Diffusing Alpha-emitters Radiation Research Articles

A Comprehensive Review of Diffusing Alpha-Emitters Radiation Therapy (DaRT): From Dosimetry to Its Biological Effectiveness

Diffusing alpha-emitters radiation therapy (DaRT) represents a groundbreaking development in cancer therapy, offering a solution to the limitations of conventional radiation therapy. By deploying <sup>224</sup>Ra embedded seeds, DaRT achieves targeted delivery of high-dose alpha particles directly to tumor sites, showing considerable efficacy in tumor control and minimal damage to adjacent healthy tissues. This comprehensive review analyzes the published literature regarding mechanisms, seed production, dose calculation, measurement, and biological experiments related to DaRT. It includes in-depth discussions on mathematical models, Monte Carlo simulations for dose distribution, real-time <i>in vivo</i> dosimetry developments, and biological experiments both in vitro and <i>in vivo</i>. Clinical trial outcomes are also examined to evaluate the therapy’s effectiveness in various cancer types. DaRT utilizes <sup>224</sup>Ra-labeled seeds, using the decay chain of <sup>224</sup>Ra to deliver alpha particles effectively within a tumor. Several asymptotic diffusion-leakage models were developed to calculate the alpha dose distribution of DaRT. <i>In vivo</i> dosimetry techniques have been developed for real-time monitoring. Biological experiments demonstrated the cytotoxic effects of DaRT across various cancer cells, with varying radiosensitivity. Additionally, the enhanced effects of combined therapy with chemotherapy and immunotherapy were suggested by many <i>in vivo</i> studies. Clinical trials have shown high complete response rate in squamous cell carcinoma, with minimal side effects, suggesting DaRT’s feasibility and safety. DaRT emerges as a highly localized cancer treatment method with minimal side effects compared to traditional radiation therapy. It directly ablates tumors and potentially enhances immune responses, indicating a significant advance in cancer therapy. Future research and ongoing clinical trials will further elucidate its efficacy across different cancer types and in combination with other treatments.

A finite volume approach to dosimetric calculations in diffusing alpha-emitters radiation therapy

Objective.In diffusing alpha-emitters radiation therapy ('Alpha DaRT'), the diffusion-leakage (DL) model is used to determine the spatial distributions of the emitters and the corresponding alpha dose, critical for a successful treatment. This work first introduces a finite volume (FV) approach to develop numerical schemes to simulate the DL model in one, two and three dimensions then presents how variations over realistic ranges of the DL model parameters related to desorption, diffusion and leakage processes affect the alpha dose distribution and the position of the clinically significant alpha particle10Gy isodose. This work also presents the effects of three modeling approximations: two source geometry approximations (solid cylinder instead of hollow, pixelized cross section instead of circular), and one dosimetric approximation (single-source dose superposition instead of multiple-sources direct dose calculation).Approach.The introduced FV approach was used to obtain spatial distributions of the emitters, from which the corresponding alpha dose distributions were calculated under the assumption of a local deposition of the alpha particles' energies. Variation ranges of the DL model parameters were based on previously published data. For each modeling approximation studied, the error and relative error on the alpha dose distribution were calculated and the displacement of the10Gy isodose was evaluated.Main results.Over realistic ranges, the desorption probabilities, diffusion lengths, and leakage probabilities affect the position of the alpha particle10Gy isodose by∼0.1mm,∼1.5mm and∼0.5mm, respectively. The three modeling approximations studied have a negligible effect on the alpha particle10Gy isodose position, with displacements⩽0.01mm.Significance.This work quantitatively evaluates the relative importance of different parameters and approximations in Alpha-DaRT alpha dose calculations based on their impact not only on the dose variation at a given distance from the source but also on the displacement of clinically significant isodoses.

