Nanoparticle-enhanced Radiotherapy Research Articles

Gold nanoparticle-enhanced radiotherapy: Dependence of the macroscopic dose enhancement on the microscopic localization of the nanoparticles within the tumor vasculature.

In gold nanoparticle-enhanced radiotherapy, intravenously administered nanoparticles tend to accumulate in the tumor tissue by means of the so-called permeability and retention effect and upon irradiation with x-rays, the nanoparticles release a secondary electron field that increases the absorbed dose that would otherwise be obtained from the interaction of the x-rays with tissue alone. The concentration of the nanoparticles in the tumor, number of nanoparticles per unit of mass, which determines the total absorbed dose imparted, can be measured via magnetic resonance or computed tomography images, usually with a resolution of several millimeters. Using a tumor vasculature model with a resolution of 500 nm, we show that for a given concentration of nanoparticles, the dose enhancement that occurs upon irradiation with x-rays greatly depends on whether the nanoparticles are confined to the tumor vasculature or have already extravasated into the surrounding tumor tissue. We show that, compared to the reference irradiation with no nanoparticles present in the tumor model, irradiation with the nanoparticles confined to the tumor vasculature, either in the bloodstream or attached to the inner blood vessel walls, results in a two to three-fold increase in the absorbed dose to the whole tumor model, with respect to an irradiation when the nanoparticles have already extravasated into the tumor tissue. Therefore, it is not enough to measure the concentration of the nanoparticles in a tumor, but the location of the nanoparticles within each volume element of a tumor, be it inside the vasculature or the tumor tissue, needs to be determined as well if an accurate estimation of the resultant absorbed dose distribution, a key element in the success of a radiotherapy treatment, is to be made.

Breaking the barrier: Nanoparticle-enhanced radiotherapy as the new vanguard in brain tumor treatment.

The pursuit of effective treatments for brain tumors has increasingly focused on the promising area of nanoparticle-enhanced radiotherapy (NERT). This review elucidates the context and significance of NERT, with a particular emphasis on its application in brain tumor therapy-a field where traditional treatments often encounter obstacles due to the blood-brain barrier (BBB) and tumor cells' inherent resistance. The aims of this review include synthesizing recent advancements, analyzing action mechanisms, and assessing the clinical potential and challenges associated with nanoparticle (NP) use in radiotherapy enhancement. Preliminary preclinical studies have established a foundation for NERT, demonstrating that nanoparticles (NPs) can serve as radiosensitizers, thereby intensifying radiotherapy's efficacy. Investigations into various NP types, such as metallic, magnetic, and polymeric, have each unveiled distinct interactions with ionizing radiation, leading to an augmented destruction of tumor cells. These interactions, encompassing physical dose enhancement and biological and chemical radio sensitization, are crucial to the NERT strategy. Although clinical studies are in their early phases, initial trials have shown promising results in terms of tumor response rates and survival, albeit with mindful consideration of toxicity profiles. This review examines pivotal studies affirming NERT's efficacy and safety. NPs have the potential to revolutionize radiotherapy by overcoming challenges in targeted delivery, reducing off-target effects, and harmonizing with other modalities. Future directions include refining NP formulations, personalizing therapies, and navigating regulatory pathways. NERT holds promise to transform brain tumor treatment and provide hope for patients.

Radiation source personalization for nanoparticle-enhanced radiotherapy using dynamic contrast-enhanced MRI in the treatment planning process

