Stéphanie Corde

Synchrotron radiation based experimental determination of the optimal energy for cell radiotoxicity enhancement following photoelectric effect on stable iodinated compounds

This study was designed to experimentally evaluate the optimal X-ray energy for increasing the radiation energy absorbed in tumours loaded with iodinated compounds, using the photoelectric effect. SQ20B human cells were irradiated with synchrotron monochromatic beam tuned at 32.8, 33.5, 50 and 70 keV. Two cell treatments were compared to the control: cells suspended in 10 mg ml−1 of iodine radiological contrast agent or cells pre-exposed with 10 μM of iodo-desoxyuridine (IUdR) for 48 h. Our radiobiological end point was clonogenic cell survival. Cells irradiated with both iodine compounds exhibited a radiation sensitisation enhancement. Moreover, it was energy dependent, with a maximum at 50 keV. At this energy, the sensitisation calculated at 10% survival was equal to 2.03 for cells suspended in iodinated contrast agent and 2.60 for IUdR. Cells pretreated with IUdR had higher sensitisation factors over the energy range than for those suspended in iodine contrast agent. Also, their survival curves presented no shoulder, suggesting complex lethal damages from Auger electrons. Our results confirm the existence of the 50 keV energy optimum for a binary therapeutic irradiation based on the presence of stable iodine in tumours and an external irradiation. Monochromatic synchrotron radiotherapy concept is hence proposed for increasing the differential effect between healthy and cancerous tissue irradiation.

Performance of computed tomography for contrast agent concentration measurements with monochromatic x-ray beams: comparison of K-edge versus temporal subtraction

We investigated the performance of monochromatic computed tomography for the quantification of contrast agent concentrations. Two subtraction methods (K-edge subtraction and temporal subtraction) were evaluated and compared theoretically and experimentally in terms of detection limit, precision and accuracy. Measurements were performed using synchrotron x-rays with Lucite phantoms (10 cm and 17.5 cm in diameter) containing iodine or gadolinium solutions ranging from 50 microg ml(-1) to 5 mg ml(-1). The experiments were carried out using monochromators developed at the European Synchrotron Radiation Facility (ESRF) medical beamline. The phantoms were imaged either above and below the contrast agent K-edge, or before and after the addition of the contrast agent. Both methods gave comparable performance for phantoms less than 10 cm in diameter. For large phantoms, equivalent to a human head, the temporal subtraction is more suitable for detecting elements such as iodine, keeping a reasonable x-ray dose delivered to the phantom. A good agreement was obtained between analytical calculations, simulations and measurements. The beam harmonic content was taken into account in the simulations. It explains the performance degradation with high contrast agent concentrations. The temporal subtraction technique has the advantage of energy tunability and is well suited for imaging elements, such as iodine or gadolinium, in highly absorbing samples. For technical reasons, the K-edge method is preferable when the imaged organ is moving since the two measurements can be performed simultaneously, which is mandatory for obtaining a good subtraction.

Absolute Cerebral Blood Volume and Blood Flow Measurements Based on Synchrotron Radiation Quantitative Computed Tomography

Synchrotron radiation computed tomography opens new fields by using monochromatic x-ray beams. This technique allows one to measure in vivo absolute contrast-agent concentrations with high accuracy and precision, and absolute cerebral blood volume or flow can be derived from these measurements using tracer kinetic methods. The authors injected an intravenous bolus of an iodinated contrast agent in healthy rats, and acquired computed tomography images to follow the temporal evolution of the contrast material in the blood circulation. The first image acquired before iodine infusion was subtracted from the others to obtain computed tomography slices expressed in absolute iodine concentrations. Cerebral blood volume and cerebral blood flow maps were obtained after correction for partial volume effects. Mean cerebral blood volume and flow values (n = 7) were 2.1 ± 0.38 mL/100 g and 129 ± 18 mL · 100 g–1 · min–1 in the parietal cortex; and 1.92 ± 0.32 mL/100 g and 125 ± 17 mL · 100 g–1 · min–1 in the caudate putamen, respectively. Synchrotron radiation computed tomography has the potential to assess these two brain-perfusion parameters.