DNA damage response in a 2D-culture model by diffusing alpha-emitters radiation therapy (Alpha-DaRT)

Diffusing alpha-emitters radiation therapy (Alpha-DaRT) is a unique method, in which interstitial sources carrying 224Ra release a chain of short-lived daughter atoms from their surface. Although DNA damage response (DDR) is crucial to inducing cell death after irradiation, how the DDR occurs during Alpha-DaRT treatment has not yet been explored. In this study, we temporo-spatially characterized DDR such as kinetics of DNA double-strand breaks (DSBs) and cell cycle, in two-dimensional (2D) culture conditions qualitatively mimicking Alpha-DaRT treatments, by employing HeLa cells expressing the Fucci cell cycle-visualizing system. The distribution of the alpha-particle pits detected by a plastic nuclear track detector, CR-39, strongly correlated with γH2AX staining, a marker of DSBs, around the 224Ra source, but the area of G2 arrested cells was more widely spread 24 h from the start of the exposure. Thereafter, close time-lapse observation revealed varying cell cycle kinetics, depending on the distance from the source. A medium containing daughter nuclides prepared from 224Ra sources allowed us to estimate the radiation dose after 24 h of exposure, and determine surviving fractions. The present experimental model revealed for the first time temporo-spatial information of DDR occurring around the source in its early stages.

A diffusion-leakage model coupled with dose point kernels (DPK) for dosimetry of diffusing alpha-emitters radiation therapy (DaRT).

Diffusing alpha-emitters radiation therapy (DaRT) is a novel brachytherapy technique that leverages the diffusive flow of 224Ra progeny within the tumor volume over the course of the treatment. Cell killing is achieved by the emitted alpha particles that have a short range in tissue and high linear energy transfer. The current proposed absorbed dose calculation method for DaRT is based on a diffusion-leakage (DL) model that neglects absorbed dose from beta particles. This work aimed to couple the DL model with dose point kernels (DPKs) to account for dose from beta particles as well as to consider the non-local deposition of energy. The DaRT seed was modeled using COMSOL multiphysics and the DL model was implemented to extract the spatial information of the diffusing daughters. Using Monte-Carlo (MC) methods, DPKs were generated for 212Pb, 212Bi, and their progenies since they were considered to be the dominant beta emitters in the 224Ra radioactive decay chain. A convolution operation was performed between the integrated number densities of the diffusing daughters and DPKs to calculate the total absorbed dose over a 30-day treatment period. Both high-diffusion and low-diffusion cases were considered. The calculated DPKs showed non-negligible energy deposition over several millimeters from the source location. An absorbed dose>10Gy was deposited within a 1.8mm radial distance for the low diffusion case and a 2.2mm radial distance for the high diffusion case. When the DPK method was compared with the local energy deposition method that solely considered dose from alpha particles, differences above 1Gy were found within 1.3 and 1.8mm radial distances from the surface of the source for the low diffusion and high diffusion cases, respectively. The proposed method enhances the accuracy of the dose calculation method used for the DaRT technique.

Dose and DNA damage modelling of diffusing alpha-emitters radiation therapy using Geant4

Purpose:Diffusing alpha-emitters radiation therapy (DaRT) is a brachytherapy technique using α-particles to treat solid tumours. The high linear energy transfer (LET) and short range of α-particles make them good candidates for the targeted treatment of cancer. Treatment planning of DaRT requires a good understanding of the dose from α-particles and the other particles released in the 224Ra decay chain. Methods:The Geant4 Monte Carlo toolkit has been used to simulate a DaRT seed to better understand the dose contribution from all particles and simulate the DNA damage due to this treatment. Results:Close to the seed α-particles deliver the majority of dose, however at radial distances greater than 4 mm, the contribution of β-particles is greater. The RBE has been estimated as a function of number of double strand breaks (DSBs) and complex DSBs. A maximum seed spacing of 5.5 mm and 6.5 mm was found to deliver at least 20 Gy RBE weighted dose between the seeds for RBEDSB and RBEcDSB respectively. Conclusions:The DNA damage changes with radial distance from the seed and has been found to become less complex with distance, which is potentially easier for the cell to repair. Close to the seed α-particles contribute the majority of dose, however the contribution from other particles cannot be neglected and may influence the choice of seed spacing.