Nanoparticle-enhanced radiotherapy offers the potential to selectively increase the radiation dose imparted to the tumor while at the same time sparing the healthy structures around it. Among the recommendations of an interdisciplinary group for the clinical translation of this treatment modality, is the developing of methods to quantify the effects that the nanoparticle concentration has on the radiation dosimetry and incorporate these effects into the treatment planning process. In this work, using Monte Carlo simulations and dynamic contrast-enhanced MRI images, treatment plans for nanoparticle-enhanced radiotherapy are calculated in order to evaluate the effects that realistic distributions of the nanoparticles have on the resultant plans and to devise treatment strategies to account for these effects, including the selection of the proper x-ray source configuration in terms of energy and collimation. Dynamic contrast-enhanced MRI studies were obtained for two treatment sites, namely brain and breast. A model to convert the MRI signal to contrast agent concentration was applied to each set of images. Two treatment modalities, 3D conformal radiotherapy and Stereotactic Body Radiation Therapy, were evaluated at three different x-ray spectra, namely 6 MV from a linear accelerator, 110 kVp and 220 kVp from a tungsten target. For the breast patient, as the nanoparticle distribution varies markedly with time, the treatment plans were obtained at two different times after administration. It was determined that maximum doses to the healthy structures around the tumor are mostly determined by the minimum nanoparticle concentration in the tumor. The presence of highly hypoxic or necrotic tissue, which fails to accumulate the nanoparticles, or leakage of the contrast agent into the surrounding healthy tissue, make irradiation with conventional conformal radiotherapy unfeasible for kilovoltage beam energies, as the uniform beam apertures lack the ability to compensate for the non-uniform distribution of the nanoparticles. Therefore, proper quantification of the nanoparticle distribution not only in the target volume but also in the surrounding tissues and structures is crucial for the proper planning of nanoparticle-enhanced radiotherapy and a treatment delivery with a high-degree of freedom, such as small-field stereotactic body radiotherapy, should be the method of choice for this treatment modality.

Depth Dose Enhancement in Orthovoltage Nanoparticle-Enhanced Radiotherapy: A Monte Carlo Phantom Study.

This study was to examine the depth dose enhancement in orthovoltage nanoparticle-enhanced radiotherapy for skin treatment by investigating the impact of various photon beam energies, nanoparticle materials, and nanoparticle concentrations. A water phantom was utilized, and different nanoparticle materials (gold, platinum, iodine, silver, iron oxide) were added to determine the depth doses through Monte Carlo simulation. The clinical 105 kVp and 220 kVp photon beams were used to compute the depth doses of the phantom at different nanoparticle concentrations (ranging from 3 mg/mL to 40 mg/mL). The dose enhancement ratio (DER), which represents the ratio of the dose with nanoparticles to the dose without nanoparticles at the same depth in the phantom, was calculated to determine the dose enhancement. The study found that gold nanoparticles outperformed the other nanoparticle materials, with a maximum DER value of 3.77 at a concentration of 40 mg/mL. Iron oxide nanoparticles exhibited the lowest DER value, equal to 1, when compared to other nanoparticles. Additionally, the DER value increased with higher nanoparticle concentrations and lower photon beam energy. It is concluded in this study that gold nanoparticles are the most effective in enhancing the depth dose in orthovoltage nanoparticle-enhanced skin therapy. Furthermore, the results suggest that increasing nanoparticle concentration and decreasing photon beam energy lead to increased dose enhancement.

Radiation as a Tool against Neurodegeneration-A Potential Treatment for Amyloidosis in the Central Nervous System.

Radiotherapy (RT) is a relatively safe and established treatment for cancer, where the goal is to kill tumoral cells with the lowest toxicity to healthy tissues. Using it for disorders involving cell loss is counterintuitive. However, ionizing radiation has a hormetic nature: it can have deleterious or beneficial effects depending on how it is applied. Current evidence indicates that radiation could be a promising treatment for neurodegenerative disorders involving protein misfolding and amyloidogenesis, such as Alzheimer’s or Parkinson’s diseases. Low-dose RT can trigger antioxidant, anti-inflammatory and tissue regeneration responses. RT has been used to treat peripheral amyloidosis, which is very similar to other neurodegenerative disorders from a molecular perspective. Ionizing radiation prevents amyloid formation and other hallmarks in cell cultures, animal models and pilot clinical trials. Although some hypotheses have been formulated, the mechanism of action of RT on systemic amyloid deposits is still unclear, and uncertainty remains regarding its impact in the central nervous system. However, new RT modalities such as low-dose RT, FLASH, proton therapy or nanoparticle-enhanced RT could increase biological effects while reducing toxicity. Current evidence indicates that the potential of RT to treat neurodegeneration should be further explored.

