Local Dose Enhancement Research Articles

Dosimetric consequences of gold nanoparticle clustering during photon irradiation.

The radiation dose enhancement caused by introducing gold nanoparticles (GNP) into cells can increase the dose locally absorbed. A disconnect between experimentally determined survival and dose enhancements predicted by Monte Carlo simulations on macroscopic scales, suggests small-scale energy deposition patterns play an important role in GNP dose enhancement. Clustering of the GNPs could potentially alter small-scale energy deposition patterns. Here we use Monte Carlo simulations to quantify energy deposition patterns in the presence of clustered GNPs and address the question of whether clustering of the nanoparticles affects the energy deposition patterns and ultimately cellular response. Using the PENELOPE Monte Carlo code, we examine the absorption of energy in the environment of a single irradiated GNP following its interaction with a set of primary monoenergetic photon beams. We introduce successive GNPs to form a cluster about the particle in which the primary photon interactions occur and report on the energy deposited locally (within a 500 nm radius) and nonlocally (beyond 500 nm) in the surrounding water-equivalent medium as a function of the number of additional GNPs and the packing geometry they assume. When additional GNPs cluster in tightly packed formations about a GNP in which an incident photon interacts, both the energy deposited locally and released nonlocally are reduced relative to the case where other GNPs are not present. The degree of the reduction depends on incident photon energy, the number of GNPs added to the cluster, and the packing geometry. With 90 additional GNPs in a hexagonal close packing (HCP) cluster about a directly irradiated test particle, the local energy deposition was reduced to 29% (of the value in the absence of neighbors) in the most extreme monoenergetic case. Energy released into the nonlocal volume was most affected by the cluster for low-incident photon energies (< 40 keV), where reductions to 26% of the value in the absence of a cluster were shown. The packing geometry mitigated these results. When the irradiated GNP was on the periphery of the HCP cluster, or when the cluster was confined to a plane, the observed effects were weaker and when an equal number of GNPs were uniformly distributed in the local volume, the changes were trivial (less than 2%). The findings provide grounds for reconciling the observations of cell survival with Monte Carlo predictions of GNP dose enhancement. This work is significant because it demonstrates that GNP clustering needs to be understood and accounted to optimize local dose enhancement.

Technical Note: A simulation study on the feasibility of radiotherapy dose enhancement with calcium tungstate and hafnium oxide nano- and microparticles.

To assess the radiotherapy dose enhancement (RDE) potential of calcium tungstate (CaWO4 ) and hafnium oxide (HfO2 ) nano- and microparticles (NPs). A Monte Carlo simulation study was conducted to gauge their respective RDE potentials relative to that of the broadly studied gold (Au) NP. The study was warranted due to the promising clinical and preclinical studies involving both CaWO4 and HfO2 NPs as RDE agents in the treatment of various types of cancers. The study provides a baseline RDE to which future experimental RDE trends can be compared to. All three materials were investigated in silico with the software Penetration and Energy Loss of Positrons and Electrons (PENELOPE 2014) developed by Francesc Salvat and distributed in the United States by the Radiation Safety Information Computational Center (RSICC) at Oak Ridge National Laboratory. The work utilizes the extensively studied Au NP as the "gold standard" for a baseline. The key metric used in the evaluation of the materials was the local dose enhancement factor (DEFloc ). An additional metric used, termed the relative enhancement ratio (RER), evaluates material performance at the same mass concentrations. The results of the study indicate that Au has the strongest RDE potential using the DEFloc metric. HfO2 and CaWO4 both underperformed relative to Au with lower DEFloc of 2-3 × and 4-100 ×, respectively. The computational investigation predicts the RDE performance ranking to be: Au > HfO2 > CaWO4 .

Local dose enhancement of proton therapy by ceramic oxide nanoparticles investigated with Geant4 simulations

Nanoparticles (NPs) have been shown to enhance X-ray radiotherapy and proton therapy of cancer. The effectiveness of radiation damage is enhanced in the presence of high atomic number (high-Z) NPs due to increased production of low energy, higher linear energy transfer (LET) secondary electrons when NPs are selectively internalized by tumour cells. This work quantifies the local dose enhancement produced by the high-Z ceramic oxide NPs Ta2O5 and CeO2, in the target tumour, for the first time in proton therapy, by means of Geant4 simulations. The dose enhancement produced by the ceramic oxides is compared against gold NPs. The energy deposition on a nanoscale around a single nanoparticle of 100nm diameter is investigated using the Geant4-DNA extension to model particle interactions in the water medium. Enhancement of energy deposition in nano-sized shells of water, local to the NP boundary, ranging between 14% and 27% was observed for proton energies of 5MeV and 50MeV, depending on the NP material. Enhancement of electron production and energy deposition can be correlated to the direct DNA damage mechanism if the NP is in close proximity to the nucleus.