First measurements of radon-220 diffusion in mice tumors, towards treatment planning in diffusing alpha-emitters radiation therapy.

Diffusing alpha-emitters radiation therapy ("Alpha-DaRT") is a new method for treating solid tumors with alpha particles, relying on the release of the short-lived alpha-emitting daughter atoms of radium-224 from interstitial sources inserted into the tumor. Alpha-DaRT tumor dosimetry is governed by the spread of radium's progeny around the source, as described by an approximate framework called the "diffusion-leakage model". The most important model parameters are the diffusion lengths of radon-220 and lead-212, and their estimation is therefore essential for treatmentplanning. Previous works have provided initial estimates for the dominant diffusion length, by measuring the activity spread inside mice-borne tumors several days after the insertion of an Alpha-DaRT source. The measurements, taken when lead-212 was in secular equilibrium with radium-224, were interpreted as representing the lead-212 diffusion length. The aim of this work is to provide first experimental estimates for the diffusion length of radon-220, using a newmethodology. The diffusion length of radon-220 was estimated from autoradiography measurements of histological sectionstaken from 24 mice-borne subcutaneous tumors of five different types. Unlike previous studies, the source dwell time inside the tumor was limited to 30 min, to prevent the buildup of lead-212. To investigate the contribution of potential non-diffusive processes, experiments were done in two sets: fourteen in vivo tumors, where during the treatment the tumors were still carried by the mice with active blood supply, and 10 ex-vivo tumors, where the tumors were excised before source insertion and kept in a medium at with the sourceinside. The measured diffusion lengths of radon-220, extracted by fitting the recorded activity pattern up to 1.5mm from the source, lie in the range , with no significant difference between the average values measured in in-vivo and ex-vivo tumors: versus . However, in-vivo tumors display an enhanced spread of activity 2-3mm away from the source. This effect is not explained by the current model and is much less pronounced in ex-vivotumors. The average measured radon-220 diffusion lengths in both in-vivo and ex-vivo tumors are consistent with published data on the diffusion length of radon in water and lie close to the upper limit of the previously estimated range of . The observation that close to the source there is no apparent difference between in-vivo and ex-vivo tumors, and the good agreement with the theoretical model in this region suggest that the spread of radon-220 is predominantly diffusive in this region. The departure from the model prediction in in-vivo tumors at large radial distances may hint at potential vascular contribution, which will be the subject of futureworks.

Bronchoscopic deployment and implantation of Diffusing alpha-emitters Radiation Therapy into the lung and mediastinum for treatment of lung cancer: a pre-clinical safety and feasibility study.

Radiotherapy is a standard treatment modality in cancer therapy, particularly for lung cancer. Diffusing alpha-emitters Radiation Therapy sources (hereafter, "Alpha DaRTs") are fixed with Ra-244 (half-life =3.6 days) that releases alpha-emitting atoms into the tumor tissue to an effective range of a few millimeters. The feasibility, usability, and safety of Alpha DaRTs deployment and implantation via bronchoscopy into the lung parenchyma and mediastinum in a big animal model of healthy swine was studied in two phases: (I) inert and (II) active Alpha DaRTs deployment. The Alpha DaRTs were inserted in both individual and cluster patterns based on a predefined plan. Swine health was monitored throughout the study. The usability of bronchoscopic deployment and implantation was evaluated using a user questionnaire. The movement and migration of the Alpha DaRTs were assessed. Necropsy was performed, and lungs were evaluated via gross pathology and histopathology. A total of 158 Alpha DaRTs were inserted successfully in the lung parenchyma and mediastinum of five swine in two phases. It was possible to deliver and place the Alpha DaRTs in clusters of no more than 4 mm distance between the Alpha DaRTs. No adverse event or change in the health and general condition of animals was observed. Hematologic evaluation did not show any clinically significant abnormality related to the Alpha DaRTs. Histopathology demonstrated local mild inflammatory changes, minimal fibrosis, and dystrophic mineralization with giant cells. Minimal movement and no migration of Alpha DaRTs were observed. Bronchoscopic deployment of Alpha DaRTs in the lung parenchyma and mediastinum of the porcine animal is feasible, precise, and safe.