Novel Implications of Nanoparticle-Enhanced Radiotherapy and Brachytherapy: Z-Effect and Tumor Hypoxia.

Radiotherapy and internal radioisotope therapy (brachytherapy) induce tumor cell death through different molecular signaling pathways. However, these therapies in cancer patients are constrained by dose-related adverse effects and local discomfort due to the prolonged exposure to the surrounding tissues. Technological advancements in nanotechnology have resulted in synthesis of high atomic elements such as nanomaterials, which can be used as radiosensitizers due to their photoelectric characteristics. The aim of this review is to elucidate the effects of novel nanomaterials in the field of radiation oncology to ameliorate dose-related toxicity through the application of ideal nanoparticle-based radiosensitizers such as Au (gold), Bi (bismuth), and Lu (Lutetium-177) for enhancing cytotoxic effects of radiotherapy via the high-Z effect. In addition, we discuss the role of nanoparticle-enhanced radiotherapy in alleviating tumor hypoxia through the nanodelivery of genes/drugs and other functional anticancer molecules. The implications of engineered nanoparticles in preclinical and clinical studies still need to be studied in order to explore potential mechanisms for radiosensitization by minimizing tumor hypoxia, operational/logistic complications and by overcoming tumor heterogeneity in radiotherapy/brachytherapy.

Combining a nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves the treatment efficacy in anti-PD1 resistant lung cancer

BackgroundWhile improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to immunoradiotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of immunoradiotherapy.MethodsWe combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT, and tested the treatment efficacy in an anti-PD1-resistant lung cancer model in mice. 129 Sv/Ev mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected into the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 µg), αLAG3 (200 µg), and αTIGIT (200 µg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42.ResultsThis nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice. Corresponding with this improved response is robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment.ConclusionOur results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.Graphical

Abstract 5516: Nanoparticle-enhanced radiotherapy combined with triple blockade of PD1, LAG3, and TIGIT enhances anti-tumor immune activation

Abstract Introduction: Checkpoint inhibition (CPI) has been a game-changer for cancer therapy, but most cancers do not respond. Part of the problem is that cancers employ multiple checkpoints; thus, targeting multiple checkpoint receptors simultaneously may yield increased benefit. Previously, we found that radiotherapy (XRT) in concert with a radiation-enhancing nanoparticle (NBTXR3) and PD1 blockade significantly improved tumor control both at the irradiative site and in remote, unirradiated tumors in a mouse model of anti-PD1 (αPD1)-resistant lung cancer (344SQR). Here, we tested whether blockade of TIGIT, LAG3, and PD1 in combination with NBTXR3-enhanced XRT could improve antitumor immune responses in our 344SQR tumor model. Methods: Fifty thousand 344SQR cells were inoculated in the right and left hindlimbs of 129Sv/Ev mice on day 0 and day 4 to establish primary and secondary tumors, respectively. Mice were divided into six treatment groups: 1) untreated; 2) XRT+αPD1; 3) NBTXR3+XRT+αPD1; 4) NBTXR3+XRT+αPD1+αLAG3; 5) NBTXR3+XRT+αPD1+αTIGIT; and 6) NBTXR3+XRT+αPD1+αLAG3 +αTIGIT. Primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7 and received 3 fractions of 12 Gy X-ray radiation on days 8, 9, and 10. Immune checkpoint inhibitors, composed of αPD1 (200 μg), αLAG3 (200 μg), and αTIGIT (200 μg), were intraperitoneally administered to the mice on days 5, 8, 11, 14. The expression of 770 immune-related genes were measured via NanoString from the RNA extracted from the primary and secondary tumors on day 21. Results: CPIs+NBTXR3-enhanced radiation significantly promoted the upregulation of mRNA transcripts involved in innate immunity, the humoral response, B cell function, dendritic cell (DC) function, and antigen processing within primary, irradiated tumors relative to untreated controls. No additional increase in immune gene activity in the irradiated tumors was observed when LAG3, TIGIT, or both were blocked in addition to PD1. However, within the non-irradiated tumors, triple blockade of PD1, LAG3, and TIGIT in concert with NBTXR3+XRT produced elevations in multiple immune-related pathways that were significantly higher than those produced by other treatment combinations. These pathways included both adaptive and innate immunity; B, T, and natural killer (NK) cell, and DC function; and antigen processing. Conclusions: Simultaneous inhibition of LAG3 and TIGIT in tandem with PD1 blockade and NBTXR3-enhanced radiotherapy promotes immune activation at the irradiated site. In addition, abscopal immune responses are improved with blockade of LAG3 and TIGIT. These results suggest that blockade of multiple immune checkpoints in parallel with NBTXR3-mediated radiotherapy may be effective in metastatic cancers. [Y.H. and B.G. contributed equally to this work.] Citation Format: Yun Hu, Genevieve Bertolet, Sebastien Paris, Hampartsoum Barsoumian, Jordan DA SILVA, Saumil Gandhi, Quynh-Nhu Nguyen, Maria A. Cortez, James W. Welsh. Nanoparticle-enhanced radiotherapy combined with triple blockade of PD1, LAG3, and TIGIT enhances anti-tumor immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5516.

