Cell culture is an essential tool for drug discovery, tissue engineering, and stem cell research. Conventional tissue culture produces two-dimensional (2D) cell growth with gene expression, signaling, and morphology that can differ from those in vivo and thus compromise clinical relevancy1–5. Here we report a three-dimensional (3D) culture of cells based on magnetic levitation in the presence of hydrogels containing gold and magnetic iron oxide (MIO) nanoparticles plus filamentous bacteriophage. This methodology allows for control of cell mass geometry and guided, multicellular clustering of different cell types in co-culture through spatial variance of the magnetic field. Moreover, magnetic levitation of human glioblastoma cells demonstrates similar protein expression profiles to those observed in human tumor xenografts. Taken together, these results suggest levitated 3D culture with magnetized phage-based hydrogels more closely recapitulates in vivo protein expression and allows for long-term multi-cellular studies.
The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE.
When the geant 4 particle tracking method is used to calculate the average LET values within targets with a small step limit, such as smaller than 500 μm, the authors recommend the use of LETt in the dose plateau region and LETd around the Bragg peak. For a large step limit, i.e., 500 μm, LETd is recommended along the whole Bragg curve. The transition point depends on beam parameters and can be found by determining the location where the gradient of the ratio of LETd and LETt becomes positive.
The development and use of sensitizing agents to improve the effectiveness of radiotherapy have long been sought to improve our ability to treat cancer. In this letter, we have studied the relative biological effectiveness of proton beam radiotherapy on prostate tumor cells with and without internalized gold nanoparticles. The effectiveness of proton radiotherapy for the killing of prostate tumor cells was increased by approximately 15%–20% for those cells containing internalized gold nanoparticles.
Background The relative biological effectiveness (RBE) for particle therapy is a complex function of particle type, radiation dose, linear energy transfer (LET), cell type, endpoint, etc. In the clinical practice of proton therapy, the RBE is assumed to have a fixed value of 1.1. This assumption, along with the effects of physical uncertainties, may mean that the biologically effective dose distributions received by the patient may be significantly different from what is seen on treatment plans. This may contribute to unforeseen toxicities and/or failure to control the disease. Variability of Proton RBE It has been shown experimentally that proton RBE varies significantly along the beam path, especially near the end of the particle range. While there is now an increasing acceptance that proton RBE is variable, there is an ongoing debate about whether to change the current clinical practice. Clinical Evidence A rationale against the change is the uncertainty in the models of variable RBE. Secondly, so far there is no clear clinical evidence of the harm of assuming proton RBE to be 1.1. It is conceivable, however, that the evidence is masked partially by physical uncertainties. It is, therefore, plausible that reduction in uncertainties and their incorporation in the estimation of dose actually delivered may isolate and reveal the variability of RBE in clinical practice. Nevertheless, clinical evidence of RBE variability is slowly emerging as more patients are treated with protons and their response data are analyzed. Modelling and Incorporation of RBE in the Optimization of Proton Therapy The improvement in the knowledge of RBE could lead to better understanding of outcomes of proton therapy and in the improvement of models to predict RBE. Prospectively, the incorporation of such models in the optimization of intensity-modulated proton therapy could lead to improvements in the therapeutic ratio of proton therapy.
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