Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

Alpha-emitter Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has become mainstream therapy of metastatic neuroendocrine tumors not controlled by somatostatin analog therapy. Currently, beta particle-emitting radiopharmaceuticals are the mainstay of PRRT. Alpha particle-emitting radiopharmaceuticals have a theoretic advantage over beta emitters in terms of improved therapeutic efficacy due to higher cancer cell death and lower nontarget tissue radiation-induced adverse events due to shorter path length of alpha particles. We discuss the available evidence for and the role of alpha particle PRRT.

Physics and small-scale dosimetry of α $\alpha$ -emitters for targeted radionuclide therapy: The case of 211 At $

BACKGROUND: Monte Carlo simulations have been considered for a long time the gold standard for dose calculations in conventional radiotherapy and are currently being applied for the same purpose in innovative radiotherapy techniques such as targeted radionuclide therapy (TRT). PURPOSE: We present in this work a benchmarking study of the latest version of the Transport d'Ions Lourds Dans l'Aqua & Vivo (TILDA-V ) Monte Carlo track structure code, highlighting its capabilities for describing the full slowing down of α $\alpha$ -particles in water and the energy deposited in cells by α $\alpha$ -emitters in the context of TRT. METHODS: We performed radiation transport simulations of α $\alpha$ -particles (10 keV u - 1 ${\rm u}^{-1}$ -100 MeV u - 1 ${\rm u}^{-1}$ ) in water with TILDA-V and the Particle and Heavy Ion Transport code System (PHITS) version 3.33. We compared the predictions of each code in terms of track parameters (stopping power, range and radial dose profiles) and cellular S-values of the promising radionuclide astatine-211 ( 211 At $^{211}{\rm At}$ ). Additional comparisons were made with available data in the literature. RESULTS: The stopping power, range and radial dose profiles of α $\alpha$ -particles computed with TILDA-V were in excellent agreement with other calculations and available data. Overall, minor differences with PHITS were ascribed to phase effects, that is, related to the use of interaction cross sections computed for water vapor or liquid water. However, important discrepancies were observed in the radial dose profiles of monoenergetic α $\alpha$ -particles, for which PHITS results showed a large underestimation of the absorbed dose compared to other codes and experimental data. The cellular S-values of 211 At $^{211}{\rm At}$ computed with TILDA-V  agreed within 4% with the values predicted by PHITS and MIRDcell. CONCLUSIONS: The validation of the TILDA-V code presented in this work opens the possibility to use it as an accurate simulation tool for investigating the interaction of α $\alpha$ -particles in biological media down to the nanometer scale in the context of medical research. The code may help nuclear medicine physicians in their choice of α $\alpha$ -emitters for TRT. Further research will focus on the application of TILDA-V for quantifying radioinduced damage on the deoxyribonucleic acid (DNA) molecule.

Radium deposition in human brain tissue: A Geant4-DNA Monte Carlo toolkit study.

NASA has encouraged studies on 226Ra deposition in the human brain to investigate the effects of exposure to alpha particles with high linear energy transfer, which could mimic some of the exposure astronauts face during space travel. However, this approach was criticized, noting that radium is a bone-seeker and accumulates in the skull, which means that the radiation dose from alpha particles emitted by 226Ra would be heavily concentrated in areas close to cranial bones rather than uniformly distributed throughout the brain. In the high background radiation areas of Ramsar, Iran, extremely high levels of 226Ra in soil contribute to a large proportion of the inhabitants' radiation exposure. A prospective study on Ramsar residents with a calcium-rich diet was conducted to improve the dose uniformity due to 226Ra throughout the cerebral and cerebellar parenchyma. The study found that exposure of the human brain to alpha particles did not significantly affect working memory but was significantly associated with increased reaction times. This finding is crucial because astronauts on deep space missions may face similar cognitive impairments due to exposure to high charge and energy particles. The current study was aimed to evaluate the validity of the terrestrial model using the Geant4 Monte Carlo toolkit to simulate the interactions of alpha particles and representative cosmic ray particles, acknowledging that these radiation types are only a subset of the complete space radiation environment.