Nanoparticle-enhanced radiotherapy synergizes with PD-L1 blockade to limit post-surgical cancer recurrence and metastasis

Cancer recurrence after surgical resection (SR) is a considerable challenge, and the biological effect of SR on the tumor microenvironment (TME) that is pivotal in determining postsurgical treatment efficacy remains poorly understood. Here, with an experimental model, we demonstrate that the genomic landscape shaped by SR creates an immunosuppressive milieu characterized by hypoxia and high-influx of myeloid cells, fostering cancer progression and hindering PD-L1 blockade therapy. To address this issue, we engineer a radio-immunostimulant nanomedicine (IPI549@HMP) capable of targeting myeloid cells, and catalyzing endogenous H2O2 into O2 to achieve hypoxia-relieved radiotherapy (RT). The enhanced RT-mediated immunogenic effect results in postsurgical TME reprogramming and increased susceptibility to anti-PD-L1 therapy, which can suppress/eradicate locally residual and distant tumors, and elicits strong immune memory effects to resist tumor rechallenge. Our radioimmunotherapy points to a simple and effective therapeutic intervention against postsurgical cancer recurrence and metastasis.

Effective atomic number and photon buildup factor of bismuth doped tissue for photon and particles beam interaction

Abstract Introduction: The doping of high Z nanoparticles into the tumor tissue increases the therapeutic efficiency of radiotherapy called nanoparticle enhanced radiotherapy (NERT). In the present study, we are identifying the effective types of radiation and effective doping concentration of bismuth radiosensitizer for NERT application by analyzing effective atomic number (Zeff) and photon buildup factor (PBF) of bismuth (Bi) doped soft tissue for the photon, electron, proton, alpha particle, and carbon ion interactions. Material and methods: The direct method was used for the calculation of Zeff for photon and electron beams (10 keV-30 MeV). The phy-X/ZeXTRa software was utilized for the particle beams such as proton, alpha particle, and carbon ions (1-15 MeV). Bismuth doping concentrations of 5, 10, 15, 20, 25 and 30 mg/g were considered. The PBF was calculated over 15 keV-15 MeV energies using phy-X/PSD software. Results: The low energy photon (<100 keV) interaction with a higher concentration of Bi dopped tissue gives the higher values of Zeff. The Zeff increased with the doping concentration of bismuth for all types of radiation. The Zeff was dependent on the type of radiation, the energy of radiation, and the concentration of Bi doping. The particle beams such as electron, proton, alpha particle, and carbon ion interaction gives the less values of Zeff has compared to photon beam interaction. On the other hand, the photon buildup factor values were decreased while increasing the Bi doping concentration. Conclusions: According to Zeff and PBF, the low energy photon and higher concentration of radiosensitizer are the most effective for nanoparticle enhanced radiotherapy application. Based on the calculated values of Zeff, the particle beams such as electron, proton, alpha particle, and carbon ions were less effective for NERT application. The presented values of Zeff and PBF are useful for the radiation dosimetry in NERT.