The low-LET radiation contribution to the tumor dose in diffusing alpha-emitters radiation therapy.

Diffusing alpha-emitters Radiation Therapy ("Alpha DaRT") is a new technique that enables the use of alpha particles for the treatment of solid tumors. Alpha DaRT employs interstitial sources carrying a few Ci of Ra below their surface, designed to release a chain of short-lived atoms (progeny of Ra) which emit alpha particles, along with beta, Auger, and conversion electrons, x- and gamma rays. These atoms diffuse around the source and create-primarily through their alpha decays-a lethal high-dose region measuring a few millimeters indiameter. While previous studies focused on the dose from the alpha emissions alone, this work addresses the electron and photon dose contributed by the diffusing atoms and by the atoms remaining on the source surface, for both a single Alpha DaRT source and multi-source lattices. This allows to evaluate the low-LET contribution to the tumor dose and tumor cell survival, and demonstrate the sparing of surrounding healthytissue. The low-LET dose is calculated using the EGSnrc and FLUKA Monte Carlo (MC) codes. We compare the results of a simple line-source approximation with no diffusion to those of a full simulation, which implements a realistic source geometry and the spread of diffusing atoms. We consider two opposite scenarios: one with low diffusion and high Pb leakage, and the other with high diffusion and low leakage. The low-LET dose in source lattices is calculated by superposition of single-source contributions. Its effect on cell survival is estimated with the linear quadratic model in the limit of low doserate. For sources carrying 3 Ci/cm Ra arranged in a hexagonal lattice with 4mm spacing, the minimal low-LET dose between sources is Gy for the two test cases and is dominated by the beta contribution. The low-LET dose drops below 5Gy mm away from the outermost source in the lattice with an effective maximal dose rate of Gy/h. The accuracy of the line-source/no-diffusion approximation is for the total low-LET dose over clinically relevant distances (2-4mm). The low-LET dose reduces tumor cell survival by a factor of . The low-LET dose in Alpha DaRT can be modeled by conventional MC techniques with appropriate leakage corrections to the source activity. For 3 Ci/cm Ra sources, the contribution of the low-LET dose can reduce cell survival inside the tumor by up to two orders of magnitude. The low-LET dose to surrounding healthy tissue is negligible. Increasing source activities by a factor of 5 can bring the low-LET dose itself to therapeutic levels, in addition to the high-LET dose contributed by alpha particles, leading to a "self-boosted" Alpha DaRT configuration, and potentially allowing to increase the latticespacing.

A finite element method for modeling diffusion of alpha-emitting particles in tissue.

