[en] Despite the use of multimodal treatments incorporating surgery, chemotherapy and radiotherapy, local control of gliomas remains a major challenge. The potential of a new treatment approach called indirect radio-chemo-beta therapy using the synergy created by combining methotrexate (MTX) with bromodeoxyuridine (BrUdR) under optimum energy x-ray irradiation is assessed. 9L rat gliosarcoma cells pre-treated with 0.01 μM MTX and/or 10 μM BrUdR were irradiated in vitro with 50 kVp, 125 kVp, 250 kVp, 6 MV and 10 MV x-rays. The cytotoxicity was assessed using clonogenic survival as the radiobiological endpoint. The photon energy with maximum effect was determined using radiation sensitization enhancement factors at 10% clonogenic survival (SER_1_0_%). The cell cycle distribution was investigated using flow cytometric analysis with propidium iodide staining. Incorporation of BrUdR in the DNA was detected by the fluorescence of labelled anti-BrUdR antibodies. The radiation sensitization enhancement exhibits energy dependence with a maximum of 2.3 at 125 kVp for the combined drug treated cells. At this energy, the shape of the clonogenic survival curve of the pharmacological agents treated cells changes substantially. This change is interpreted as an increased lethality of the local radiation environment and is attributed to supplemented inhibition of DNA repair. Radiation induced chemo-beta therapy was demonstrated in vitro by the targeted activation of combined pharmacological agents with optimized energy tuning of x-ray beams on 9 L cells. Our results show that this is a highly effective form of chemo-radiation therapy. (paper)

[en] Metastases from cutaneous squamous cell carcinoma (cSCC) occur in 2%–5% of cases. Surgery is the standard treatment, often combined with adjuvant radiotherapy. Concurrent carboplatin treatment with post-operative radiotherapy may be prescribed, although it has not shown benefit in recent clinical trials in high-risk cSCC patients. The novel high-Z nanoparticle thulium (III) oxide has been shown to enhance radiation dose delivery to brain tumors by specific uptake of these nanoparticles into the cancerous tissue. As the dose-enhancement capacity of thulium oxide nanoparticles following radiotherapy against metastatic cSCC cells is unknown, its efficacy as a radiosensitizer was evaluated, with and without carboplatin. Novel and validated human patient-derived cell lines of metastatic cSCC were used. The sensitivity of the cells to radiation was investigated using short-term proliferation assays as well as clonogenic survival as the radiobiological endpoint. Briefly, cells were irradiated with 125 kVp orthovoltage x-rays (0–6 Gy) with and without thulium oxide nanoparticles (99.9% trace metals basis; 50 µg ml⁻¹) or low dose carboplatin pre-sensitization. Cellular uptake of the nanoparticles was first confirmed by microscopy and found to have no impact on short-term cell survival for the cSCC cells, highlighting the biocompatibility of thulium oxide nanoparticles. Clonogenic cell survival assays confirmed radio-sensitization when exposed to thulium nanoparticles, with the cell sensitivity increasing by a factor of 1.24 (calculated at the 10% survival fraction) for the irradiated cSCC cells. The combination of carboplatin with thulium oxide nanoparticles with irradiation did not result in significant further reductions in survival compared to nanoparticles alone. This is the first study to provide in vitro data demonstrating the independent radiosensitization effect of high-Z nanoparticles against metastatic cSCC with or without carboplatin. Further preclinical investigations with radiotherapy plus high-Z nanoparticles for the management of metastatic cSCC are warranted. (paper)

[en] In the last 25 years microbeam radiation therapy (MRT) has emerged as a promising alternative to conventional radiation therapy at large, third generation synchrotrons. In MRT, a multi-slit collimator modulates a kilovoltage x-ray beam on a micrometer scale, creating peak dose areas with unconventionally high doses of several hundred Grays separated by low dose valley regions, where the dose remains well below the tissue tolerance level. Pre-clinical evidence demonstrates that such beam geometries lead to substantially reduced damage to normal tissue at equal tumour control rates and hence drastically increase the therapeutic window. Although the mechanisms behind MRT are still to be elucidated, previous studies indicate that immune response, tumour microenvironment, and the microvasculature may play a crucial role. Beyond tumour therapy, MRT has also been suggested as a microsurgical tool in neurological disorders and as a primer for drug delivery.

The physical properties of MRT demand innovative medical physics and engineering solutions for safe treatment delivery. This article reviews technical developments in MRT and discusses existing solutions for dosimetric validation, reliable treatment planning and safety. Instrumentation at synchrotron facilities, including beam production, collimators and patient positioning systems, is also discussed. Specific solutions reviewed in this article include: dosimetry techniques that can cope with high spatial resolution, low photon energies and extremely high dose rates of up to 15 000 Gy s⁻¹, dose calculation algorithms—apart from pure Monte Carlo Simulations—to overcome the challenge of small voxel sizes and a wide dynamic dose-range, and the use of dose-enhancing nanoparticles to combat the limited penetrability of a kilovoltage energy spectrum. Finally, concepts for alternative compact microbeam sources are presented, such as inverse Compton scattering set-ups and carbon nanotube x-ray tubes, that may facilitate the transfer of MRT into a hospital-based clinical environment.