Incorporation of Low Concentrations of Gold Nanoparticles: Complex Effects on Radiation Response and Fate of Cancer Cells.

(1) Background: In oncology research, a long-standing discussion exists about pros and cons of metal nanoparticle-enhanced radiotherapy and real mechanisms behind the tumor cell response to irradiation (IR) in presence of gold nanoparticles (GNPs). A better understanding of this response is, however, necessary to develop more efficient and safety nanoparticle (NP) types designed to disturb specific processes in tumor cells. (2) Aims and Methods: We combined 3D confocal microscopy and super-resolution single molecule localization microscopy (SMLM) to analyze, at the multiscale, the early and late effects of 10 nm-GNPs on DNA double strand break (DSB) induction and repair in tumor cells exposed to different doses of photonic low-LET (linear energy transfer) radiation. The results were correlated to different aspects of short and long-term cell viability. SkBr3 breast cancer cells (selected for the highest incidence of this cancer type among all cancers in women, and because most breast tumors are treated with IR) were incubated with low concentrations of GNPs and irradiated with 60Co γ-rays or 6 MV X-rays. In numerous post-irradiation (PI) times, ranging from 0.5 to 24 h PI, the cells were spatially (3D) fixed and labeled with specific antibodies against γH2AX, 53BP1 and H3K9me3. The extent of DSB induction, multi-parametric micro- and nano-morphology of γH2AX and 53BP1 repair foci, DSB repair kinetics, persistence of unrepaired DSBs, nanoscale clustering of γH2AX and nanoscale (hetero)chromatin re-organization were measured by means of the mentioned microscopy techniques in dependence of radiation dose and GNP concentration. (3) Results: The number of γH2AX/53BP1 signals increased after IR and an additional increase was observed in GNP-treated (GNP(+)) cells compared to untreated controls. However, this phenomenon reflected slight expansion of the G2-phase cell subpopulation in irradiated GNP(+) specimens instead of enhanced DNA damage induction by GNPs. This statement is further supported by some micro- and nano-morphological parameters of γH2AX/53BP1 foci, which slightly differed for cells irradiated in absence or presence of GNPs. At the nanoscale, Ripley’s distance frequency analysis of SMLM signal coordinate matrices also revealed relaxation of heterochromatin (H3K9me3) clusters upon IR. These changes were more prominent in presence of GNPs. The slight expansion of radiosensitive G2 cells correlated with mostly insignificant but systematic decrease in post-irradiation survival of GNP(+) cells. Interestingly, low GNP concentrations accelerated DSB repair kinetics; however, the numbers of persistent γH2AX/53BP1 repair foci were slightly increased in GNP(+) cells. (4) Conclusions: Low concentrations of 10-nm GNPs enhanced the G2/M cell cycle arrest and the proportion of radiosensitive G2 cells, but not the extent of DNA damage induction. GNPs also accelerated DSB repair kinetics and slightly increased presence of unrepaired γH2AX/53BP1 foci at 24 h PI. GNP-mediated cell effects correlated with slight radiosensitization of GNP(+) specimens, significant only for the highest radiation dose tested (4 Gy).

Gold Nanoparticle DNA Damage by Photon Beam in a Magnetic Field: A Monte Carlo Study.

Ever since the emergence of magnetic resonance (MR)-guided radiotherapy, it is important to investigate the impact of the magnetic field on the dose enhancement in deoxyribonucleic acid (DNA), when gold nanoparticles are used as radiosensitizers during radiotherapy. Gold nanoparticle-enhanced radiotherapy is known to enhance the dose deposition in the DNA, resulting in a double-strand break. In this study, the effects of the magnetic field on the dose enhancement factor (DER) for varying gold nanoparticle sizes, photon beam energies and magnetic field strengths and orientations were investigated using Geant4-DNA Monte Carlo simulations. Using a Monte Carlo model including a single gold nanoparticle with a photon beam source and DNA molecule on the left and right, it is demonstrated that as the gold nanoparticle size increased, the DER increased. However, as the photon beam energy decreased, an increase in the DER was detected. When a magnetic field was added to the simulation model, the DER was found to increase by 2.5–5% as different field strengths (0–2 T) and orientations (x-, y- and z-axis) were used for a 100 nm gold nanoparticle using a 50 keV photon beam. The DNA damage reflected by the DER increased slightly with the presence of the magnetic field. However, variations in the magnetic field strength and orientation did not change the DER significantly.

