Radiosensitization Effect Of Gold Nanoparticles Research Articles

Geant4 track structure simulation of electron beam interaction with a gold nanoparticle

Application of nanoparticles as radiosensitizer in various radiation therapy modalities have recently attracted considerable interest. Although experimental findings have shown radiosensitization effect of gold nanoparticles (GNPs) when combining with electron irradiations, observing the recent literature reveals the lack of a standard analysis regarding the modification effects caused by the presence of GNP on physical energy deposition pattern in electron fields. The aim of the current study is to evaluate and verify radioenhancement effects of GNPs under electron beams. Monte Carlo track structure simulation that is the generally accepted approach for investigation of radiation effects in the nanometer scale was conducted by the use of Geant4-DNA code to track electrons down to the 7.4 eV energy. Macroscopic megavoltage energy electron spectrum from an intraoperative electron radiation source was used to irradiate a water phantom while particles were tracked to score the microscopic (nanometer) beam spectrum. Then, a single 50 nm gold nanoparticle was irradiated with the nanobeam where secondary electrons and energy deposition were scored. The results reveal a non-negligible dose escalation of up to 12% at close vicinities of the nanoparticle gradually decreasing at further distances that is caused by low energy electrons originated in the NP. Although, the amount of calculated dose enhancement show dependence on the parameters of the microscopic simulation, the current result provides a theoretical evidence in support of the physical dose enhancement in GNP aided electron radiotherapy.

Radiosensitization Effect of Gold Nanoparticles on Plasmid DNA Damage Induced by Therapeutic MV X-rays.

Gold nanoparticles (AuNPs) can be used with megavolt (MV) X-rays to exert radiosensitization effects, as demonstrated in cell survival assays and mouse experiments. However, the detailed mechanisms are not clear; besides physical dose enhancement, several chemical and biological processes have been proposed. Reducing the AuNP concentration while achieving sufficient enhancement is necessary for the clinical application of AuNPs. Here, we used positively charged (+) AuNPs to determine the radiosensitization effects of AuNPs combined with MV X-rays on DNA damage in vitro. We examined the effect of low concentrations of AuNPs on DNA damage and reactive oxygen species (ROS) generation. DNA damage was promoted by 1.4 nm +AuNP with dose enhancement factors of 1.4 ± 0.2 for single-strand breaks and 1.2 ± 0.1 for double-strand breaks. +AuNPs combined with MV X-rays induced radiosensitization at the DNA level, indicating that the effects were physical and/or chemical. Although −AuNPs induced similar ROS levels, they did not cause considerable DNA damage. Thus, dose enhancement by low concentrations of +AuNPs may have occurred with the increase in the local +AuNP concentration around DNA or via DNA binding. +AuNPs showed stronger radiosensitization effects than −AuNPs. Combining +AuNPs with MV X-rays in radiation therapy may improve clinical outcomes.

Radiosensitization Effect of Gold Nanoparticles in Proton Therapy

The number of proton therapy facilities and the clinical usage of high energy proton beams for cancer treatment has substantially increased over the last decade. This is mainly due to the superior dose distribution of proton beams resulting in a reduction of side effects and a lower integral dose compared to conventional X-ray radiotherapy. More recently, the usage of metallic nanoparticles as radiosensitizers to enhance radiotherapy is receiving growing attention. While this strategy was originally intended for X-ray radiotherapy, there is currently a small number of experimental studies indicating promising results for proton therapy. However, most of these studies used low proton energies, which are less applicable to clinical practice; and very small gold nanoparticles (AuNPs). Therefore, this proof of principle study evaluates the radiosensitization effect of larger AuNPs in combination with a 200 MeV proton beam. CHO-K1 cells were exposed to a concentration of 10 μg/ml of 50 nm AuNPs for 4 hours before irradiation with a clinical proton beam at NRF iThemba LABS. AuNP internalization was confirmed by inductively coupled mass spectrometry and transmission electron microscopy, showing a random distribution of AuNPs throughout the cytoplasm of the cells and even some close localization to the nuclear membrane. The combined exposure to AuNPs and protons resulted in an increase in cell killing, which was 27.1% at 2 Gy and 43.8% at 6 Gy, compared to proton irradiation alone, illustrating the radiosensitizing potential of AuNPs. Additionally, cells were irradiated at different positions along the proton depth-dose curve to investigate the LET-dependence of AuNP radiosensitization. An increase in cytogenetic damage was observed at all depths for the combined treatment compared to protons alone, but no incremental increase with LET could be determined. In conclusion, this study confirms the potential of 50 nm AuNPs to increase the therapeutic efficacy of proton therapy.

Dosimetric evaluation of gold nanoparticle aided intraoperative radiotherapy with the Intrabeam system using Monte Carlo simulations

Radiosensitization using high atomic number nanoparticles (NPs) has been shown to be an effective method to enhance radiotherapy efficiency. The pathways by which NPs cause sensitization, are generally categorized as physical, chemical and biological effects. Specifically in the case of keV photon radiotherapy where the contribution of physical effects in radiosensitization mechanism is considerable, Monte Carlo (MC) simulations have been an efficient tool to predict the radioenhancement level and to calculate dose enhancement factor (DEF). To-date, several analytical, simulational and experimental studies have reported the radiosensitization effect of gold nanoparticles (GNPs) in various brachytherapy situations. In this work we report for the first time, the DEFs achievable in intraoperative radiotherapy through use of the Intrabeam system and its spherical applicators with addition of GNPs. The MCNPX Monte Carlo code was used for radiation transport and dose calculations. The results of macroscopic and microscopic analysis show that for the Intrabeam system and a homogeneous distribution of 50 nm diameter GNPs, respective DEFs of up to some 1.5, 2, 2.5 and 3 in the tumour bed can be achieved with 5, 10, 15 and 20 mg/g concentrations. Due to rapid change in electron spectra, DEFs greater than 1 mm separation from the applicator surface decrease with distance, offering an additional advantage.

A Monte Carlo study on the radio-sensitization effect of gold nanoparticles in brachytherapy of prostate by 103Pd seeds

Abstract 103Pd seed is being used for prostate brachytherapy. Additionally, the dose enhancement effect of gold nanoparticles (GNP) has been reported in previous studies. The aim of this study was to characterize the dosimetric effect of gold nanoparticles in brachytherapy with a 103Pd source. Two brachytherapy seeds including 103 Pd source was simulated using MCNPX Monte Carlo code. The seeds’ models were validated by comparing the MC with reported results. Then, GNPs (10 nm in diameter) with a concentration of 7mg Au/g were simulated uniformly inside the prostate of a humanoid computational phantom. Additionally, the dose enhancement factor (DEF) of nanoparticles was calculated for both modeled brachytherapy seeds. A good agreement was found between the MC calculated and the reported dosimetric parameters. For both seeds, an average DEF of 23% was obtained in tumor volume for prostate brachytherapy. The application of GNPs in conjunction with 103Pd seed in brachytherapy can enhance the delivered dose to the tumor and consequently leads to better treatment outcome.

The contribution of hydrogen peroxide to the radiosensitizing effect of gold nanoparticles.

Plasmid DNA in aerated aqueous solution is used as a probe to determine whose of the reactive oxygen species (ROS) generated after absorption of ultra-soft X-rays (USX) take part in biomolecule damage in the presence and in absence of Gold Nano-Particles (GNP) and specific scavengers. Citrate-coated GNPs with core sizes of 6, 10 and 25 nm are synthetized and characterized, especially in terms of plasmon band shift, ζ-potential and hydrodynamic radii (respectively 9, 21 and 30 nm). We confirm the radiosensitizing effect of GNP and show that the SSB number per plasmid increases when, for a same mass of gold element, the core size of the gold nanoparticles decreases. Hydroxyl radicals (OH) are scavenged using the positively-charged 2-amino-2-hydroxymethyl-1,3-propanediol (TRIS) and the neutral dimethyl sulfoxide (DMSO) molecules. Due to both negatively-charged environments of DNA and GNP, at identical scavenging capacity, TRIS is more effective at quenching OH than DMSO. The strong radiosensitizing effect of hydroxyl radicals is confirmed. Methanoate anions are then used to transform OH into hydrogen peroxide; the latter being known to be non-aggressive regarding DNA in the absence of easily oxidable metallic ions (Fenton reactions). Surprisingly, in the presence of GNP, high DNA damage yields are observed even though hydrogen peroxide might not be hold as responsible. Conversely, the radiosensitizing effect of GNP is not observed anymore when H2O2 is scavenged using pyruvate ions. We demonstrate that hydrogen peroxide constitutes quite unexpectedly a hidden stock of OH which are activated at the surface of the GNP by decomposition of H2O2 molecules.

The effect of gold nanoparticles on dose enhancement factor of human intestinal colon cancer HT-29 cells

Introduction: Radiation therapy is an important procedure for treatment of more than half of tumors. One way to increase the efficiency of radiation therapy is application of radiosensitizer at the site of tumor. gold nanoparticles (GNPs) have several characteristics that make them attractive for using with radiation therapy including small size (1–100 nm), biocompatibility, preferentially passive accumulation in tumor and the feasibility to surface modification to actively target cancerous cells. The aim of this paper was investigating the radiosensitizing effect of GNPs in human intestinal colon cancer HT-29 cells as a less radiosensitive tumor cell. Materials and Methods: Radiosensitizing effects of GNPs were comparatively evaluated in vitro for intestinal colon cancer (HT-29) cell line by colony formation assay at 6 MV photon energy. Cells were treated with only ionizing irradiation (IR) as control group or combination of GNPs and ionizing irradiation (GNPs+IR). GNPs had average size of 15 nm and were used at concentration of 0.1 mM. Results: The survival curve was obtained using MATLAB software and dose enhancement factor (DEF) was calculated by dividing of LD50 (50% lethal dose) of IR group with combination treatment group (GNPs+IR). GNPs could enhance treatment response by factor of 1.47(DEF=1.47). Conclusion: Our results showed that GNPs can sensitize HT-29 tumor cells and thus can be used to enhance the radiation therapy efficiency.

Radiosensitization of breast cancer cells using AS1411 aptamer-conjugated gold nanoparticles

Introduction: A main choice for cancer treatment is radiotherapy. But, the radiotherapy disadvantage is damages caused by radiation given to normal tissues/organs surrounding cancer. One way to avoid this is via increasing radiosensitization of cancer cells. Gold nanoparticles (GNPs) have shown sensitizing effect on cancer cells by enhancing their absorbed dose. Unlike earlier delivery techniques developed for nanotherapeutics, active targeting can achieve specific effect and higher uptake of GNPs in tumors while leave healthy cells untouched and consequently improve the therapeutic index. To achieve active targeting, GNPs should be equipped with functional ligands which can recognize and adhere to the receptors of cancer cells. Aptamers are small DNA-molecule/RNA-fragments with high specificity and affinity towards target molecules. AS1411 aptamer can specifically bind to over-expressed nucleolin on the membrane of tumor cells including breast cancer. This aptamer is capable to enter cancer cells through specific ligand–receptor interaction. Greater uptake of GNPs by cells may induce increased radiation effects. Cancer stem cells are a small population of cells within a tumor capable for self-renewal and differentiation into various cell types. Materials and Methods: We hypothesized that conjugation of GNPs with AS1411 (AS1411/GNPs) could increase GNPs-mediated radiosensitization in breast cancer cells. We hypothesized that AS1411/GNPs would radiosensitize breast cancer stem/progenitor cells grown to three- dimensional (3D) mammospheres. Cytotoxicity studies of the GNPs and AS1411/GNPs were done on two different cancer cell lines of MCF-7 and MDA-MB-231 with MTT assay. Atomic absorption spectroscopy (AAS) confirmed the cellular uptake of particles. Radiosensitizing effect of GNPs and AS1411/GNPs on MDA-MB 231 and MCF- 7 cells assessed by clonogenic assay. Results: Clonogenic survival data revealed that AS1411/GNPs at 12.5 mg/L results in radiosensitization of breast cancer cells. Mammosphere of MCF-7 was more resistant than their monolayer counterparts. Conclusion: The combination of the sensitizing GNPs with the AS14411 aptamer can be regarded for improved treatment of breast cancer cells especially for the mammosphere MCF-7 cancer cells mimicking cancerous tumors.

The role of thioredoxin reductase in gold nanoparticle radiosensitization effects.

To identify new mechanisms responsible for the radiosensitization effect of gold nanoparticles (GNPs). A549 lung carcinoma cells were incubated with 10-nm GNPs during 6 or 24h before to be exposed to 25keV/μm protons or 225kV x-rays. GNP incubation led to a time-dependent mitochondria membrane depolarization, oxidative stress and to x-ray and proton radiosensitization. Moreover, a marked inhibition of thioredoxin reductase was observed. Irradiation of cells invalidated for thioredoxin reductase evidenced a radiosensitization effect, suggesting that this enzyme is a potential GNP target. We suggest that GNPs play a radiosensitizer role by weakening detoxification systems. Altogether, these results open up promising novel strategies for the development of nanotechnologies associated to radiotherapy.

Abstract 3710: Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer

Abstract Introduction: More than 50% of cancer patients receive radiation therapy at some point during their care. Gold nanoparticles (GNPs) can amplify the radiation dose by facilitating the ejection of low-energy photoelectrons, resulting in increased DNA damage. One of the main challenges of radiation therapy in cancer is to sustain this damage for longer durations. DNA single-strand breaks (SSBs) are repaired by base excision repair, which utilizes Poly(ADP-ribose) polymerase (PARP). PARP inhibition during radiotherapy provides an attractive alternative in maximizing treatment outcomes. Here, we explore a strategy to combine the radiosensitizing effect of GNPs with the DNA-repair inhibiting ability of NanoTalazoparib (nTLZ), a liposomal formulation of the PARP inhibitor, talazoparib (TLZ). Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments. Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way. Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer. This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital. Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.

Enhancing the effect of 4 MeV electron beam using gold nanoparticles in breast cancer cells

Gold nanoparticles (GNPs) have been applied as radiosensitizer in radiotherapy. Limited reports have shown that GNPs may be effective as a dose enhancer agent for electron radiation therapy. Some Monte Carlo Simulation studies have shown that selecting suitable size of GNPs and electron energies are critical for effective dose enhancement. The aim of this study was to assess possible radiosensitization effect of GNPs on cancer cell treated with 4MeV electron beams. Approximately 10nm GNPs were synthesized and characterized by electron microscope and dynamic light scattering. MCF-7 and MDA-MB-231 breast cancer cells were used and their viability was measured by MTT assay. Radiosensitization effect of GNPs under 4MeV electron beams was measured by clonogenic assay. The result showed a concentration dependent uptake of GNPs without reducing cell viability at concentrations ≤50mg/L. Incubation of cancer cells with GNPs caused a significant decrease in their viability following exposure to electron beams as well as a decrease in their survival fraction when compared to control. The sensitizer enhancement ratio (SER) by electron beams in MCF-7 cells was 1.43 and 1.40 in presence of 25 and 50mg/L GNPs, respectively. For MDA-MB-231 cells, it was 1.62 in presence of 25mg/L GNPs. Our data demonstrated the significant dose enhancement of the GNPs in combination with 4MeV electron beams that could be applicable for the treatment of superficial tumors and intra operative radiation therapy.

Therapeutic Applications of Microbubbles with Nanoparticle Encapsulation

E-mail: [email protected] New developments in imaging physics have found promising biomedical applications. One example is the combination of ultrasound and photoacoustics that has demonstrated new opportunities in both imaging and therapeutic applications with functionalized microbubbles playing a pivotal role. The microbubbles typically used in ultrasonic imaging as the contrast agent present unique mechanical properties and the associated acoustic cavitation has been exploited for therapeutic purposes. Similarly, gold nanoparticles (AuNPs) are found to be a good contrast agent for photoacoustic imaging for its bioconjugation capabilities. The efficient light absorption of AuNPs and abilities to tune their optical properties have also led to new photothermal therapy methods. New development in combined diagnosis with therapy for both modalities have also been introduced. AuNPs encapsulated with microbubbles (AuMBs) have been introduced as a photoacoustic and ultrasound dual-modality contrast agent. Applications can be extended to theranosis purpose. In a previous study, an enhanced delivery method of AuNPs is proposed by using microbubbles as a targeted carrier and by inducing acoustic cavitation to enhance permeability. At least 10 times improvement in AuNP delivery and twenty degrees of temperature elevation were achieved. An optical microscope which collects the two photon fluorescence emitted by AuNPs further confirms the enhanced delivery. Finally, in vivo delivery of AuNPs was demonstrated with laser-induced thermotherapy that showed hyperthermia (>45°C) with sonoporation. Therefore, controlled release of AuNPs is feasible with acoustic cavitation and the procedure can further improve therapeutic effects of the AuNPs. Such functionalized microbubbles can also be used by exploiting the radiosensitization effect of gold nanoparticles (AuNPs) to enhance the cell-killing of ionization on tumor cells. In our research, we utilized AuMBs together with ultrasound as a radiosensitizer. Pre-radiotherapy cavitation carried out by acoustic stimulation increased the permeability of cell membrane and intracellular uptake of AuNPs. Simultaneous measurement of cavitation during ultrasound treatment also confirmed the production of cavitation. After combined treatment of AuMBs and ultrasound, Huh7 cells, a notoriously radioresistant cancer cells, was exposed to various dose of irradiation by a 6-MV linear accelerator. Cologenic assay showed a significant radiosensitization with AuMB+US, especially with high-dose irradiation (10 Gy). A dose modifying factor at 60% survival fraction (DMF60%) of 0.74 was obtained with AuMB and ultrasound treatment.

Recent advances of gold nanoparticles for cancer radiotherapy

Based on a review of currently published 40 papers (20 published in recent 5 years, 20 published in recent 10 years) on gold nanoparticles for cancer radiotherapy, the general characteristics, theoretical studies, in vitro experiment, in vivo experiment, and the clinical prospects of targeted radiotherapy with gold nanoparticles were reviewed. Three key aspects guarantee further investigation for the full understanding of the radiosensitization effect of gold nanoparticles: the cellular localization and tissue distribution of nanoparticles and influential factors; the micro dose enhancement effect of gold nanoparticles, and the molecular biological mechanism. More cross disciplinary collaboration, research, development and translation are needed before gold nanoparticles are put into clinical trials. Key words: Malignancy neoplasms/radiotherapy; Gold nanoparticles

Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays

Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x-ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP’s application in clinical treatment.

SU-E-T-518: Investigation of Gold Nanoparticle Radiosensitization for Carbon Ion Therapy

Purpose The aim of this work is to investigate the radiosensitization effect of gold nanoparticles (GNP) in carbon ion irradiation. Nano-scale dosimetric characteristics of GNP interaction with carbon ions as well as the secondary particles generated as a carbon beam traverses the water phantom were studied. Methods Monte Carlo simulations were carried out using TOPAS (Tool for Particle Simulation). First, a water phantom was irradiated by the carbon ion beam and the particle shower spectrum at several depths was recorded in phase spaces. We analyzed the number and energy spectrum of each particle type. Then, the phase spaces obtained from Step 1 were modified to nanometer scale to irradiate a single 50 nm GNP. The secondary electrons that escaped from the GNPs following interactions with each particle type were recorded as phase spaces. The number and energy spectrum of the secondary electrons were studied. The same simulations were repeated replacing the GNPs with water nanoparticles (WNPs) with the same size. The energy absorbed in either GNP or WNP was scored. Results There is a large amount of secondary particles generated through carbon ion beam interaction with the water phantom. Analysis of the secondary electrons generated by the primary particles which escape from the nanoparticle revealed that majority (above 80%) of these electrons were generated by the GNP interaction with Carbon beam itself, making it the biggest contributor to the enhancement. The ratio of the energy absorbed by GNP and WNP is about 8–10 for charged particles and above 3000 for gammas. Conclusion We showed in the study the GNPs may potentially be used to enhance carbon ion therapy, and the main mechanism of enhancement is the interaction with Carbon ion particles itself.

Biological modeling of gold nanoparticle enhanced radiotherapy for proton therapy

Gold nanoparticles (GNPs) have shown potential as a radiosensitizer for radiation therapy using photon beams. Recently, experimental studies have been carried out using proton beams showing the GNP enhanced responses in proton therapy. In this work, we established a biological model to investigate the change in survival of irradiated cells due to the radiosensitizing effect of gold nanoparticles. Results for proton, megavoltage (MV) photon and kilovoltage (kV) photon beams are compared. For each particle source, we assessed various treatment depths, GNP cellular uptakes and sizes. We showed that kilovoltage photons caused the highest enhancement due to the high interaction probability between GNPs and kV photons. The cell survival fraction can be significantly reduced for both proton and MV photon irradiations if GNPs accumulate in the cell. For instance, the sensitizer enhancement ratio (SER) is 1.33 for protons in the middle of a spread out Bragg peak for 1 µM of internalized 50 nm GNPs. If the GNPs can all be internalized into the cell nucleus, the SER for proton therapy increases from 1.33 to 1.81. The results also show that for the same mass of GNPs in the cells, one can expect the greatest sensitization by smaller GNPs, i.e. a SER of 1.33 for 1 µM of internalized 50 nm GNPs and a SER of 3.98 for the same mass of 2 nm GNPs. We concluded that if the GNPs cannot be internalized into the cytoplasm, no GNP enhancement will be observed for proton treatment. Meanwhile, proton radiotherapy can potentially be enhanced with GNPs if they can be internalized into cells, and especially the cell nucleus.

Hypoxia and cellular localization influence the radiosensitizing effect of gold nanoparticles (AuNPs) in breast cancer cells.

Hypoxia exists in all solid tumors and leads to clinical radioresistance and adverse prognosis. We hypothesized that hypoxia and cellular localization of gold nanoparticles (AuNPs) could be modifiers of AuNP-mediated radiosensitization. The possible mechanistic effect of AuNPs on cell cycle distribution and DNA double-strand break (DSB) repair postirradiation were also studied. Clonogenic survival data revealed that internalized and extracellular AuNPs at 0.5 mg/mL resulted in dose enhancement factors of 1.39 ± 0.07 and 1.09 ± 0.01, respectively. Radiosensitization by AuNPs was greatest in cells under oxia, followed by chronic and then acute hypoxia. The presence of AuNPs inhibited postirradiation DNA DSB repair, but did not lead to cell cycle synchronization. The relative radiosensitivity of chronic hypoxic cells is attributed to defective DSB repair (homologous recombination) due to decreased (RAD51)-associated protein expression. Our results support the need for further study of AuNPs for clinical development in cancer therapy since their efficacy is not limited in chronic hypoxic cells.

WE-G-BRE-02: Biological Modeling of Gold Nanoparticle Radiosensitization for Proton Therapy

Purpose: The aim of this work is to investigate the radiosensitization effect of gold nanoparticles (GNP) in a proton beam. A computational model was built using the Local Effect Model (LEM) to predict the biological outcome of gold nanoparticle (GNP) sensitization. We present the results using a clinical proton beam, 6MV photon beam and two kilovoltage photon beams. Methods: First, Monte Carlo simulations were carried out using TOPAS (TOol for PArticle Simulation) to obtain the spatial dose distribution in the vicinity of GNPs. The dose distribution was then used as an input for LEM, which predicts dose-response curves for high linear energy transfer radiation using the track structure. The cell survival curves were evaluated for three particle sources (proton beam, MV photon beam and kV photon beam), various treatment depths for each particle source, various GNP uptakes and two different GNP sizes. Results: For proton therapy, the GNP sensitization effect is highly dependent on the treatment depth due to the energy-dependent interaction probability. We predict that if GNPs can be taken up by the cell nucleus, proton therapy can be significantly enhanced. If GNPs are only internalized into the cytoplasm, proton therapy can still be enhanced by GNPs and if GNPs are not internalized into cells, there will be no direct damage to the nucleus. For the same GNP uptake and concentration, the cell survival at 2Gy is reduced by 80% using kilovoltage photons, 50% using protons and only 2% using clinical MV photons. Finally, for the same weight of GNPs taken up by the cells, 10 nm GNPs causes 3 times more damage than 50 nm GNPs. Conclusion: We showed that GNPs have potential to be used to enhance radiation therapy for clinical proton beams.

Optimal energy for cell radiosensitivity enhancement by gold nanoparticles using synchrotron-based monoenergetic photon beams.

Gold nanoparticles have been shown to enhance radiation doses delivered to biological targets due to the high absorption coefficient of gold atoms, stemming from their high atomic number (Z) and physical density. These properties significantly increase the likelihood of photoelectric effects and Compton scattering interactions. Gold nanoparticles are a novel radiosensitizing agent that can potentially be used to increase the effectiveness of current radiation therapy techniques and improve the diagnosis and treatment of cancer. However, the optimum radiosensitization effect of gold nanoparticles is strongly dependent on photon energy, which theoretically is predicted to occur in the kilovoltage range of energy. In this research, synchrotron-generated monoenergetic X-rays in the 30–100 keV range were used to investigate the energy dependence of radiosensitization by gold nanoparticles and also to determine the photon energy that produces optimum effects. This investigation was conducted using cells in culture to measure dose enhancement. Bovine aortic endothelial cells with and without gold nanoparticles were irradiated with X-rays at energies of 30, 40, 50, 60, 70, 81, and 100 keV. Trypan blue exclusion assays were performed after irradiation to determine cell viability. Cell radiosensitivity enhancement was indicated by the dose enhancement factor which was found to be maximum at 40 keV with a value of 3.47. The dose enhancement factor obtained at other energy levels followed the same direction as the theoretical calculations based on the ratio of the mass energy absorption coefficients of gold and water. This experimental evidence shows that the radiosensitization effect of gold nanoparticles varies with photon energy as predicted from theoretical calculations. However, prediction based on theoretical assumptions is sometimes difficult due to the complexity of biological systems, so further study at the cellular level is required to fully characterize the effects of gold nanoparticles with ionizing radiation.

The In Vivo Radiosensitizing Effect of Gold Nanoparticles Based MRI Contrast Agents.

Owing to the high atomic number (Z) of gold element, the gold nanoparticles appear as very promising radiosensitizing agents. This character can be exploited for improving the selectivity of radiotherapy. However, such an improvement is possible only if irradiation is performed when the gold content is high in the tumor and low in the surrounding healthy tissue. As a result, the beneficial action of irradiation (the eradication of the tumor) should occur while the deleterious side effects of radiotherapy should be limited by sparing the healthy tissue. The location of the radiosensitizers is therefore required to initiate the radiotherapy. Designing gold nanoparticles for monitoring their distribution by magnetic resonance imaging (MRI) is an asset due to the high resolution of MRI which permits the accurate location of particles and therefore the determination of the optimal time for the irradiation. We recently demonstrated that ultrasmall gold nanoparticles coated by gadolinium chelates (Au@DTDTPA-Gd) can be followed up by MRI after intravenous injection. Herein, Au@DTDTPA and Au@DTDTPA-Gd were prepared in order to evaluate their potential for radiosensitization. Comet assays and in vivo experiments suggest that these particles appear well suited for improving the selectivity of the radiotherapy. The dose which is used for inducing similar levels of DNA alteration is divided by two when cells are incubated with the gold nanoparticles prior to the irradiation. Moreover, the increase in the lifespan of tumor bearing rats is more important when the irradiation is performed after the injection of the gold nanoparticles. In the case of treatment of rats with a brain tumor (9L gliosarcoma, a radio-resistant tumor in a radiosensitive organ), the delay between the intravenous injection and the irradiation was determined by MRI.