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Ionizing radiation damage to DNA plays a fundamental role in cancer therapy. X-ray photoelectron-spectroscopy (XPS) allows simultaneous irradiation and damage monitoring. Although water radiolysis is essential for radiation damage, all previous XPS studies were performed in vacuum. Here we present near-ambient-pressure XPS xperiments to directly measure DNA damage under water atmosphere. They permit in-situ monitoring of the effects of radicals on fully hydrated double-stranded DNA. The results allow us to distinguish direct damage, by photons and secondary low-energy electrons (LEE), from damage by hydroxyl radicals or hydration induced modifications of damage pathways. The exposure of dry DNA to x-rays leads to strand-breaks at the sugar-phosphate backbone, while deoxyribose and nucleobases are less affected. In contrast, a strong increase of DNA damage is observed in water, where OH-radicals are produced. In consequence, base damage and base release become predominant, even though the number of strand-breaks increases further.
The change of DNA radiation damage upon hydration: In-situ observations by near-ambient-pressure XPS
(2023)
Ionizing radiation damage to DNA plays a fundamental role in cancer therapy. X-ray photoelectron-spectroscopy (XPS) allows simultaneous irradiation and damage monitoring. Although water radiolysis is essential for radiation damage, all previous XPS studies were performed in vacuum. Here we present near-ambient-pressure XPS experiments to directly measure DNA damage under water atmosphere. They permit in-situ monitoring of the effects of radicals on fully hydrated double-stranded DNA. The results allow us to distinguish direct damage, by photons and secondary low-energy electrons (LEE), from damage by hydroxyl radicals or hydration induced modifications of damage pathways. The exposure of dry DNA to x-rays leads to strand-breaks at the sugar-phosphate backbone, while deoxyribose and nucleobases are less affected. In contrast, a strong increase of DNA damage is observed in water, where OH-radicals are produced. In consequence, base damage and base release become predominant, even though the number of strand-breaks increases further.
Small-angle X-ray scattering (SAXS) can be used for structural de- termination of biological macromolecules and polymers in their na- tive states. To improve the reliability of such experiments, the re- duction of radiation damage occurring from exposure to X-rays is needed.One method, is the use of scavenger molecules that protect macromolecules against radicals produced by radiation exposure.In this study we investigate the feasibility to apply the compatible solute, osmolyte and radiation protector Ectoine (THP(B)) as a scavenger throughout SAXS measurements of single-stranded DNA-binding protein Gene-V Protein (G5P/GVP). Therefore we monitor the radiation induced changes of G5P during bio-SAXS. The resulting microscopic energy-damage relation was determined by particle scattering simu- lations with TOPAS/Geant4. The results are interpreted in terms of radical scavenging as well as post-irradiation effects, related to preferential-exclusion from the protein surface. Thus, Ectoine provides an non-disturbing way to improve structure-determination of proteins via bio-SAXS in future studies.
Showcasing research from the Federal Institute for Material Research and Testing Berlin and Fraunhofer Institute for Celltherapy and Immunology Branch Bioanalytics and Bioprocesses Potsdam.
Bio-SAXS of single-stranded DNA-binding proteins: Radiation protection by the compatible solute ectoine.
We aimed to increase the possible undisturbed exposure time during bio-SAXS measurements of single-stranded DNA-binding proteins. Therefore small angle X-ray scattering was performed on Gene-V Protein (G5P/GVP), which is involved in DNA repair processes. To achieve this, irradiations were performed in presence and absence of the hydroxyl-radical scavenger and osmolyte Ectoine, which showed efficient radiation protection and prevented protein aggregation, thus allows for a non-disturbing way to improve structure-determination of biomolecules.
Radiation biophysics
(2023)
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.
Models for TOPAS/Geant4 to estimate the microscopic dose received by biomolecules during bioSAXS experiments.
The C++ classes in this repository extend the functionality of the TOPAS (http://www.topasmc.org/) Monte-Carlo program, which is itself a wrapper of the Geant4 MCS Toolkit (http://geant4.org).
X-ray photoelectron-spectroscopy (XPS) allows simultaneous irradiation and damage monitoring. Although water radiolysis is essential for radiation damage, all previous XPS studies were performed in vacuum. Here we present near-ambient-pressure XPS experiments to directly measure DNA damage under water atmosphere. They permit in-situ monitoring of the effects of radicals on fully hydrated double-stranded DNA. Our results allow us to distinguish direct damage, by photons and secondary low-energy electrons (LEE), from damage by hydroxyl radicals or hydration induced modifications of damage pathways. The exposure of dry DNA to x-rays leads to strand-breaks at the sugar-phosphate backbone, while deoxyribose and nucleobases are less affected. In contrast, a strong increase of DNA damage is observed in water, where OH-radicals are produced. In consequence, base damage and base release become predominant, even though the number of strand-breaks increases further. Furthermore, first data about the degradation of single-stranded DNA binding-proteins (G5P / GV5 and hmtSSB) under vacuum and NAP-XPS conditions are presented.
We give an overview about recent work concerning ionizing radiation damage to Oligonucleotides, plasmid DNA, DNA binding proteins (G5P), and DNA-protein complexes.
We focus on combining new experimental setups with Geant4/TOPAS particle scattering simulations to understand the effets of ionizing radiation.
In the last years, secondary low-energy electrons (LEE) emerged as important, if not predominant, reductive pathway in ionizing damage of biomolecules. These electrons are created in copious amount as result of inelastic scattering of high energy radiation at water. Until now, all experiments the quantification of the effects of LEEs on the biomolecular damage was either performed in vacuum with LEE sources or with DNA on surfaces in humid atmosphere.
We present a new experimental setup to irradiate biomolecules with electrons under physiological conditions. In combination with monte carlo simulations this setup makes it possible to determine microdosimetric quantities for biomolecules in liquid environment under electron irradiation.
