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Dose enhancement by gold nanoparticles (AuNP) increases the biological effectiveness of Radiation damage in biomolecules and tissue. To apply them effectively during cancer therapy their influence on the locally delivered dose has to be determined. Hereby, the AuNP locations strongly influence the energy deposit in the nucleus, mitochondria, membrane and the cytosol of the targeted cells. To estimate these effects, particle scattering simulations are applied. In general, different approaches for modeling the AuNP and their distribution within the cell are possible. In this work, two newly developed continuous and discrete-geometric models for simulations of AuNP in cells are presented.
These models are applicable to simulations of internal emitters and external radiation sources. Most of the current studies on AuNP focus on external beam therapy. In contrast, we apply the presented models in Monte-Carlo particle scattering simulations to characterize the energy deposit in cell organelles by radioactive 198AuNP. They emit beta and gamma rays and are therefore considered for applications with solid tumors. Differences in local dose enhancement between randomly distributed and nucleus targeted nanoparticles are compared. Hereby nucleus targeted nanoparticels showed a strong local dose enhancement in the radio sensitive nucleus. These results are the foundation for future experimental work which aims to obtain a mechanistic understanding of cell death induced by radioactive 198Au.
Reference Materials at BAM
(2021)
DNA basierte Dosimetrie
(2020)
We propose the development of a standardized DNA based dosimeter. This dosimeter will improve the comparability between the results of different laboratories in radiation research. Compared to conventional methods in dosimetry, this Approach provides direct access to the relation between radiation interaction and biological damage. Moreover, it enables the systematic investigation of the relation between the microscopic characteristics of radiation and DNA damage over a wide dose range.
Ectoine is a small zwitterionic osmolyte and compatible solute, which does not interfere with cell metabolism even at molar concentrations. Plasmid DNA (pUC19) was irradiated with ultraviolet radiation (UV-C at 266 nm) under quasi physiological conditions (PBS) and in pure water in the presence and absence of ectoine (THP(B)) and hydroxyectoine (THP(A)). Different types of UV induced DNA damage were analysed: DNA single-strand breaks (SSBs), abasic sites and cyclobutane pyrimidine dimers (CPDs). A complex interplay between these factors was observed with respect to the nature and occurrence of DNA damage with 266 nm photons. In PBS, the cosolutes showed efficient protection against base damage, whilst in pure water, a dramatic shift from SSB damage to base damage was observed when cosolutes were added. To test whether these effects are caused by ectoine binding to DNA, further experiments were conducted: small-angle X-ray scattering (SAXS), surface-plasmon resonance (SPR) measurements and Raman spectroscopy. The results show, for the first time, a close interaction between ectoine and DNA. This is in stark contrast to the assumption made by preferential exclusion models, which are often used to interpret the behaviour of compatible solutes within cells and with biomolecules. It is tentatively proposed that the alterations of UV damage to DNA are attributed to ectoine influence on nucleobases through the direct interaction between ectoine and DNA.
Particle scattering simulations are an useful tool to plan experiments, design detectors, estimate doses in irradiated materials and medical treatment planning.
Geant4 is a Monte-Carlo toolkit for the simulation of of particles scattering in matter. Photons, electrons, ions etc can be simulated with energies in the eV to GeV range. Their interactions with matter in arbitrary scattering geometries be studied. Scattering models, cross sections and material parameters can be set to cover interactions in gas, liquid and solid state. The import of geometries from computer aided design files or the protein data base is possible.
It is currently being applied in high energy and nuclear physics, accelerator and detector design, space application, dosimetry and medical sciences.
In this first part of the talk a brief overview over the structure, functionality and possible applications of Geant4 will be given. In the second part an example application will be presented: The determination of the microscopic dose-damage relations in aqueous environment for electron irradiated plasmid DNA will be explained. Therefore, we combine electron scattering simulations in water with calculations concerning the movement of biomolecules to obtain the energy deposit in the biologically relevant nanoscopic volume. We present, how to combine these simulational results and experimental data via a generalized damage model to determine the microscopic dose-damage relation at a molecular level.
The determination of microscopic dose-damage relations in aqueous environment is of fundamental interest for dosimetry and its application in radiation-therapy and protection. We present a combined experimental and simulational approach to quantify the microscopic energy deposit at biomolecules in liquid environment which is applicable to a wide range of primary radiation sources, e.g. photons, electrons or ions, and targets, such as DNA, proteins or cells.Therefore, we combine Geant4 particle-scattering simulations in water with calculations concerning the movement of biomolecules to obtain the energy deposit in the biologically relevant nanoscopic volume. We present, how to combine these simulational results and experimental data via a generalised damage model to determine the microscopic dose-damage relation at a molecular level.
To show the viability of this approach, we apply this method to an experimentally challenging system, the direct irradiation of plasmid DNA (pUC19) in water with electrons as primary particles. Here we combine electron-scattering simulations with calculations concerning the diffusion and convection induced movement of the DNA, within a coarse-grained model of the irradiated liquid. Additionally a microscopic target model for DNA molecules based on the relation of lineal energy and radiation quality is used to calculate their effective target volume.