Diffusing alpha-emitters Radiation Therapy ("DaRT") is a promising new modality for the treatment of solid tumors. Interstitial sources containing 224 Ra are inserted into the tumor, producing alpha particles via the decay of 224 Ra and its daughters. The alpha particles are able to produce a "kill region" of several mm due to the diffusion of the alpha-emitting atoms. The Diffusion-Leakage (D-L) model has been proposed to describe the movement of the alpha-emitters used in DaRT in tumor tissue. To date, estimating the dose delivered under the D-L model has been accomplished with numerical solutions based on finite difference methods, namely DART1D and DART2D, as well as with asymptotic expressions for the long time limit. The aim of this work is to develop a flexible method of finite elements for solving the D-L model and to validate prior solutions of the D-L model. We develop a two-dimensional finite element solution to the D-L model implemented using the FEniCS software library. Our approach solves the variational formulation of the D-L equationson an unstructured mesh of triangular Lagrangian elements. We calculate the local dose in the mid- and axial planes of the source and validate our results against the one- and two-dimensional solutions obtained using the previously proposed numerical scheme, DART1D and DART2D. We use our model to estimate the change in dose in the source midplane as a function of the physical parameters used in the D-Lmodel. The local dose at the end of a 30 day treatment period estimated by our numerical method differs from DART1D and DART2D by less than 1% in the source midplane and less than 3% along the source axis over clinically relevant distances, with the largest discrepancies in high gradient areas where the Finite Element Method (FEM) mesh has a higher element density. We find that within current experimentally estimated ranges for D-L model parameters, the dose in the source midplane at a distance of 2mm can vary by over a factor of 3. The 2D finite element model reproduces the calculated dose obtained with DART1D and DART2D under the assumptions D-L model. The variation in predicted dose within current experimental ranges for model parameters suggests the necessity of further studies to better determine their statistical distributions. Finally, the FEM model can be used to calculate dose from DaRT in a variety of realistic 2D geometries beyond the D-Lmodel.

193 Application of a Novel Monte Carlo Based Method to Determine the Embedded Distributions of Alpha-Emitters from Their Measured Alpha Spectra in Diffusing Alpha-Emitters Radiation Therapy (DaRT)

193 Application of a Novel Monte Carlo Based Method to Determine the Embedded Distributions of Alpha-Emitters from Their Measured Alpha Spectra in Diffusing Alpha-Emitters Radiation Therapy (DaRT)

In-silico calculations of DNA damage induced by [formula omitted]-particles in the 224Ra DaRT decay chain for a better understanding of the radiobiological effectiveness of this treatment

Diffusing alpha-emitters radiation Therapy (DaRT) is an interstitial brachytherapy technique using 224Ra seeds. For accurate treatment planning a good understanding of the early DNA damage due to α-particles is required. Geant4-DNA was used to calculate the initial DNA damage and radiobiological effectiveness due to α-particles with linear energy transfer (LET) values in the range 57.5–225.9 keV/μm from the 224Ra decay chain. The impact of DNA base pair density on DNA damage has been modelled, as this parameter varies between human cell lines. Results show that the quantity and complexity of DNA damage changes with LET as expected. Indirect damage, due to water radical reactions with the DNA, decreases and becomes less significant at higher LET values as shown in previous studies. As expected, the yield of complex double strand breaks (DSBs), which are harder for a cell to repair, increases approximately linearly with LET. The level of complexity of DSBs and radiobiological effectiveness have been found to increase with LET as expected. The quantity of DNA damage has been shown to increase for increased DNA density in the expected base pair density range of human cells. The change in damage yield as a function of base pair density is largest for higher LET α-particles, an increase of over 50% for individual strand breaks between 62.7 and 127.4 keV/μm. This change in yield shows that the DNA base pair density is an important parameter for modelling DNA damage particularly at higher LET where the DNA damage is greatest and most complex.

Simulation of particle release for Diffusing Alpha-Emitters Radiation Therapy

We used Monte Carlo simulations to study release of 224Ra daughter nuclei from the seed used for Diffusing Alpha-Emitters Radiation Therapy (DART). Calculated desorption probabilities for 216Po (15%) and 212Pb (12%) showed that they make a significant contribution to total release from the seed. We also showed that the dose to tissue from decays inside the 10 mm long seed exceeds 2.9 Gy for initial 224Ra activity of 3 μCi (111 kBq).

Alpha dose modeling in diffusing alpha-emitters radiation therapy-Part I: single-seed calculations in one and two dimensions.