This opens up new possibilities in radiation research to access the LEE damage under well defined physiological condition, for more complex systems, such as DNA-Protein complexes and even living cells.
Dose enhancement by gold nanoparticles (AuNP) was shown to increase the biological effectiveness of radiation damage in biomolecules and tissue. Most of the current studies focus on external beam therapy on combination with AuNP. Here we present a Monte-Carlo study (Geant4) to characterise radioactive AuNP. Radioactive ¹⁹⁸Au emits beta and gamma rays and is considered for applications with solid tumours. To effectively apply ¹⁹⁸AuNP their energy deposit characteristics have to be determined in terms of intrinsic and extrinsic properties e.g. AuNP diameter, AuNP density, and their clustering behaviour. After each decay process, the energy deposit, inelastic scattering events, kinetic energy spectrum of secondary particles within the AuNP themselves and in a spherical target volume of water up to 1 μm radius were determined. Simulations were performed for AuNP radii ranging from 2.5 nm to 20 nm radius, different cluster sizes and densities. The results show an increase of the energy deposit in the vicinity of the AuNP up to 150 nm. This effect nearly vanishes for distances up to one micron. For the case of AuNP clusters and the same activity, the enhancement of the energy deposit increases with the relative gold mass percentage and therefore can be adjusted by changing AuNP radius or clustering behaviour.
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.
Dose enhancement by gold nanoparticles (AuNP) was shown to increase the biological effectiveness of radiation damage in biomolecules and tissue. Most of the current studies focus on external beam therapy on combination with AuNP. Here we present a Monte-Carlo study (Geant4) to characterise radioactive AuNP. Radioactive ¹⁹⁸Au emits beta and gamma rays and is considered for applications with solid tumours. To effectively apply ¹⁹⁸AuNP their energy deposit characteristics have to be determined in terms of intrinsic and extrinsic properties e.g. AuNP diameter, AuNP density, and their clustering behaviour. After each decay process, the energy deposit, inelastic scattering events, kinetic energy spectrum of secondary particles within the AuNP themselves and in a spherical target volume of water up to 1 μm radius were determined. Simulations were performed for AuNP radii ranging from 2.5 nm to 20 nm radius, different cluster sizes and densities. The results show an increase of the energy deposit in the vicinity of the AuNP up to 150 nm. This effect nearly vanishes for distances up to one micron. For the case of AuNP clusters and the same activity, the enhancement of the energy deposit increases with the relative gold mass percentage and therefore can be adjusted by changing AuNP radius or clustering behaviour.
To enhance the biological effects of radiation damage in cancerous cells, we present an alternative approach to the use of gold nanoparticles (AuNP), focusing on the synthesis and characterization of highly monodisperse, spherical radioactive gold nanoparticles 198AuNP. The size of the AuNP size was optimized with the help of Geant4/TOPAS particle scattering simulations, and energy deposition per nm3 per decay for varying radii (2–10 nm) was evaluated. This work is the foundation for ongoing experimental work to evaluate cell death induced by 198AuNP which aims for the use of radioactive gold nanoparticles in cancer treatment.
The damage caused by ionizing radiation to biomolecules, especially DNA, is the reason to treat cancer via radiation therapy. A better understanding of the molecular processes and the quantification of the various damaging mechanisms is the prerequisit to develope 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. Due to the high amount of water in biological tissue, most of the damage is caused by the secondary particles produced by the interaction of the IR with water. Thereby a multitude of species are produced, e.g. kinetic low energy electrons, prehydrated electrons, OH-radicals and ions. The quantification of the contribution to DNA damage of the various species is of interest. Here we present an experimental approach to disentangle their relative DNA strand break yield. Plasmid DNA is irradiated in water with electrons under the presence of different scavengers. With the presented method it will be possible to reveal the relative contributions of OH-radicals, low energy electrons and prehydrated electrons to the DNA single and double strand break yield.
Ionizing radiation damage to DNA plays a fundamental role in cancer therapy. X-ray photoelectron-spectroscopy (XPS) allows simultaneous irradiation and damage monitoring. Although water radiolysis is essential for radiation damage, all previous XPS studies were performed in vacuum. Here we present near-ambient-pressure XPS experiments to directly measure DNA damage under water atmosphere. They permit in-situ monitoring of the effects of radicals on fully hydrated double-stranded DNA. The results allow us to distinguish direct damage, by photons and secondary low-energy electrons (LEE), from damage by hydroxyl radicals or hydration induced modifications of damage pathways. The exposure of dry DNA to x-rays leads to strand-breaks at the sugar-phosphate backbone, while deoxyribose and nucleobases are less affected. In contrast, a strong increase of DNA damage is observed in water, where OH-radicals are produced. In consequence, base damage and base release become predominant, even though the number of strand-breaks increases further.
Ionizing radiation damage to DNA plays a fundamental role in cancer therapy. X-ray photoelectron-spectroscopy (XPS) allows simultaneous irradiation and damage monitoring. Although water radiolysis is essential for radiation damage, all previous XPS studies were performed in vacuum. Here we present near-ambient-pressure XPS experiments to directly measure DNA damage under water atmosphere. They permit in-situ monitoring of the effects of radicals on fully hydrated double-stranded DNA. The results allow us to distinguish direct damage, by photons and secondary low-energy electrons (LEE), from damage by hydroxyl radicals or hydration induced modifications of damage pathways. The exposure of dry DNA to x-rays leads to strand-breaks at the sugar-phosphate backbone, while deoxyribose and nucleobases are less affected. In contrast, a strong increase of DNA damage is observed in water, where OH-radicals are produced. In consequence, base damage and base release become predominant, even though the number of strand-breaks increases further.