Reduced side effects by proton microchannel radiotherapy: study in a human skin model

Abstract

The application of a microchannel proton irradiation was compared to homogeneous irradiation in a three-dimensional human skin model. The goal is to minimize the risk of normal tissue damage by microchannel irradiation, while preserving local tumor control through a homogeneous irradiation of the tumor that is achieved because of beam widening with increasing track length. 20 MeV protons were administered to the skin models in 10- or 50-μm-wide irradiation channels on a quadratic raster with distances of 500 μm between each channel (center to center) applying an average dose of 2 Gy. For comparison, other samples were irradiated homogeneously at the same average dose. Normal tissue viability was significantly enhanced after microchannel proton irradiation compared to homogeneous irradiation. Levels of inflammatory parameters, such as Interleukin-6, TGF-Beta, and Pro-MMP1, were significantly lower in the supernatant of the human skin tissue after microchannel irradiation than after homogeneous irradiation. The genetic damage as determined by the measurement of micronuclei in keratinocytes also differed significantly. This difference was quantified via dose modification factors (DMF) describing the effect of each irradiation mode relative to homogeneous X-ray irradiation, so that the DMF of 1.21 ± 0.20 after homogeneous proton irradiation was reduced to 0.23 ± 0.11 and 0.40 ± 0.12 after microchannel irradiation using 10- and 50-μm-wide channels, respectively. Our data indicate that proton microchannel irradiation maintains cell viability while significantly reducing inflammatory responses and genetic damage compared to homogeneous irradiation, and thus might improve protection of normal tissue after irradiation.

The influence of the channel size on the reduction of side effects in microchannel proton therapy

“…As in the previous study (Zlobinskaya et al 2013), the reconstructed human skin model (EFT400; EpiDermFT TM , surface area 1 cm 2 ) was obtained from MatTek Corporation, Ashland, MA, USA. This three-dimensional, multilayered, differentiated tissue model with an epidermal and a dermal layer consists of human-derived epidermal keratinocytes and dermal fibroblasts, cultured on special cell culture inserts.…”

“…First experimental evidence has demonstrated that a proton microchannel irradiation reduces irradiation effects in a human skin model in comparison with conventional broad-beam irradiation (Zlobinskaya et al 2013). In this study, 20-MeV protons were applied on the central 4 9 4 mm 2 of the skin in a focused microchannel mode (50-lm-wide channels on a 500 9 500 lm 2 matrix) or a homogeneous mode with the same mean dose of 2 Gy at the ion microprobe SNAKE in Munich (Superconducting Nanoprobe for Applied nuclear [Kern] physics Experiments; Hauptner et al 2004;Greubel et al 2008;Schmid et al 2010).…”

“…1). This study is the continuation of our pilot study (Zlobinskaya et al 2013) on proton microchannel radiotherapy, to fully investigate the potential of this radiotherapy method to minimize the risk of normal tissue damage in radiotherapy. For comparability of the effects, the previously used human skin model was again taken as a representative of normal tissue, to simulate the acute side effects and induced radiation damage in the deeper lying tissues.…”

“…Normal tissue damage or even secondary cancer induction is a major concern in radiotherapy, with detrimental effects on the patient's well-being after tumor therapy. Proton microchannel radiotherapy, a spatially fractionated radiotherapy approach using sub-millimeter or even micrometer-sized proton beams which spread out into the tumor to homogeneously irradiate the cancer cells, was recently invented (Zlobinskaya et al 2013). The proton microchannel approach is similar to the X-ray microbeam radiation therapy (MRT) method developed at Brookhaven National Laboratory (Slatkin et al 1995) and the European Synchrotron Radiation Facility (ESRF; Laissue et al 2007;Serduc et al 2008;Brauer-Krisch et al 2003, 2005, where side effects in the healthy tissue are substantially reduced since only a small fraction of the irradiated area suffers from large doses, but the other fraction obtains only small doses.…”

“…MTT tissue viability test and micronucleus assay revealed higher cellular viability and lower genetic damage after microchannel irradiation compared to homogeneous broad-beam irradiation. Inflammatory response, measured via the release of inflammatory cytokines in the culture medium, was also significantly lower using the microchannel irradiation mode (Zlobinskaya et al 2013).…”