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

BACKGROUND: 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. PURPOSE: 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. METHODS: 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 equations on 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-L model. RESULTS: 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 2 mm can vary by over a factor of 3. CONCLUSIONS: 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-L model.

Development of local-power-free, remote α-particle detection using optical fibers.

We demonstrate the application of fluorescence optical fiber coupled to a telecom grade fiber as a sensor for alpha particles using alpha-specific ZnS(Ag) scintillation materials whose wavelength is down-shifted into a low-loss region of the telecom grade fiber transmission band. Telecom-grade fiber optics offer a solution for sensing alpha radiation in deep repositories and cask storage for radioactive materials due to the stability of SiO2 under normal environmental conditions and its relative radiation hardness at low radiation doses. Long-term nuclear waste storage facilities require sensors for the detection of leakage of radioactive materials that are maintenance-free, do not require power and can survive with no 'wear out' mechanisms for decades. By accomplishing the wavelength transformation, we maximize efficiencies in the detection of α-particles and signal transport and can detect alpha scintillation at distances on the order of >1 km with a sensor that is ~3% efficient and can be easily scaled as a sensor array. This paper describes the construction and testing of the sensor including manufacture of the controlled thickness films, verification of the wavelength shift from 450 to 620 nm and optimization of the sensitivity as a function of thickness. We also model the relative sensitivity of the film as a function of film thickness, and we demonstrate a signal-to-noise ratio of 10 at a range of greater than 1 km.

A comparative study of EM-CCD and CMOS cameras for particle ion trajectory imaging.

High-resolution and real-time imaging of particle ion trajectories is essential in nuclear medicine and nuclear engineering. One potential method to achieve high-resolution real-time trajectory imaging of particle ions involves utilizing an imaging system that integrates a scintillator plate with a magnifying unit and a cooled electron multiplying charge-coupled device (EM-CCD) camera. However, acquiring an EM-CCD camera might prove challenging due to the discontinuation of CCD sensor manufacturing by vendors. As an alternative imaging approach, a low-noise, high-sensitivity camera utilizing a cooled complementary metal-oxide-semiconductor (CMOS) sensor offers a promising solution for imaging particle ion trajectories. Yet, it remains uncertain whether CMOS-based cameras can perform as effectively as CCD-based cameras in capturing particle ion trajectories. To address these concerns, we conducted a comparative analysis of the imaging performance between a CMOS-based system and an EM-CCD-based system for capturing alpha particle trajectories. The results revealed that both systems could image the trajectories of alpha particle, but the spatial resolution with the CMOS-based camera exceeded that of the EM-CCD-based camera, primarily due to the smaller pixel size of the sensor. While the signal-to-noise ratio (SNR) of the trajectory image from the CMOS-based camera initially lagged behind that from the EM-CCD-based camera, this disparity was mitigated by implementing binning techniques on the CMOS-based camera images. In conclusion, our findings suggest that a cooled CMOS camera could serve as a viable alternative for imaging particle ion trajectories.

Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.

Profound DNA methylomic differences between single- and multi-fraction alpha irradiations of lung fibroblasts.

BACKGROUND: Alpha (α)-radiation is a ubiquitous environmental agent with epigenotoxic effects. Human exposure to α-radiation at potentially harmful levels can occur repetitively over the long term via inhalation of naturally occurring radon gas that accumulates in enclosed spaces, or as a result of a single exposure from a nuclear accident. Alterations in epigenetic DNA methylation (DNAm) have been implicated in normal aging and cancer pathogenesis. Nevertheless, the effects of aberrations in the methylome of human lung cells following exposure to single or multiple α-irradiation events on these processes remain unexplored. RESULTS: We performed genome-wide DNAm profiling of human embryonic lung fibroblasts from control and irradiated cells using americium-241 α-sources. Cells were α-irradiated in quadruplicates to seven doses using two exposure regimens, a single-fraction (SF) where the total dose was given at once, and a multi-fraction (MF) method, where the total dose was equally distributed over 14 consecutive days. Our results revealed that SF irradiations were prone to a decrease in DNAm levels, while MF irradiations mostly increased DNAm. The analysis also showed that the gene body (i.e., exons and introns) was the region most altered by both the SF hypomethylation and the MF hypermethylation. