Nanoparticle radiosensitization: from extended local effect modeling to a survival modification framework of compound Poisson additive killing and its carbon dots validation.

Objective. To construct an analytical model instead of local effect modeling for the prediction of the biological effectiveness of nanoparticle radiosensitization.Approach. An extended local effects model is first proposed with a more comprehensive description of the nanoparticles mediated local killing enhancements, but meanwhile puts forward challenging issues that remain difficult and need to be further studied. As a novel method instead of local effect modeling, a survival modification framework of compound Poisson additive killing is proposed, as the consequence of an independent additive killing by the assumed equivalent uniform doses of individual nanoparticles per cell under the LQ model. A compound Poisson killing (CPK) model based on the framework is thus derived, giving a general expression of nanoparticle mediated LQ parameter modification. For practical use, a simplified form of the model is also derived, as a concentration dependent correction only to theαparameter, with the relative correction (α″/α) dominated by the mean number, and affected by the agglomeration of nanoparticles per cell. For different agglomeration state, a monodispersion model of the dispersity factorη = 1, and an agglomeration model of 2/3 < Î· < 1, are provided for practical prediction of (α″/α) value respectively.Main results. Initial validation by the radiosensitization of HepG2 cells by carbon dots showed a high accuracy of the CPK model. In a safe range of concentration (0.003-0.03µgµl-1) of the carbon dots, the prediction errors of the monodispersion and agglomeration models were both within 2%, relative to the clonogenic survival data of the sensitized HepG2 cells.Significance. The compound Poisson killing model provides a novel approach for analytical prediction of the biological effectiveness of nanoparticle radiosensitization, instead of local effect modeling.

Dosimetric Deviations of Bragg-Peak Position Shifts in Uniform Magnetic Fields for Magnetic Resonance Imaging-Guiding Proton Radiotherapy: A Monte Carlo Study.

Objective: To investigate dosimetric deviations in scanning protons for Bragg-peak position shifts, which were caused by proton spiral tracks in an ideal uniform field of magnetic resonance (MRI) imaging-guided proton radiotherapy (MRI-IGPRT). Methods: The FLUKA Monte-Carlo (MC) code was used to simulate the spiral tracks of protons penetrating water with initial energies of 70-270 MeV under the influence of field strength of 0.0-3.0 Tesla in commercial MRI systems. Two indexes, lateral shift (marked as WD) perpendicular to the field and a penetration-depth shift (marked as ΔDD) along the beam path, were employed for the Bragg-peak position of spiral proton track analysis. A comparison was performed between MC and classical analytical model to check the simulation results. The shape of the 2D/3D dose distribution of proton spots at the depth of Bragg-Peak was also investigated. The ratio of Gaussian-fit value between longitudinal and transverse major axes was used to indicate the asymmetric index. The skewness of asymmetry was evaluated at various dose levels by the radius ratio of circumscribed and inscribed circles by fitting a semi-ellipse circle of 2D distribution. Results: The maximum of WD deflection is 2.82 cm while the maximum of shortening ΔDD is 0.44 cm for proton at 270 MeV/u under a magnetic field of 3.0 Tesla. The trend of WD and ΔDD from MC simulation was consistent with the analytical model, which means the reverse equation of the analytical model can be applied to determine the proper field strength of the magnet and the initial energy of the proton for the planned dose. The asymmetry of 2D/3D dose distribution under the influence of a magnetic field was increased with higher energy, and the skewness of asymmetry for one proton energy at various dose levels was also increased with a larger radius, i.e., a lower dose level. Conclusions: The trend of the spiral proton track under a uniform magnetic field was obtained in this study using either MC simulation or the analytical model, which can provide an optimized and planned dose of the proton beam in the clinical application of MRI-IGPRT.

Overexpression of IGFBP5 Enhances Radiosensitivity Through PI3K-AKT Pathway in Prostate Cancer.

BACKGROUND: Radiotherapy is the main treatment for localized prostate cancer. The therapeutic effects of radiotherapy are highly dependent on radiosensitivity of target tumors. Here, we investigated the impact of insulin-like growth factor-binding protein 5 (IGFBP5) on irradiation therapy in prostate cancer. METHODS: IGFBP5 gene was overexpressed in human prostate cancer cell lines, PC3 and DU145, with transfection of lentivirus expression vector. Radiosensitivity of the cell lines was assessed with colony formation, cell cycle and cell proliferation assays. The expression of proteins associated with the PI3K-AKT pathway was determined by Western blotting. The effect of IGFBP5 knockdown on PI3K-AKT pathway was tested using PI3K inhibitor. RESULTS: Higher expression of IGFBP5 improved the efficacy of radiotherapy for prostate cancer patients. The effects of IGFBP5 were linked to the PI3K-AKT signaling pathway. Overexpression of IGFBP5 enhanced radiosensitivity and induced G2/M phase arrest in prostate cancer cells. In contrast, it decreased PI3K, p-AKT expression and cell viability. These effects were reversed by IGFBP5 knockdown. CONCLUSION: Our results reveal that IGFBP5 regulates radiosensitivity in prostate cancer via the PI3K-AKT pathway. It is, therefore, a potential biomarker of tumors that influences the therapeutic effect of radiotherapy.

Charged particle radiobiology beamline using tandem accelerator-based MeV protons and carbon ions: a pilot study on the track-end radiation quality, variable biological effectiveness and Bayesian beam dosimetry.

For in vitro cell irradiation using tandem accelerator-based MeV protons and carbon ions, by TOPAS simulation, a pilot study of performance evaluation is presented on a collimation beamline for 3 MeV protons and 10 MeV carbon ions from a 2 × 3 MV tandem accelerator. Based on the elements and source parameters, a collimated beam of 2.8 MeV protons or 2.5 MeV carbon ions, with 5.175 mm or 5.166 mm full width tenth maximum (FWTM), respectively, can be delivered to the target cell dish. TOPAS simulations and/or deterministic algorithms present a Bragg curve of linear energy transfer (LET) (10-70 keV µm-1) along a 138 µm range of the proton beam, and a declining LET of the carbon beam (900-100 keV µm-1) within 4 µm range. Based on the biophysical models for relative biological effectiveness (RBE) of protons, TOPAS RBE scorers presents a set of depth-variation curves of the proton RBE (for V79 and DU145 cells), linearly related to the Bragg curve of the proton LET. Based on the microdosimetric-kinetic (MK) theory, in the 4 µm range for a monolayer cell thickness, the mean RBEα (V79 cells) of the carbon ion beam is estimated as 3.612 (late S phase) and 1.737 (G 1/S phase) for the mean LET of 492 keV µm-1. For practical irradiations, a tunable proton RBE can be acquired by changing the thickness of the cell dish. For the low-energy high-fluence (rate) beams, indirect beam measurements are proposed to detect the proton-beam induced scattering/recoil protons from a beam-intercepting Mylar film, and the carbon-beam induced backscattered electrons from a gold-deposited Havar-foil beam window. Statistical dosimetry for the indirect measurement is established, using a Bayesian model based on the preset number of detection counts, by which the mean value of the whole-dish dose can be prescribed and the uncertainty introduced in the survival data can be corrected.