X-ray Dose-Enhancing Impact of Functionalized Au-Fe3O4 Nanoheterodimers on MCF-7 and A549 Multicellular Tumor Spheroids.

The efficiency of nanoparticle-enhanced radiotherapy was studied by loading MCF-7 and A549 multicellular tumor spheroids (MCTSs) with caffeic acid- and nitrosonium-functionalized Au-Fe3O4 nanoheterodimers (Au-Fe3O4 NHDs). Transmission electron microscope images of MCTS cross-sectional sections visualized the invasion and distribution of the nitrosonium- and caffeic acid-functionalized Au-Fe3O4 NHDs (NO- and CA-NHDs) in the A549 and MCF-7 MCTSs, whereas the iron content of the MCTSs were quantified using the ferrozine assay. The synergistic impact of intracellular NO- and CA-NHDs and X-ray irradiation on the growth dynamics of the A549 and MCF-7 MCTSs was surveyed by monitoring their temporal evolution under a light microscope over a period of 14 days. The emergence of hypoxia during the spheroid growth was followed by detecting the lactate efflux of MCTSs without and with NO- and CA-NHDs. The performance of the NO- and CA-NHDs as X-ray dose-enhancing agents in the A549 and MCF-7 MCTSs was clarified by performing clonogenic cell survival assays and determining the respective dose-modifying factors for X-ray doses of 0, 2, 4, and 6 Gy. The NO- and CA-NHDs were shown to perform as potent X-ray dose-enhancing agents in A549 and MCF-7 MCTSs. Moreover, the CA-NHDs boosted their radio-sensitizing efficacy by inhibiting the lactate efflux as impairing metabolic reprogramming. A synergistic effect on the MCTS destruction was observed for the combination of both NHDs since the surfactants differ in their antitumor effect.

Analysis of physical dose enhancement in nano-scale for nanoparticle-based radiation therapy: a Cluster and endothelial cell model

Objective(s): One major difficulty of conventional radiotherapy is the lack of selectivity between the tumor and the organs at risk. In nanoparticle aided radiotherapy, heavy elements are present at higher concentrations in the tumor than normal tissues. This study aimed to model the characteristics of secondary electrons generated from the interaction of clusters comprised of five different nanoparticles including Gold, Gadolinium, Iridium, Bismuth, and Hafnium atoms with low energy x-rays (similar to brachytherapy sources in terms of energy) as a function of nanoparticle size and beam energy. Materials and Methods: To better evaluate the contributions of secondary electrons in energy deposition, and also to develop a framework in analyzing further measurements in the future, we attempted to enhance and promote existing mathematical models for energy deposition in endothelial cells by nanoparticle-enhanced radiotherapy. Also, the MCNPX Monte Carlo code was used to model the identical geometry and the dose enhancement factor was calculated for all types of simulated nano-clusters.Results: Our results showed that for our model consist of a nano-cluster and an endothelial cell the DEF significantly depends on the energy of photons and L- and K-edge binding energy of the atoms inside the nano-cluster. However, for Gd at the energy 60 keV, a higher dose enhancement factor was seen.Conclusion: It can be concluded that the mathematical model considers the DEF variation with photon energy and the effect of NP type is considered in DEF calculations. However, the MC method has indicated very high sensitivity to photon energy, and NP type compared to the mathematical method.