A study on a dental device for the prevention of mucosal dose enhancement caused by backscatter radiation from dental alloy during external beam radiotherapy.

The changes in dose distribution caused by backscatter radiation from a common commercial dental alloy (Au–Ag–Pd dental alloy; DA) were investigated to identify the optimal material and thicknesses of a dental device (DD) for effective prevention of mucositis. To this end, 1 cm3 of DA was irradiated with a 6-MV X-ray beam (100 MU) in a field size of 10 × 10 cm2 using a Novalis TX linear accelerator. Ethylene vinyl acetate copolymer, polyolefin elastomer, and polyethylene terephthalate (PET) were selected as DD materials. The depth dose along the central axis was determined with respect to the presence/absence of DA and DDs at thicknesses of 1–10 mm using a parallel-plate ionization chamber. The dose in the absence of DDs showed the lowest value at a distance of 5 mm from the DA surface and gradually increased with distance between the measurement point and the DA surface for distances of ≥5 mm. Except for PET, no significant difference between the DA dose curves for the presence and absence of DDs was observed. In the dose curve, PET showed a slightly higher dose for DA with DD than for DA without DD for thicknesses of ≥4 mm. The findings herein suggest that the optimal DD material for preventing local dose enhancement of the mucosa caused by DA backscatter radiation should have a relatively low atomic number and physical density and that optimal DD thickness should be chosen considering backscatter radiation and percentage depth dose.

Sci‐Sat AM: Radiation Dosimetry and Practical Therapy Solutions ‐ 02: Dosimetric effects of gold nanoparticle surface coatings

Introduction:Gold nanoparticles (GNPs) can enhance radiation therapy within a tumour, increasing local energy deposition under irradiation, but experimental evidence suggests the enhancement is not as large as predicted by dose enhancement alone. Many studies neglect to account for surface coatings that are frequently used to optimize GNP uptake and biological distribution. This study uses Monte Carlo methods to investigate the consequences on local dose enhancement due to including these surface coatings.Methods:Using the PENELOPE Monte Carlo code system, GNP irradiation was simulated both with and without surface coatings of polyethylene glycol (PEG) of various molecular weights. Dose was scored to the gold, coating, and surrounding water, and the dosimetric differences between these scenarios were examined.Results:The simulated PEG coating absorbs a large portion of the energy that would otherwise be deposited in the medium. The mean dose to water was reduced by up to 2.5, 3.5, and 4.5% for GNPs of diameters 50, 20, and 10 nm, respectively. This effect was more pronounced for smaller GNPs, thicker coatings, and low photon source energies where the enhancement due to GNPs is the greatest. The molecular weight of the coating material did not have a significant impact on the dose.Conclusions:The inclusion of a coating material in GNP enhanced radiation may reduce the dose enhancement due to the nanoparticles. Both the composition and size of the coating play a role in the level of this reduction and should be considered carefully.

SU‐F‐T‐426: Measurement of Dose Enhancement Due to Backscatter From Modern Dental Materials

Purpose:High‐density materials used in dental restoration can cause significant localized dose enhancement due to electron backscatter in head‐and‐neck radiotherapy, increasing the risk of mucositis. The materials used in prosthetic dentistry have evolved in the last decades from metal alloys to ceramics. We aim to determine the dose enhancement caused by backscatter from currently‐used dental materials.Methods:Measurements were performed for three different dental materials: lithium disilicate (Li2Si2O5), zirconium dioxide (ZrO2), and gold alloy. Small thin squares (2×2×0.15 cm3) of the material were fabricated, and placed into a phantom composed of tissue‐equivalent material. The phantom was irradiated with a single 6 MV photon field. A thin‐window parallel‐plate ion chamber was used to measure the dose at varying distances from the proximal interface between the material and the plastic.Results:The dose enhancement at the interface between the high‐density and tissue‐equivalent materials, relative to a homogeneous phantom, was 54% for the gold alloy, 31% for ZrO2, and 9% for Li2Si2O5. This enhancement decreased rapidly with distance from the interface, falling to 11%, 5%, and 0.5%, respectively, 2 mm from the interface. Comparisons with the modeling of this effect in treatment planning systems are performed.Conclusion:While dose enhancement due to dental restoration is smaller with ceramic materials than with metal alloys, it can still be significant. A spacer of about 2–3 mm would be effective in reducing this enhancement, even for metal alloys.