Intensive research in recent years has resulted in practical solutions to most of the technical challenges in MRT. Treatment planning, dosimetry and patient safety systems at synchrotrons have matured to a point that first veterinary and clinical studies in MRT are within reach. Should these studies confirm the promising results of pre-clinical studies, the authors are confident that MRT will become an effective new radiotherapy option for certain patients. (topical review)

[en] Synchrotron microbeam radiation therapy (MRT) is a novel technique that uses a spatially fractionated field to induce cancer selectivity in treatment. Complemented with high-Z nanoparticles, MRT treatment of cancer becomes even more targeted and sparing of healthy tissue. For the first time, this study determines the factors that affect synchrotron microbeam activation therapy (SMART) using thulium nanoparticles (TmNPs). (author)

[en] Gold nanoparticles have demonstrated significant radiosensitization of cancer treatment with x-ray radiotherapy. To understand the mechanisms at the basis of nanoparticle radiosensitization, Monte Carlo simulations are used to investigate the dose enhancement, given a certain nanoparticle concentration and distribution in the biological medium. Earlier studies have ordinarily used condensed history physics models to predict nanoscale dose enhancement with nanoparticles. This study uses Geant4-DNA complemented with novel track structure physics models to accurately describe electron interactions in gold and to calculate the dose surrounding gold nanoparticle structures at nanoscale level. The computed dose in silico due to a clinical kilovoltage beam and the presence of gold nanoparticles was related to in vitro brain cancer cell survival using the local effect model. The comparison of the simulation results with radiobiological experimental measurements shows that Geant4-DNA and local effect model can be used to predict cell survival in silico in the case of x-ray kilovoltage beams. (paper)

[en] Highlights: • We examined the biological effect of differing dose-rates for 10 MV from a LINAC. • Cell survival curves were used to determine the α and β values (radiosensitivity). • A reduction in dose rate has no effect on the survival curve of 9L cells. • A lower dose rate killed more MCF-7 cells. • We showed that dose-rate is important in determining the efficacy of IMRT. - Abstract: Radiation therapy is rapidly evolving toward the delivery of higher dose rates to improve cancer treatment. In vitro experiments were performed to investigate the response of 9L and MCF-7 cancer cell lines, exposed to 10 MV X-ray radiations. Up to 8 Gy was delivered at a dose-rate of 50 cGy/min compared to 5 Gy/min. The data obtained emphasizes the importance of taking into account not only the physical, but also the radiobiological parameters, when planning a particular cancer treatment.

[en] The effects of high hydrostatic pressure on the structure and dynamics of model membrane systems were investigated using neutron scattering. Diffraction experiments show shifts of the pre- and main-phase transitions of multi lamellar vesicles of 1,2-di-myristoyl-sn-glycero-3-phosphocholine (DMPC) to higher temperatures with increased pressure which are close to results observed previously by other techniques, namely (10.4 ± 1.0) K kbar"-"1 and (20.0 ± 0.5) K kbar"-"1 for the two transitions. Backscattering spectroscopy reveals that the mean square displacements in the liquid phase are about 10% smaller at 300 bar and about 20% smaller at 600 bar compared to atmospheric pressure, whereas in the gel phase below the main phase transition the mean square displacements show a smaller difference in the dynamics of the three pressure values within the studied pressure range. (authors)

[en] Highlights: • Facilesynthesis of inorganic Bi(OH)₃ nanoparticles. • High biocompatibility in human skin and dog kidney cells in vitro. • Ultraviolet filter capable of reducing the photocatalytic activity of TiO₂ and ZnO. • Preparation of TiO₂/Bi(OH)₃ and classical TiO₂/ZnO sunscreen formulations. • Significantly improved photoprotection and photostability compared to TiO₂/ZnO. - Abstract: In this study we investigate readily synthesised Bi(OH)₃ nanoparticles as a novel, multifunctional ultraviolet filter for sunscreen. The absorbance of Bi(OH)₃ NPs in the ultraviolet region is comparable to that of both ZnO and TiO₂ NPs used in commercial sunscreens. In vitro photoprotection results show that the combination of TiO₂/Bi(OH)₃ is more efficient than TiO₂/ZnO over the whole UV range, with an increase in sun protection factor of 28%. The emulsions show rheological properties comparable to those of commercial sunscreens. The combination of TiO₂/Bi(OH)₃ led to insignificant damage on pre-painted steel panels after exterior exposure for twelve weeks. We also demonstrate that the addition of Bi(OH)₃ NPs reduces the degradation of crystal violet by photocatalytically active TiO₂ or ZnO NPs under ultraviolet exposure. Finally, assessment of the biocompatibility of Bi(OH)₃ with HaCaT keratinocytes and Madin-Darby Canine Kidney (MDCK) cells in vitro is described.