Diffusing alpha-emitters Radiation Therapy ("DaRT") is a new method, presently in clinical trials, which allows treating solid tumors by alpha particles. DaRT relies on interstitial seeds carrying μCi-level 224 Ra activity below their surface, which release a chain of short-lived alpha emitters that spread throughout the tumor volume primarily by diffusion. Alpha dose calculations in DaRT are based on describing the transport of alpha emitting atoms, requiring new modelingtechniques. A previous study introduced a simplified framework, the "Diffusion-Leakage (DL) model", for DaRT alpha dose calculations, and employed it to a point source, as a basic building block of arbitrary configurations of line sources. The aim of this work, which is divided into two parts, is to extend the model to realistic seed geometries (in Part I), and to employ single-seed calculations to study the properties of DaRT seed lattices (Part II). Such calculations can serve as a pragmatic guide for treatment planning in future clinicaltrials. We derive a closed-form asymptotic solution for an infinitely long cylindrical source, and extend it to an approximate time-dependent expression that assumes a uniform temporal profile at all radial distances from the source. We then develop a finite-element one-dimensional numerical scheme for a complete time-dependent solution of this geometry and validate it against the closed-form expressions. Finally, we discuss a two-dimensional axisymmetric scheme for a complete time-dependent solution for a seed of finite diameter and length. Different solutions are compared over the relevant parameter space, providing guidelines on their usability and limitations. We show that approximating the seed as a finite line source comprised of point-like segments significantly underestimates the correct alpha dose, as predicted by the full two-dimensional calculation. The time-dependent one-dimensional solution is shown to coincide to sub-percent-level with the two-dimensional calculation in the seed midplane, and maintains an accuracy of a few percent up to ∼2mm from the seed edge. For actual treatment plans, the full two-dimensional solution should be used to generate dose lookup tables, similarly to the TG-43 format employed in conventional brachytherapy. Given the accuracy of the one-dimensional solution up to ∼2mm from the seed edge it can be used for efficient parametric studies of DaRT seedlattices.

Alpha dose modeling in diffusing alpha-emitters radiation therapy. Part II: Lattice studies.

Diffusing alpha-emitters radiation therapy ("DaRT") is a new method, presently in clinical trials, which allows treating solid tumors by alpha particles. DaRT relies on interstitial seeds carrying μCi-level 224 Ra activity on their surface, which release a chain of short-lived alpha emitters that spread throughout the tumor volume primarily by diffusion. Alpha dose calculations in DaRT are based on describing the transport of alpha emitting atoms, requiring new modelingtechniques. A previous study introduced a simplified framework, the "diffusion-leakage (DL) model," for DaRT alpha dose calculations, and employed it to a point source, as a basic building block of arbitrary configurations of line sources. The aim of this work, which is divided into two parts, is to extend the model to realistic seed geometries (in Part I), and to employ single-seed calculations to study the properties of DaRT seed lattices (Part II). Such calculations can serve as a pragmatic guide for treatment planning in future clinicaltrials. We employ the superposition of single-seed solutions, developed in Part I, to study the alpha dose in DaRT seed lattices and investigate the sensitivity of the required seed activity and spacing to changes in the DL model parameters and to seed placementerrors. We show that the rapid fall-off of the dose, which guarantees sparing healthy tissue already 2-3 mm away from the tumor, strongly favors a hexagonal, rather than square, seed placement pattern. Realistic variations in the seed manufacturing parameters (224 Ra activity and emission rate of its daughters) are shown to have a negligible effect on the required lattice spacing. On the other hand, tumor parameters (i.e., diffusion lengths and 212 Pb leakage probability), as well as seed placement errors, have a significanteffect. In most cases, hexagonal lattice spacing on the scale of ∼3.5-4.5 mm using seeds carrying a few μCi/cm 224 Ra will enable overcoming realistic uncertainties in measured tumor environment parameters, as well as seed placement errors, and result in therapeutically relevant alpha dose levels.