TU‐H‐CAMPUS‐TeP3‐05: Evaluation of the Microscopic Dose Enhancement in the Nanoparticle‐Enhanced Auger Therapy

Purpose:The aim of this study is to apply Monte Carlo simulations to investigate the nanoparticle dose enhancement for Auger therapy.Methods:Two nanoparticle fabrications were considered: nanoshell and nanosphere. In the first step, a single nanoparticle was irradiated with Auger emitters. The electrons were scored in a phase space at the outer surface of the nanoparticle with Geant4‐Penelope. In the second step, the previously recorded phase space was used as a source and placed at the center of a cell‐size water phantom. The nanoscale dose was evaluated in water around the nanoparticle with Geant4‐DNA. The dose enhancement factor (DEF) is defined as the ratio of doses with and without nanoparticles. The nanoparticles were replaced by corresponding water nanoparticle with the same size and volume source which represents typical situation of Auger emitters without nanoparticle. Various sizes/materials of nanoparticles and isotopes were considered.Results:Nanoshell ‐ Microscopic dose was increased up to 130% at 20 – 100 nm distances from the surface of Au‐125I nanoshell. However, dose at less than 20 nm distance was reduced due to absorbed low energy electrons in gold nanoshell. The amounts and regions of the dose enhancement were dependent on nanoshell size, materials, and isotopes. Nanosphere ‐ The increased amounts of electrons up to 300% and reduced average energy with nanosphere were observed compared with water nanoparticle. We observed localized dose enhancement (up to a factor 3.6) in the immediate vicinity (&lt; 50 nm) of Au‐125 I nanosphere. The dose enhancement patterns vary according to nanosphere sizes and isotopes.Conclusion:We conclude that Auger therapy with nanoparticles can lead to change of electron energy spectrum and dose enhancements at certain range. The dose enhancement patterns vary according to nanoparticle sizes, materials, and isotopes.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP: Ministry of Science, ICT and Future Planning) (No. NRF‐2013M2B2B1075776)

SU‐G‐TeP3‐13: The Role of Nanoscale Energy Deposition in the Development of Gold Nanoparticle‐Enhanced Radiotherapy

Purpose:Gold nanoparticles (GNPs) can enhance radiotherapy effects. The high photoelectric cross section of gold relative to tissue, particularly at lower energies, leads to localized dose enhancement. However in a clinical context, photon energies must also be sufficient to reach a target volume at a given depth. These properties must be balanced to optimize such a therapy. Given that nanoscale energy deposition patterns around GNPs play a role in determining biological outcomes, in this work we seek to establish their role in this optimization process.Methods:The PENELOPE Monte Carlo code was used to generate spherical dose deposition kernels in 1000 nm diameter spheres around 50 nm diameter GNPs in response to monoenergetic photons incident on the GNP. Induced “lesions” were estimated by either a local effect model (LEM) or a mean dose model (MDM). The ratio of these estimates was examined for a range of photon energies (10 keV to 2 MeV), for three sets of linear‐quadratic parameters.Results:The models produce distinct differences in expected lesion values, the lower the alpha‐beta ratio, the greater the difference. The ratio of expected lesion values remained constant within 5% for energies of 40 keV and above across all parameter sets and rose to a difference of 35% for lower energies only for the lowest alpha‐beta ratio.Conclusion:Consistent with other work, these calculations suggest nanoscale energy deposition patterns matter in predicting biological response to GNP‐enhanced radiotherapy. However the ratio of expected lesions between the different models is largely independent of energy, indicating that GNP‐enhanced radiotherapy scenarios can be optimized in photon energy without consideration of the nanoscale patterns. Special attention may be warranted for energies of 20 keV or below and low alpha‐beta ratios.

