS: MC modeling was performed using the radiobiology extension TOol for PArticle Simulation TOPAS-nBio MC simulation code to study the radiobiological effects produced from GdNC on a segment of DNA, a spherical cellular model, and from the modeling of previous experimental measurements. The average RBE values were calculated from two methods, microdosimetric kinematic (MK) and biological weighting r(y) within a 2 nm DNA segment for GdNC. The single-strand breaks (SSBs) and double-strand breaks (DSBs) were calculated from within the nucleus of a 20 µm diameter, spherical cell model. From a previous experimental proton therapy measurement using a spread-out Bragg peak (SOBP) of 4.5-9.5 cm and a delivered absorbed dose of 10.4 Gy, the amount of Gd neutron captures was calculated and used to quantify the amount of GdNC absolute dose from particle therapy. RESULTS: The average RBE from microdosimetric kinematic and biological weighting was 1.35, and 1.70 for a 10% cell survival on HSG cell-line and weighting function data from early intestinal tolerance of mice. From a central isotropic GdNC source, the energy deposition is found to decrease from roughly 2.7 eV per capture down to approximately 0.01 eV per capture, a drop of two orders of magnitude within 50 nm. This result suggests that Gd needs to be close to the DNA (within 10-20 nm) in order for neutron capture to induce a significant dose enhancement due to the short-range electrons emitted after Gd neutron capture. Within a spherical cell model, the SSBs, and DSBs were determined to be 39 and 1.5 per neutron capture, respectively. From the total neutron captures produced from an experimental proton therapy measurement on a 3000 PPM Gd solution, an insignificant absolute Gd dose enhancement was quantified to be 5.4 × 10-6  Gy per Gy of administered proton dose. CONCLUSION: From this study and literature review, the production of secondary thermal neutrons from proton therapy is determined to be a limiting factor and unlikely to produce a clinically useful dose enhancement for secondary neutron capture therapy. Moreover, alternative neutron sources, such as, a compact deuterium-tritium (D-T) neutron generator, a "high yield" deuterium-deuterium (D-D) generator, or an industrial strength (100 mg) 252 Cf source were investigated, with the 252 Cf source the most likely to be capable of producing enough neutrons for 1 Gy of localized GdNC absolute dose within a reasonable treatment time.

Neutron activation of gadolinium for ion therapy: a Monte Carlo study of charged particle beams.

This study investigates the photon production from thermal neutron capture in a gadolinium (Gd) infused tumor as a result of secondary neutrons from particle therapy. Gadolinium contrast agents used in MRI are distributed within the tumor volume and can act as neutron capture agents. As a result of particle therapy, secondary neutrons are produced and absorbed by Gd in the tumor providing potential enhanced localized dose in addition to a signature photon spectrum that can be used to produce an image of the Gd enriched tumor. To investigate this imaging application, Monte Carlo (MC) simulations were performed for 10 different particles using a 5-10 cm spread out-Bragg peak (SOBP) centered on an 8 cm3, 3 mg/g Gd infused tumor. For a proton beam, 1.9 × 106 neutron captures per RBE weighted Gray Equivalent dose (GyE) occurred within the Gd tumor region. Antiprotons ([Formula: see text]), negative pions (- π), and helium (He) ion beams resulted in 10, 17 and 1.3 times larger Gd neutron captures per GyE than protons, respectively. Therefore, the characteristic photon based spectroscopic imaging and secondary Gd dose enhancement could be viable and likely beneficial for these three particles.

Investigating neutron activated contrast agent imaging for tumor localization in proton therapy: a feasibility study for proton neutron gamma-x detection (PNGXD).

Proton neutron gamma-x detection (PNGXD) is a novel imaging concept being investigated for tumor localization during proton therapy that uses secondary neutron interactions with a gadolinium contrast agent (GDCA) to produce characteristic photons within the 40-200 keV energy region. The purpose of this study is to experimentally investigate the feasibility of implementing this procedure by performing experimental measurements on a passive double scattering proton treatment unit. Five experimental measurements were performed with varying concentrations and irradiation conditions. Photon spectra were measured with a 25 mm2, 1 mm thick uncollimated X-123 CdTe spectrometer. For a 10.4 Gy administration on a 100 ml volume phantom with 10 mg g-1 Gd solution placed in a water phantom, 1129 ± 184 K-shell Gd counts were detected. For an administered dose of 21 Gy and the same Gd solution measured in air, resulted in 3296 ± 256 counts. A total of 1094 ± 171, 421 ± 150 and 23 ± 141 K-shell Gd counts were measured for Gd concentrations of 10 mg g-1, 1 mg g-1 and 0 mg g-1 for 7 Gy dose in air. The signal to noise ratio for these five measurements were: 7, 15, 6, 3, and 0.2, respectively. The spectrum contained 43 keV K α and 49 keV K ß peaks, however a small amount of 79.5 and 181.9 keV prompt gamma rays were detected from gadolinium neutron capture. This discrepancy is due to a drop in the intrinsic detection efficiency of the CdTe spectrometer over this energy range. The measurements were compared with Monte-Carlo simulation to determine the contributions of Gd neutron capture from internal and external neutrons on a passive scattering proton therapy unit and to investigate the discrepancy in detected characteristic x-rays versus prompt gamma rays.

Collective Excitations in Protein as a Measure of Balance Between its Softness and Rigidity.

In this article, we elucidate the protein activity from the perspective of protein softness and flexibility by studying the collective phonon-like excitations in a globular protein, human serum albumin (HSA), and taking advantage of the state-of-the-art inelastic X-ray scattering (IXS) technique. Such excitations demonstrate that the protein becomes softer upon thermal denaturation due to disruption of weak noncovalent bonds. On the other hand, no significant change in the local excitations is detected in ligand- (drugs) bound HSA compared to the ligand-free HSA. Our results clearly suggest that the protein conformational flexibility and rigidity are balanced by the native protein structure for biological activity.