Lack of Cell Death Enhancement after Irradiation with Monochromatic Synchrotron X Rays at the K-Shell Edge of Platinum Incorporated in Living SQ20B Human Cells as cis-Diamminedichloroplatinum (II)

Abstract Corde, S., Biston, M. C., Elleaume, H., Estève, F., Charvet, A. M., Joubert, A., Ducros, V., Bohic, S., Simionovici, A., Brochard, T., Nemoz, C., Renier, Troprès, I., Fiedler, S., Bravin, A., M., Thomlinson, W., Le Bas, J. F. and Balosso, J. Lack of Cell Death Enhancement after Irradiation with Monochromatic Synchrotron X Rays at the K-Shell Edge of Platinum Incorporated in Living SQ20B Human Cells as cis-Diamminedichloroplatinum (II). Radiat. Res. 158, 763–770 (2002). In this paper we describe the results of experiments using synchrotron radiation to trigger the Auger effect in living human cancer cells treated with a widely used chemotherapy drug: cis-diamminedichloroplatinum (II) (cisplatin). The experiments were carried out at the ID17 beamline of the European Synchrotron Radiation Facility, which produces a high-fluence monochromatic beam that is adjustable from 20 to 80 keV. Cisplatin was chosen as the carrier of platinum atoms in the cells because of its alkylating-like activity and the irradiation was done with monochromatic beams above and below the platinum K-shell edge (78.39 keV). Cell survival curves were comparable with those obtained for the same cells under conventional irradiation conditions. At a low dose of cisplatin (0.1 μM, 48 h), no difference was seen in survival when the cells were irradiated above and below the K-shell edge of platinum. Higher cisplatin concentrations were investigated to enhance the cellular platinum content. The results with 1 μM cisplatin for 12 h showed no difference when the cells were irradiated with beams above or below the platinum K-shell edge with the exception of the higher cell death resulting from drug toxicity. The intracellular content of platinum was significant, as measured macroscopically by inductively coupled plasma mass spectrometry. Its subcellular localization and particularly its presence in the cell nucleus were verified by microscopic synchrotron X-ray fluorescence. This was the first known attempt at K-shell edge photon activation of stable platinum in living cells with a platinum complex used for chemotherapy. Its evident toxicity in these cells leads us to put forth the hypothesis that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation above the K-shell edge. However, K-shell edge photon activation of stable elements provides a powerful technique for the understanding of the biological effects of Auger processes. Further avenues of development are discussed.

Optimal energy for cell radiosensitivity enhancement by gold nanoparticles using synchrotron-based monoenergetic photon beams

Gold nanoparticles have been shown to enhance radiation doses delivered to biological targets due to the high absorption coefficient of gold atoms, stemming from their high atomic number (Z) and physical density. These properties significantly increase the likelihood of photoelectric effects and Compton scattering interactions. Gold nanoparticles are a novel radiosensitizing agent that can potentially be used to increase the effectiveness of current radiation therapy techniques and improve the diagnosis and treatment of cancer. However, the optimum radiosensitization effect of gold nanoparticles is strongly dependent on photon energy, which theoretically is predicted to occur in the kilovoltage range of energy. In this research, synchrotron-generated monoenergetic X-rays in the 30–100 keV range were used to investigate the energy dependence of radiosensitization by gold nanoparticles and also to determine the photon energy that produces optimum effects. This investigation was conducted using cells in culture to measure dose enhancement. Bovine aortic endothelial cells with and without gold nanoparticles were irradiated with X-rays at energies of 30, 40, 50, 60, 70, 81, and 100 keV. Trypan blue exclusion assays were performed after irradiation to determine cell viability. Cell radiosensitivity enhancement was indicated by the dose enhancement factor which was found to be maximum at 40 keV with a value of 3.47. The dose enhancement factor obtained at other energy levels followed the same direction as the theoretical calculations based on the ratio of the mass energy absorption coefficients of gold and water. This experimental evidence shows that the radiosensitization effect of gold nanoparticles varies with photon energy as predicted from theoretical calculations. However, prediction based on theoretical assumptions is sometimes difficult due to the complexity of biological systems, so further study at the cellular level is required to fully characterize the effects of gold nanoparticles with ionizing radiation.

Synchrotron stereotactic radiotherapy: dosimetry by Fricke gel and Monte Carlo simulations.

Synchrotron stereotactic radiotherapy (SSR) consists in loading the tumour with a high atomic number element (Z), and exposing it to monochromatic x-rays from a synchrotron source (50-100 keV), in stereotactic conditions. The dose distribution results from both the stereotactic monochromatic x-ray irradiation and the presence of the high Z element. The purpose of this preliminary study was to evaluate the two-dimensional dose distribution resulting solely from the irradiation geometry, using Monte Carlo simulations and a Fricke gel dosimeter. The verification of a Monte Carlo-based dosimetry was first assessed by depth dose measurements in a water tank. We thereafter used a Fricke dosimeter to compare Monte Carlo simulations with dose measurements. The Fricke dosimeter is a solution containing ferrous ions which are oxidized to ferric ions under ionizing radiation, proportionally to the absorbed dose. A cylindrical phantom filled with Fricke gel was irradiated in stereotactic conditions over several slices with a continuous beam (beam section = 0.1 x 1 cm2). The phantom and calibration vessels were then imaged by nuclear magnetic resonance. The measured doses were fairly consistent with those predicted by Monte Carlo simulations. However, the measured maximum absolute dose was 10% underestimated regarding calculation. The loss of information in the higher region of dose is explained by the diffusion of ferric ions. Monte Carlo simulation is the most accurate tool for dosimetry including complex geometries made of heterogeneous materials. Although the technique requires improvements, gel dosimetry remains an essential tool for the experimental verification of dose distribution in SSR with millimetre precision.