Evaluation of dose enhancement with gold nanoparticles in kilovoltage radiotherapy using the new EGS geometry library in Monte Carlo simulation

<abstract><sec> <title>Purpose</title> <p>This study compared the dose enhancement predicted in kilovoltage gold nanoparticle-enhanced radiotherapy using the newly developed EGS lattice and the typical gold-water mixture method in Monte Carlo simulation. This new method considered the gold nanoparticle-added volume consisting of solid nanoparticles instead of a gold-water mixture. In addition, this particle method is more realistic in simulation.</p> </sec><sec> <title>Methods</title> <p>A heterogeneous phantom containing bone and water was irradiated by the 105 and 220 kVp x-ray beams. Gold nanoparticles were added to the tumour volume with concentration varying from 3–40 mg/mL in the phantom. The dose enhancement ratio (DER), defined as the ratio of dose at the tumour with and without adding gold nanoparticles, was calculated by the gold-water mixture and particle method using Monte Carlo simulation for comparison.</p> </sec><sec> <title>Results</title> <p>It is found that the DER was 1.44–4.71 (105 kVp) and 1.27–2.43 (220 kVp) for the gold nanoparticle concentration range of 3–40 mg/mL, when they were calculated by the gold-water mixture method. The DER was slightly larger and equal to 1.47–4.84 (105 kVp) and 1.29–2.5 (220 kVp) for the same concentration range, when the particle method was used. Moreover, the DER predicted by both methods increased with an increase of nanoparticle concentration, and a decrease of x-ray beam energy.</p> </sec><sec> <title>Conclusion</title> <p>The deviation of DER determined by the particle and gold-water mixture method was insignificant when considering the uncertainty in the calculation of DER (2%) in the nanoparticle concentration range of 3–40 mg/mL. It is therefore concluded that the gold-water mixture method could predict the dose enhancement as accurate as the newly developed particle method.</p> </sec></abstract>

Depth Dose Enhancement on Flattening-Filter-Free Photon Beam: A Monte Carlo Study in Nanoparticle-Enhanced Radiotherapy

The aim of this study is to investigate the variations of depth dose enhancement (DDE) on different nanoparticle (NP) variables, when using the flattening-filter-free (FFF) photon beam in nanoparticle-enhanced radiotherapy. Monte Carlo simulation under a macroscopic approach was used to determine the DDE ratio (DDER) with variables of NP material (gold (Au) and iron (III) oxide (Fe2O3)), NP concentration (3–40 mg/mL) and photon beam (10 MV flattening-filter (FF) and 10 MV FFF). It is found that Au NPs had a higher DDER than Fe2O3 NPs, when the depths were shallower than 6 and 8 cm for the 10 MV FF and 10 MV FFF photon beams, respectively. However, in a deeper depth range of 10–20 cm, DDER for the Au NPs was lower than Fe2O3 NPs mainly due to the beam attenuation and photon energy distribution. It is concluded that DDER for the Au NPs and Fe2O3 NPs decreased with an increase of depth in the range of 10–20 cm, with rate of decrease depending on the NP material, NP concentration and the use of FF in the photon beam.

Dose Enhancement for the Flattening-Filter-Free and Flattening-Filter Photon Beams in Nanoparticle-Enhanced Radiotherapy: A Monte Carlo Phantom Study.

Monte Carlo simulations were used to predict the dose enhancement ratio (DER) using the flattening-filter-free (FFF) and flattening-filter (FF) photon beams in prostate nanoparticle-enhanced radiotherapy, with multiple variables such as nanoparticle material, nanoparticle concentration, prostate size, pelvic size, and photon beam energy. A phantom mimicking the patient’s pelvis with various prostate and pelvic sizes was used. Macroscopic Monte Carlo simulation using the EGSnrc code was used to predict the dose at the prostate or target using the 6 MV FFF, 6 MV FF, 10 MV FFF, and 10 MV FF photon beams produced by a Varian TrueBeam linear accelerator (Varian Medical System, Palo Alto, CA, USA). Nanoparticle materials of gold, platinum, iodine, silver, and iron oxide with concentration varying in the range of 3–40 mg/ml were used in simulations. Moreover, the prostate and pelvic size were varied from 2.5 to 5.5 cm and 20 to 30 cm, respectively. The DER was defined as the ratio of the target dose with nanoparticle addition to the target dose without nanoparticle addition in the simulation. From the Monte Carlo results of DER, the best nanoparticle material with the highest DER was gold, based on all the nanoparticle concentrations and photon beams. Smaller prostate size, smaller pelvic size, and a higher nanoparticle concentration showed better DER results. When comparing energies, the 6 MV beams always had the greater enhancement ratio. In addition, the FFF photon beams always had a better DER when compared to the FF beams. It is concluded that gold nanoparticles were the most effective material in nanoparticle-enhanced radiotherapy. Moreover, lower photon beam energy (6 MV), FFF photon beam, higher nanoparticle concentration, smaller pelvic size, and smaller prostate size would all increase the DER in prostate nanoparticle-enhanced radiotherapy.