PHSOR10 Presentation Time: 1:15 PM: Dosimetry Comparison Platform for Diffusing Alpha Emitters Radiation Therapy (DaRT) in Focal Prostate Brachytherapy

<h3>Purpose</h3> Dosimetry calculation for diffusing alpha emitters radiation therapy (DaRT) is challenging because it needs to combine both diffusion modelling and radiation transport computation. We have developed a 3D dosimetry platform to compare standard focal Ir-192 HDR and Ra-224 DaRT dosimetry for real prostate focal brachytherapy cases. <h3>Materials and Methods</h3> For DaRT dose calculation, diffusion length data on prostate tumors was based on autoradiography measurements performed 4-5 days post treatment. Leakage probability was inferred from blood and urine measurements from DaRT patients. The MIM Symphony software (MIM Software Inc, Cleveland, OH) was installed for dosimetry calculation for both standard Ir-192 source and DaRT needles (AphaTAU Medical, Jerusalem, Israel) for treatment planning. For testing purposes, the dose calculation was performed on 5 focal prostate brachytherapy cases using the standard focal dosimetry technique. <h3>Results</h3> For DaRT dose calculation, TG-43 parameters were calculated in prostate for permanent implantation of 3 microCi needles: anisotropy function, dose-rate constant, radial-dose function and geometry function. For standard dose calculation, parameters used in MIM Symphony were validated with our clinical Oncentra platform. For 5 patients, standard focal HDR brachytherapy dosimetry calculation was performed retroactively. Prescription doses were 13 or 15 Gy at the PTV. Doses to organs at risk were also evaluated: Urethra D10% (16-91%) and Rectum V75cc (0-0,6 cc), for example. <h3>Conclusions</h3> A 3D dose calculation technique was developed for DaRT based on diffusion modelling and radiation transport. With the use of this technique integrated into the MIM Symphony treatment planning software, we have developed a 3D dosimetry comparison platform for DaRT and standard (HDR or LDR) prostate brachytherapy. The advantage of DaRT for OAR protection can thus be retrospectively studied with this platform on a cohort of prostate patients from our clinic.

Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts.

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.

Diffusing Alpha-Emitters Radiation Therapy Promotes a Proimmunogenic Tumor Microenvironment and Synergizes With Programmed Cell Death Protein 1 Blockade

Diffusing alpha-emitters Radiation Therapy (DaRT) releases alpha-emitting atoms into the tumor microenvironment. The treatment effectively ablates human and mice xenografts and shows 100% response rates in skin or head and neck squamous cell carcinoma patients. DaRT induces specific and systemic antitumor immune activation and synergizes with immune stimulation and modulation in mice. Here, the transcriptional profile activated by DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition by programmed cell death protein 1 (PD-1) blockade were studied. Squamous cell carcinoma tumor- bearing BALB/C mice were treated with DaRT or inert seeds in combination with anti-PD-1 (aPD-1) or IgG control antibody. Sixteen days after seed insertion, tumors and spleens were subjected to immunophenotyping and immunohistochemical staining. Combination of DaRT and aPD-1 was tested for efficacy. Gene expression analysis was performed on mRNA extracted from tumors 7 days after DaRT or inert insertion using Nanostring PanCancer-IO-360 panel, and tumors and spleens were subjected to flow cytometry analysis. DaRT in combination with aPD-1 delayed tumor development, induced CD3 and CD8 lymphocytes infiltration more efficiently than either monotherapy. The combined treatment reduced splenic polymorphonuclear myeloid derived suppressor cells more than aPD-1 therapy or control. Granzyme B release in the tumor was increased only in the combinational treatment and was correlated with T-lymphocyte infiltration. Gene expression and gene set enrichment analysis of mRNA levels 7 days after DaRT insertion indicated that DaRT upregulated apoptosis, p53 signaling, G1/S-related arrest, interferon signaling and myeloid related transcription, while downregulating DNA repair, cell proliferation, and notch-related transcription. Flow cytometry showed that DaRT increased dendritic cells activation and led to changes in MDSCs distribution. DaRT promotes a "hot" tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade induced effector T cell function and improved treatment efficacy. This study provides rationale for investigating DaRT and aPD-1 combination in patients with squamous cell carcinoma.