Quantitative investigation of physical factors contributing to gold nanoparticle-mediated proton dose enhancement

Some investigators have shown tumor cell killing enhancement in vitro and tumor regression in mice associated with the loading of gold nanoparticles (GNPs) before proton treatments. Several Monte Carlo (MC) investigations have also demonstrated GNP-mediated proton dose enhancement. However, further studies need to be done to quantify the individual physical factors that contribute to the dose enhancement or cell-kill enhancement (or radiosensitization). Thus, the current study investigated the contributions of particle-induced x-ray emission (PIXE), particle-induced gamma-ray emission (PIGE), Auger and secondary electrons, and activation products towards the total dose enhancement. Specifically, GNP-mediated dose enhancement was measured using strips of radiochromic film that were inserted into vials of cylindrical GNPs, i.e. gold nanorods (GNRs), dispersed in a saline solution (0.3 mg of GNRs/g or 0.03% of GNRs by weight), as well as vials containing water only, before proton irradiation. MC simulations were also performed with the tool for particle simulation code using the film measurement setup. Additionally, a high-purity germanium detector system was used to measure the photon spectrum originating from activation products created from the interaction of protons and spherical GNPs present in a saline solution (20 mg of GNPs/g or 2% of GNPs by weight). The dose enhancement due to PIXE/PIGE recorded on the films in the GNR-loaded saline solution was less than the experimental uncertainty of the film dosimetry (<2%). MC simulations showed highly localized dose enhancement (up to a factor 17) in the immediate vicinity (<100 nm) of GNRs, compared with hypothetical water nanorods (WNRs), mostly due to GNR-originated Auger/secondary electrons; however, the average dose enhancement over the entire GNR-loaded vial was found to be minimal (0.1%). The dose enhancement due to the activation products from GNPs was minimal (<0.1%) as well. In conclusion, under the currently investigated conditions that are considered clinically relevant, PIXE, PIGE, and activation products contribute minimally to GNP/GNR-mediated proton dose enhancement, whereas Auger/secondary electrons contribute significantly but only at short distances (<100 nm) from GNPs/GNRs.

FTIR Study of the Biochemical Effects Induced by X-Ray Irradiations Combined with GD Nanoparticles in F98 Glioma Cells

Radiotherapy (RT) plays a key role in the treatment of cancer, its main challenge being to reach tumor curative doses while sparing the surrounding healthy tissue. One strategy to improve the clinical outcome is to increase the dose effects inside the tumor; this can be achieved by using specific nanoparticles (NP). Indeed, numerous studies have shown an enhanced effectiveness of tumor cell killing when NP are associated to irradiation. However, the mechanisms of action are not yet clear: in addition to the damage due to a possible local dose enhancement, the interaction of NP with essential biological macromolecules could lead to changes in the cellular function. These effects might increase their anticancer efficacy when amplified with irradiation.In this study, we used F98 glioma rat cells as an in vitro model to evaluate the intracellular biochemical changes induced by X-ray irradiations in combination with Gadolinium NP using Fourier transform infrared microspectroscopy (FTIR). FTIR allows in situ chemical structure determination of intracellular biomolecules and it has significantly contributed to the study of cell cycle and death types. FTIR measurements were carried out using the internal source of infrared radiation at SESAME synchrotron (Jordan). Principal Component Analysis (PCA) was performed to show the variances between the different sets of spectra. Noticeable spectra alterations in the presence or absence of NP were detected in the proteins, DNA and lipids regions, indicating changes in the cellular function (even in the absence of irradiation). In particular, biochemical changes related to apoptosis were detected, such as a shift of the Amide I band to the lower frequency range in the presence of NP. These results will be discussed in relation to cell viability studies.

183 - Internalization of iron nanoparticles by macrophages for the improvement of glioma treatment

Rationale: An alternative approach for the improvement of radiotherapy consists in increasing differentially the radiation dose between tumors and healthy tissues using nanoparticles (NPs) that have been beforehand internalized into the tumor. These high-Z NPs can be photo-activated by monochromatic synchrotron X-rays, leading to a local dose enhancement delivered to the neighboring tumor cells[1]. This enhancement is due to secondary and Auger electrons expelled from the NPs by the radiations. In order to carry the NPs into the tumor center, macrophages are currently under study for their phagocytosis and diapedesis abilities[2] (cf. Figure adapted from [3] and [4]). In this study we characterized J774A.1 macrophages’ internalization kinetics and subcellular distribution of iron NPs and compared them to the internalization abilities of the F98 glioblastoma cell line. Materials and Methods: Three aspects of internalization were examined: first, the location of internalized NPs in J774A.1 macrophages and F98 glioblastoma cells following a 24h incubation with iron NPs (0.3 mg/mL in the cell culture medium) was determined by optical microscopy after cell slicing. Subsequently, the iron intake after a 24h incubation with NPs (0.3 mg/mL and 0.06 mg/mL in the cell culture medium) was characterized for the two types of cells using ICP-MS. Finally, the internalization dynamics were studied by live phase-contrast microscopy imagining for 11 hours and by absorbance measurements for 24 hours using a plate reader. Results: F98 tumor cells and J774A.1 macrophages are both able to endocytose NPs: we measured ~61±10 pg of internalized iron per macrophage compared with ~33±5 pg per F98 cell (initial iron concentration: 0.3 mg/mL in culture medium). F98 internalizing NPs for 10 hours showed stress signs during the first minutes after the NPs injection, but behaved like F98 control cells during the rest of the experiment. Finally, we determined that the internalization kinetics for J774A.1 had a typical saturation time of one hour. Conclusion: Macrophages seem to be promising vectors for NPs, being able to endocytose and retain in their cytoplasm larger quantities of NPs than tumor cells. Our following studies will attempt to shed light on their other potential abilities as “Trojan Horses”.

Targeted radiotherapy enhancement during electronic brachytherapy of accelerated partial breast irradiation (APBI) using controlled release of gold nanoparticles

Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia) and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during electronic brachytherapy APBI while reducing normal tissue toxicity. We propose to incorporate GNPs into a micrometer-thick polymer film on the surface of routinely used lumpectomy balloon applicators and provide subsequent treatment using a 50 kVp Xoft device. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 7 mg/g and 43 mg/g. An analytical approach from previously published work was employed to estimate the dose enhancement due to GNPs as a function of distance up to 1 cm from the lumpectomy cavity surface. Clinically significant dose enhancement values of at least 1.2, due to 2 nm GNPs, were found at 1 cm away from the lumpectomy cavity wall when using electronic brachytherapy APBI. Higher customizable dose enhancement was also achieved at other distances as a function of nanoparticle size. Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy.

Radiotherapy dose enhancement using BNCT in conventional LINACs high-energy treatment: Simulation and experiment

AimTo employ the thermal neutron background that affects the patient during a traditional high-energy radiotherapy treatment for BNCT (Boron Neutron Capture Therapy) in order to enhance radiotherapy effectiveness. BackgroundConventional high-energy (15–25MV) linear accelerators (LINACs) for radiotherapy produce fast secondary neutrons in the gantry with a mean energy of about 1MeV due to (γ, n) reaction. This neutron flux, isotropically distributed, is considered as an unavoidable undesired dose during the treatment. Considering the moderating effect of human body, a thermal neutron fluence is localized in the tumour area: this neutron background could be employed for BNCT by previously administering 10B-Phenyl-Alanine (10BPA) to the patient. Materials and methodsMonte Carlo simulations (MCNP4B-GN code) were performed to estimate the total amount of neutrons outside and inside human body during a traditional X-ray radiotherapy treatment.Moreover, a simplified tissue equivalent anthropomorphic phantom was used together with bubble detectors for thermal and fast neutron to evaluate the moderation effect of human body. ResultsSimulation and experimental results confirm the thermal neutron background during radiotherapy of 1.55E07cm−2Gy−1.The BNCT equivalent dose delivered at 4cm depth in phantom is 1.5mGy-eq/Gy, that is about 3Gy-eq (4% of X-rays dose) for a 70Gy IMRT treatment. ConclusionsThe thermal neutron component during a traditional high-energy radiotherapy treatment could produce a localized BNCT effect, with a localized therapeutic dose enhancement, corresponding to 4% or more of photon dose, following tumour characteristics. This BNCT additional dose could thus improve radiotherapy, acting as a localized radio-sensitizer.

MO‐FG‐BRA‐07: Theranostic Gadolinium‐Based AGuIX Nanoparticles for MRI‐Guided Radiation Therapy

Purpose:AGuIX are gadolinium‐based nanoparticles, initially developed for MRI, that have a potential role in radiation therapy as a radiosensitizer. Our goal is to demonstrate that these nanoparticles can both be used as an MRI contrast agent, as well as to obtain local dose enhancement in a pancreatic tumor when delivered in combination with an external beam irradiation.Methods:We performed in vitro cell uptake and radiosensitization studies of a pancreatic cancer cell line in a low energy (220kVp) beam, a standard clinical 6MV beam (STD) and a flattening filter free clinical 6MV beam (FFF). After injection of 40mM of nanoparticles, a biodistribution study was performed in vivo on mice with subcutaneous xenograft pancreatic tumors. In vivo radiation therapy studies were performed at the time point of maximum tumor uptake.Results:The concentration of AGuIX nanoparticles in Panc‐1 pancreatic cancer cells, determined in vitro by MRI and ICPMS, peaks after 30 minutes with 0.3% of the initial concentration (5mg/g). Clonogenic assays show a significant effect (p&lt;0.05) when the AGuIX are coupled with MV photon irradiation (DEF20%=1.31). Similar AGuIX tumor uptake is found in vivo by both MRI and ICPMS 30 minutes after intravenous injection. For long term survival studies, the choice of the radiation dose is determined with 5 control groups (3mice/group) irradiated with 0, 5, 10, 15, and 20Gy. Afterwards, 4 groups (8mice/group) are used to evaluate the effect of the nanoparticles. A Logrank test is performed as a statistical test to evaluate the effect of the nanoparticles.Conclusion:The combination of the MRI contrast and radiosensitization properties of gadolinium nanoparticles reveals a strong potential for usage with MRI‐guided radiation therapy.

Gold Nanoparticles in Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations

Objective of the study: To explore the potential for therapeutic gain with gold nanoparticles in arteriovenous malformation radiosurgery based on their interaction with photons and protons. Study methods: Radiation dose enhancement resulting from the interaction of gold nanoparticles with irradiation ranging from kilovoltage to megavoltage photons and protons was researched in the literature. The role of angiogenesis and its regulation via vascular endothelial growth factors and cell membrane receptors, especially for endothelial cells in arteriovenous malformations, was investigated as a way for selective arteriovenous malformation deposition. Results: Radiation dose enhancement with gold nanoparticles is described in the literature but has so far only been investigated for its potential in treating malignancies. Because of the high atomic number of gold (Z = 79), dose enhancement occurs with photons mainly based on secondary photon and Auger electron production and the dose enhancement factor is the highest for irradiation with kilo voltage photons. Dose enhancement happens with megavoltage photons also but to a lesser extend and is mainly due to the ionization of gold by secondary photons and electrons generated by the megavoltage photons passing through tissue. The range of the secondary photo electrons emitted by gold is sufficient to cover the entire endothelial cell content. Protons interact with the production of Auger electrons which have a very short range, insufficient to cover the entire contents of endothelial cells, but sufficient to cause a high cell membrane dose for membrane located gold nanoparticles (AuNPs). Arteriovenous malformations are dynamic entities with angiogenesis taking place. This is reflected by a different expression of angiogenic receptors on the membrane of arteriovenous malformation endothelial cells compared to normal brain blood vessels, thereby opening the opportunity for selective deposition of such particles. For the use in proton therapy a new definition for the dose enhancement factor describing the local effect of nanoparticles is proposed. Conclusion: The concept of nanoparticle enhanced radiosurgery for arteriovenous malfor-mations by selective deposition of gold nanoparticles is a novel approach. The local dose enhancement opens the way for therapeutic gain which in turn could lead to improved obliteration rates and/or a shorter latent period.

The Combined Therapeutical Effect of Metal-based Drugs and Radiation Therapy: The Present Status of Research

Conventional chemotherapy and radiation treatment are two cornerstones of cancer treatment but efforts are required to improve their "therapeutic window". The development of metal complexes, including platinum, has had an enormous impact on current cancer chemotherapy. However, these chemotherapeutic drugs can be employed only in the management of a limited number of cancers and, furthermore, their use causes significant side effects. Research over the past 10 years has produced new complexes containing heavy atoms other than platinum, such as iron, cobalt, or gold, which have been used in phase I and phase II trials. Recent preclinical research has shown promising results also using titanium, ruthenium, copper and silver. The anticancer activity of metal-based compounds and nanoparticles (gold and gadolinium in particular) is presently under evaluation in several laboratories in combination with or without X-ray therapy. In fact, if present in sufficiently high concentrations in the tumors, metals can act as a radiotherapy adjuvant: they possess an increased capability to absorb the X-ray radiation with respect to the water-based tissues. Low energy electrons will be then released close to the metal and, therefore, determine a local dose enhancement. This review will focus on the anticancer properties of new drugs and on the rationale for testing their usefulness in combined treatment.

WE-G-BRE-09: Targeted Radiotherapy Enhancement During Accelerated Partial Breast Irradiation (ABPI) Using Controlled Release of Gold Nanoparticles (GNPs)

Purpose: Several studies have demonstrated low rates of local recurrence with brachytherapy-based accelerated partial breast irradiation (APBI). However, long-term outcomes on toxicity (e.g. telangiectasia), and cosmesis remain a major concern. The purpose of this study is to investigate the dosimetric feasibility of using targeted non-toxic radiosensitizing gold nanoparticles (GNPs) for localized dose enhancement to the planning target volume (PTV) during APBI while reducing dose to normal tissue. Methods: Two approaches for administering the GNPs were considered. In one approach, GNPs are assumed to be incorporated in a micrometer-thick polymer film on the surface of routinely used mammosite balloon applicators, for sustained controlled in-situ release, and subsequent treatment using 50-kVp Xoft devices. In case two, GNPs are administered directly into the lumpectomy cavity e.g. via injection or using fiducials coated with the GNP-loaded polymer film. Recent studies have validated the use of fiducials for reducing the PTV margin during APBI with 6 MV beams. An experimentally determined diffusion coefficient was used to determine space-time customizable distribution of GNPs for feasible in-vivo concentrations of 43 mg/g. An analytic calculational approach from previously published work was employed to estimate the dose enhancement due to GNPs (2 and 10 nm) as a function of distance up to 1 cm from lumpectomy cavity. Results: Dose enhancement due to GNP was found to be about 130% for 50-kVp x-rays, and 110% for 6-MV external beam radiotherapy, 1 cm away from the lumpectomy cavity wall. Higher customizable dose enhancement could be achieved at other distances as a function of nanoparticle size. Conclusion: Our preliminary results suggest that significant dose enhancement can be achieved to residual tumor cells targeted with GNPs during APBI with electronic brachytherapy or external beam therapy. The findings provide a useful basis for developing nanoparticle-aided APBI, with potential to significantly reduce normal tissue/skin toxicity.

WE‐A‐108‐02: Radiotherapy Enhancement for Prostate Cancer Using Platinum‐Based Nanoparticles

Purpose: In this work, the nucleus dose enhancement (nDEF) due to photoelectric interactions with cisplatin/oxaliplatin nanoparticles (CNPs/ONPs) is investigated in comparison to the nDEF due to gold nanoparticles (AuNPs) during prostate brachytherapy. CNPs/ONPs are particularly attractive since they may provide a more cost‐effective alternative to AuNPs, but could also provide additional chemotherapy effect for prostate tumors. Methods: As in previous studies, the dose enhancement to the PCa endothelial cells (EC) was determined using analytic microdosimetry calculations to determine the energy deposited in the EC nucleus due to radiation‐induced photoelectrons emitted by the nanoparticles. Dividing the energy deposited by the mass of the nucleus yields the dose. The nDEF defined as the ratio of the overall dose to the nucleus with and without nanoparticles, was determined for a range of CNP and ONP concentrations up to the FDA approved limit, which is 1–34 mg/g and 1–50 mg/g for oxaliplatin and cisplatin, respectively. Results: For Pd‐103, the calculated nDEF due to photoelectrons alone was up to 2.4, and 2.3 for oxaliplatin, and cisplatin respectively, compared to over 3 for comparable concentrations of AuNPs. For I–125, the calculated nDEF was up to 1.95, and 1.8 for oxaliplatin, and cisplatin, respectively in comparison to 2.5 for comparable concentrations of AuNP. Conclusion: The results predict that major localized dose enhancement to PCa cells can be achieved using targeted CNPs/ONPs. A potential application strategy for this Result is to load routinely used brachytherapy spacers with such nanoparticles, which can then be sustainably released from within the tumor volume for photon‐induced dose enhancement combined to the chemotherapy effect, with no increased toxicity to healthy tissue. Overall, the results motivate further work including: Monte Carlo work incorporating dose enhancement from Auger electrons, as well as corroborative experimental work towards development of this new application strategy.