It was found that on average fewer than two ionisations within a 7.5\,nm radius around the sugar-phosphate backbone are sufficient to cause a single strand break, with a corresponding median lethal energy deposit being E\textsubscript{1/2}=6+-4\,eV. The presented method is applicable for all types of ionising radiation and a broad variety of biological targets.
The determination of the microscopic dose-damage relationship for DNA in an aqueous environment is of a fundamental interest for dosimetry and applications in radiation therapy and protection. We combine geant4 particle-scattering simulations in water with calculations concerning the movement of biomolecules to obtain the energy deposit in the biologically relevant nanoscopic volume.[1] We juxtaposition these results to the experimentally determined damage to obtain the microscopic dose-damage relationship at a molecular level. This approach is tested for an experimentally challenging system concerning the direct irradiation of plasmid DNA (pUC19) in water with electrons as primary particles.[2] Here a microscopic target model for the plasmid DNA based on the relation of lineal energy and radiation quality is used to calculate the effective target volume. It was found that on average fewer than two ionizations within a 7.5-nm radius around the sugar-phosphate backbone are sufficient to cause a single strand break, with a corresponding median lethal energy deposit being E1/2=6±4 eV.[1] The presented method is applicable for ionizing radiation (e.g., γ rays, x rays, and electrons) and a variety of targets, such as DNA, proteins, or cells.
[1] Hahn, M. B., Meyer, S., Kunte, H.-J., Solomun, T. & Sturm, H. Measurements and simulations of microscopic damage to DNA in water by 30 keV electrons: A general approach applicable to other radiation sources and biological targets. Phys. Rev. E 95, 052419 (2017).
[2] Hahn, M. B. et al. Direct electron irradiation of DNA in a fully aqueous environment. Damage determination in combination with Monte Carlo simulations. Phys. Chem. Chem. Phys. 19, 1798–1805 (2017).
The damage caused by ionizing radiation to DNA and proteins is the reason to treat cancer by radiation therapy. A better understanding of the molecular processes and quantification of the different damaging mechanisms is the prerequisite to develop more efficient therapies. Hereby the understanding of the processes involved in the damage to DNA are of key interest due to its central role in reproduction and mutation.
For radiation with low linear energy transfer (LET), most of the damage is caused by the secondary particles produced by scattering of the ionizing radiation with water. Thereby a multitude of species are produced, whereby especially kinetic low energy electrons, prehydrated electrons, OH-radicals and ions are of importance.
With higher LET the relative amount of the direct damaging effects increases. This is especially important considering the increased usage of high LET particles in radiation therapy. Therefore, the quantification of the contribution to DNA damage of direct and indirect effects and the different secondary species is of high interest due to the increase of radio biological efficiency when applying high LET radiation.
Here we present an approach to investigate the relative contributions to DNA strand break yield for radiation of different LET within a single electron microscope in combination with electron scattering simulations.
The damage caused by ionizing radiation to DNA and proteins is the reason to treat cancer by radiation therapy. A better understanding of the molecular processes and quantification of the different damaging mechanisms is the prerequisite to develop more efficient therapies. Hereby the understanding of the processes involved in the damage to DNA are of key interest due to its central role in reproduction and mutation.
For radiation with low linear energy transfer (LET), most of the damage is caused by the secondary particles produced by scattering of the ionizing radiation with water. Thereby a multitude of species are produced, whereby especially kinetic low energy electrons, prehydrated electrons, OH-radicals and ions are of importance. With higher LET the relative amount of the direct damaging effects increases. This is especially important considering the increased usage of high LET nucleons in radiation therapy. Therefore, the quantification of the contribution to DNA damage of direct and indirect effects and the different secondary species is of high interest due to the increase of radio biological efficiency when applying high LET radiation.
Here we present an approach to investigate the relative contributions to DNA strand break yield for radiation of different LET within a single electron microscope in combination with electron scattering simulations.
The damage caused by ionizing radiation to DNA and proteins is the reason to treat cancer by radiation therapy. A better understanding of the molecular processes and quantification of the different damaging mechanisms is the prerequisite to develop more efficient therapies. Hereby the understanding of the processes involved in the damage to DNA are of key interest due to its central role in reproduction and mutation.
For radiation with low linear energy transfer (LET), most of the damage is caused by the secondary particles produced by scattering of the ionizing radiation with water. Thereby a multitude of species are produced, whereby especially kinetic low energy electrons, prehydrated electrons, OH-radicals and ions are of importance. With higher LET the relative amount of the direct damaging effects increases. This is especially important considering the increased usage of high LET nucleons in radiation therapy. Therefore, the quantification of the contribution to DNA damage of direct and indirect effects and the different secondary species is of high interest due to the increase of radio biological efficiency when applying high LET radiation.
Here we present an approach to investigate the relative contributions to DNA strand break yield for radiation of different LET within a single electron microscope in combination with electron scattering simulations.