Microbeam Radiation-Induced Tissue Damage Depends on the Stage of Vascular Maturation

PURPOSE To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. METHODS AND MATERIALS CAMs were irradiated with microplanar beams (width, ∼25 μm; interbeam spacing, ∼200 μm) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. RESULTS In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. CONCLUSIONS The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time.

In vivo measurement of gadolinium concentration in a rat glioma model by monochromatic quantitative computed tomography: Comparison between gadopentetate dimeglumine and gadobutrol

Rationale and Objectives:Monochromatic quantitative computed tomography allows a nondestructive and quantitative measurement of gadolinium (Gd) concentration. This technique was used in the C6 rat glioma model to compare gadopentetate dimeglumine and gadobutrol. Methods:Rats bearing late-stage gliomas received 2.5 mmol/kg (392.5 mg Gd/kg) of gadopentetate dimeglumine (n = 5) and gadobutrol (n = 6) intravenously before the imaging session performed at the European Synchrotron Radiation Facility. Results:Monochromatic quantitative computed tomography enabled in vivo follow-up of Gd concentration as a function of time in specified regions of interest. Surprisingly, after gadobutrol injection, Gd concentrations in the center and periphery of the tumor were higher than those after gadopentetate injection, although identical in normal and contralateral area of the brain. Conclusion:The in vivo assessment of absolute Gd concentrations revealed differences in gadobutrol and gadopentetate dimeglumine behaviors in tumoral tissues despite injections in the same conditions. These differences might be attributed to different characteristics of the contrast agents.

Cerium oxide nanoparticles: influence of the high-Z component revealed on radioresistant 9L cell survival under X-ray irradiation

UNLABELLED This article pioneers a study into the influence of the high-Z component of nanoparticles on the efficacy of radioprotection some nanoparticles offer to exposed cells irradiated with X-rays. We reveal a significant decrease in the radioprotection efficacy for cells exposed to CeO2 nanoparticles and irradiated with 10 MV and 150 kVp X-rays. In addition, analysis of the 150 kVp survival curve data indicates a change in radiation quality, becoming more lethal for irradiated cells exposed to CeO2 nanoparticles. We attribute the change in efficacy to an increase in high linear energy transfer Auger electron production at 150 kVp which counterbalances the CeO2 nanoparticle radioprotection capability and locally changes the radiation quality. This study highlights an interesting phenomenon that must be considered if radiation protection drugs for use in radiotherapy are developed based on CeO2 nanoparticles. FROM THE CLINICAL EDITOR CeO2 nanoparticles are thought to offer radioprotection; however, this study reveals significant decrease in the radioprotection efficacy for cells exposed to CeO2 nanoparticles and irradiated with 10 MV and 150 kVp X-rays. This phenomenon must be considered when developing radiation protection drugs based on CeO2 nanoparticles.

Feasibility of synchrotron radiation computed tomography on rats bearing glioma after iodine or gadolinium injection

Abstract. The purpose of this work was to demonstrate the feasibility of a new imaging technique called synchrotron radiation computed tomography (SRCT). This technique leads to a direct assessment of the in vivo concentration of an iodine- or gadolinium-labeled compound. Rats bearing C6 glioma were imaged by MRI prior to the SRCT experiment. The SRCT experiments were performed after a 1.3 g I/kg (n = 5) or a 0.4 g Gd/kg (n = 5) injection. Finally, brains were sampled for histology. The SRCT images exhibited contrast enhancement at the tumor location. Ten minutes after injection, iodine and gadolinium tissular concentrations were equal to 0.80 ( ± 0.40) mg/cm3 and 0.50 ( ± 0.10) mg/cm3, respectively in the peripheral area of the tumor (respective background value: 0.20 ± 0.02 to 0.10 ± 0.01). Correlation to MRI and histology revealed that the contrast uptake occurred in the most vascularized area of the tumor. The present study summarizes the feasibility of in vivo SRCT to obtain quantitative information about iodine and gadolinium-labeled compounds. Beyond brain tumor pathology, the SRCT appears as a complementary approach to MRI and CT, for studying iodine- and gadolinium-labeled compounds by the direct achievement of the tissular concentration value in the tissue.