Brain metastasis treatment plans for contrast-enhanced synchrotron radiation therapy

Introduction Contrast-enhanced stereotactic synchrotron radiotherapy (SSRT) is an innovative treatment based on localized dose enhancement effects obtained by reinforced photoelectric absorption in brain tumors. Tumors previously loaded with high-Z elements are irradiated using medium-energy monochromatic x-rays (50–100 keV). The aim of this study is to compare SSRT treatment in the presence and absence of iodine enhancement. For a single case, SSRT was compared to conventional treatments: 3D conformational radiotherapy, modulated radiation therapy (IMRT) and dynamic stereotactic arc-therapy. Material and methods Patients bearing brain metastasis received a standard helical 3D-scan without iodine. A second scan was acquired 13 min after an 80 g iodine infusion. Two SSRT treatment plans (with/without iodine) were performed for each patient. A dedicated Monte Carlo (MC) treatment planning system (TPS) based on the ISOgray TPS was developed for this purpose. Ten coplanar beams (6 * 6 cm 2 , shaped with collimator) were simulated. MC statistical error objective was less than 5% in the 50% isodose. The treatment plan validation criteria were fixed such as 100% of the prescribed dose is delivered at the beam isocentre and the 70% isodose contains the whole target volume. The comparison elements were the 70% isodose volume, the average and maximal doses delivered to organs at risk (OAR): brainstem, optical nerves, chiasma, eyes, skull bone and healthy brain parenchyma. For the single case study, the 3D conformational radiotherapy and IMRT treatment plans were established using the Eclipse ® -Varian TPS. The dynamic arc-therapy plan was achieved on the Iplan ® -Brainlab TPS. Results Iodine-enhanced SSRT exhibits a good potential for brain metastasis treatment regarding the dose distribution and OAR criteria. Iodine accumulation in metastasis may increase the dose of 20– 30% (sparing effect). Treatment without any iodine enhancement (medium-energy stereotactic radiotherapy) is not relevant with degraded HDVs (brain, parenchyma and skull bone) comparing to conventional stereotactic surgery. In the single case study, the stereotactic dynamic arc-therapy remains the best technique in terms of dose conformation. However, OAR sparing is increased with iodine-enhanced SSRT: the dose delivered to the brainstem and the brain parenchyma is significantly reduced. Conclusion This study shows the potential dosimetric advantages of contrast-enhanced SSRT for treating brain metastasis.

Novel Multicompartment 3-Dimensional Radiochromic Radiation Dosimeters for Nanoparticle-Enhanced Radiation Therapy Dosimetry

Gold nanoparticles (AuNps), because of their high atomic number (Z), have been demonstrated to absorb low-energy X-rays preferentially, compared with tissue, and may be used to achieve localized radiation dose enhancement in tumors. The purpose of this study is to introduce the first example of a novel multicompartment radiochromic radiation dosimeter and to demonstrate its applicability for 3-dimensional (3D) dosimetry of nanoparticle-enhanced radiation therapy. A novel multicompartment phantom radiochromic dosimeter was developed. It was designed and formulated to mimic a tumor loaded with AuNps (50 nm in diameter) at a concentration of 0.5 mM, surrounded by normal tissues. The novel dosimeter is referred to as the Sensitivity Modulated Advanced Radiation Therapy (SMART) dosimeter. The dosimeters were irradiated with 100-kV and 6-MV X-ray energies. Dose enhancement produced from the interaction of X-rays with AuNps was calculated using spectrophotometric and cone-beam optical computed tomography scanning by quantitatively comparing the change in optical density and 3D datasets of the dosimetric measurements between the tissue-equivalent (TE) and TE/AuNps compartments. The interbatch and intrabatch variability and the postresponse stability of the dosimeters with AuNps were also assessed. Radiation dose enhancement factors of 1.77 and 1.11 were obtained using 100-kV and 6-MV X-ray energies, respectively. The results of this study are in good agreement with previous observations; however, for the first time we provide direct experimental confirmation and 3D visualization of the radiosensitization effect of AuNps. The dosimeters with AuNps showed small (<3.5%) interbatch variability and negligible (<0.5%) intrabatch variability. The SMART dosimeter yields experimental insights concerning the spatial distributions and elevated dose in nanoparticle-enhanced radiation therapy, which cannot be performed using any of the current methods. The authors concluded that it can be used as a novel independent method for nanoparticle-enhanced radiation therapy dosimetry.