Carotid endarterectomy accompanied by radium- 224 patch angioplasty- mediated diffusing alpha-emitters radiation therapy (DaRT) for restenosis prevention

Background and Aims : Patch angioplasty in conventional carotid endarterectomy is suggested to reduce the risk of restenosis and recurrent ipsilateral stroke compared with primary closure. Diffusing alpha-emitters radiation therapy (DaRT) is a new treatment modality, which utilizes seeds embedded with a low activity of radium- 224 (224Ra). Each seed continuously emits the short-lived alpha particles, which spread over several mm around it, creating a 'apoptotic region' of high alpha-particle dose.

Characterization of MOSFET Dosimeters for Alpha Particle Therapy

Alpha particle therapy, such as diffusing alpha-emitters radiation therapy (DaRT) and targeted alpha-particle therapy (TAT), exploits the short range and high linear energy transfer (LET) of alpha particles to destroy cancer cells locally with minimal damage to surrounding healthy cells. Dosimetry for DaRT and TAT is challenging, as their radiation sources produce mixed radiation fields of <inline-formula> <tex-math notation="LaTeX">$\alpha $ </tex-math></inline-formula> particles, <inline-formula> <tex-math notation="LaTeX">$\beta $ </tex-math></inline-formula> particles, and <inline-formula> <tex-math notation="LaTeX">$\gamma $ </tex-math></inline-formula> rays. There is currently no dosimeter for real-time <b><i>in vivo</i></b> dosimetry of DaRT or TAT. Metal-oxide-semiconductor field-effect transistors (MOSFETs) have features that are ideal for this scenario. They can be read out in real-time nondestructively, store information permanently, and their sensitivity to radiation can be varied by changing the bias on the gate during irradiation. Moreover, owing to their compactness, MOSFETs can fit into fine-gauge needle applicators, such as those used to carry radioactive seeds into the tumor. This study characterized the response of MOSFETs designed at the Centre for Medical and Radiation Physics, University of Wollongong. Irradiations were performed with a mono-energetic helium ion beam (He^2&#x002B;) of 5.5 MeV and an Americium-241 (²⁴¹Am) source, for MOSFETs with three different gate oxide thicknesses (0.55, 0.68, and 1.0 <inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula>). The results showed that the response was linear with alpha dose up to 25 Gy. Also, it was found that a gate bias of between 15 and 60 V would optimize the sensitivity to alpha particles with energy of 5.5 MeV.

A New Approach for a Safe and Reproducible Seeds Positioning for Diffusing Alpha-Emitters Radiation Therapy of Squamous Cell Skin Cancer: A Feasibility Study.

The purpose of this study is to discuss how to use an external radio-opaque template in the Diffusing Alpha-emitters Radiation Therapy (DaRT) technique's pre-planning and treatment stages. This device would help to determine the proper number of sources for tumour coverage, accounting for subcutaneous invasion and augmenting DaRT safety. The procedure will be carried out in a first phase on a phantom and then applied to a clinical case. A typical DaRT procedure workflow comprises steps like tumour measurements and delineation, source number assessment, and therapy administration. As a first step, an adhesive fiberglass mesh (spaced by 2 mm) tape was applied on the skin of the patient and employed as frame of reference. A physician contoured the lesion and marked the entrance points for the needles with a radio opaque ink marker. According to the radio opaque marks and metabolic uptake the clinical target volume was defined, and with a commercial brachytherapy treatment planning system (TPS) it was possible to simulate and adjust the spatial seeds distribution. After the implant procedure a CT was again performed to check the agreement between simulations and seeds positions. With the procedure described above it was possible to simulate a DaRT procedure on a phantom in order to train physicians and subsequently apply the novel approach on patients, outlining the major issues involved in the technique. The present work innovates and supports DaRT technique for the treatment of cutaneous cancers, improving its efficacy and safety.