Contrast Enhancement for Portal Imaging in Nanoparticle-Enhanced Radiotherapy: A Monte Carlo Phantom Evaluation Using Flattening-Filter-Free Photon Beams.

Our team evaluated contrast enhancement for portal imaging using Monte Carlo simulation in nanoparticle-enhanced radiotherapy. Dependencies of percentage contrast enhancement on flattening-filter (FF) and flattening-filter-free (FFF) photon beams were determined by varying the nanoparticle material (gold, platinum, iodine, silver, iron oxide), nanoparticle concentration (3–40 mg/mL) and photon beam energy (6 and 10 MV). Phase-space files and energy spectra of the 6 MV FF, 6 MV FFF, 10 MV FF and 10 MV FFF photon beams were generated based on a Varian TrueBeam linear accelerator. We found that gold and platinum nanoparticles (NP) produced the highest contrast enhancement for portal imaging, compared to other NP with lower atomic numbers. The maximum percentage contrast enhancements for the gold and platinum NP were 18.9% and 18.5% with a concentration equal to 40 mg/mL. The contrast enhancement was also found to increase with the nanoparticle concentration. The maximum rate of increase of contrast enhancement for the gold NP was equal to 0.29%/mg/mL. Using the 6 MV photon beams, the maximum contrast enhancements for the gold NP were 79% (FF) and 78% (FFF) higher than those using the 10 MV beams. For the FFF beams, the maximum contrast enhancements for the gold NP were 53.6% (6 MV) and 53.8% (10 MV) higher than those using the FF beams. It is concluded that contrast enhancement for portal imaging can be increased when a higher atomic number of NP, higher nanoparticle concentration, lower photon beam energy and no flattening filter of photon beam are used in nanoparticle-enhanced radiotherapy.

Recommendations for clinical translation of nanoparticle-enhanced radiotherapy.

A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative's recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

Monte Carlo Simulation on the Imaging Contrast Enhancement in Nanoparticle-enhanced Radiotherapy.

This study focused on the imaging in radiotherapy by finding the relationship between the imaging contrast ratio and appropriate gold, iodine, iron oxide, silver, and platinum nanoparticle concentrations; the relationship between the imaging contrast ratio and different beam energies for the different nanoparticle concentrations; the relationship between the contrast ratio and various beam energies for gold nanoparticles; and the relationship between the contrast ratio and different thicknesses of the incident layer of the phantom including variety of gold nanoparticles (GNPs) concentration. Monte Carlo simulation was used to model the gold, iodine, iron oxide, silver, and platinum nanoparticle concentration which were infused within a heterogeneous phantom (50 cm × 50 cm × 10.5 cm) choosing different concentrations (3, 7, 18, 30, and 40 mg), and beams (100, 120, 130, and 140 kVp) correspondingly that were delivered into the phantom. The results showed obvious connection between the high concentration and having a high imaging contrast ratio, low energy and a high contrast ratio, small thickness, and a high contrast ratio. The superior nanoparticle obtained was GNP, the better concentration was 40 mg, the better beam energy was 100 kVp, and the better thickness was 0.5 cm. It is concluded that our study successfully proved that medical imaging contrast could be improved by increasing the contrast ratio using GNP as the finest choice to accomplish this improvement considering a high concentration, low beam energy, and a small thickness.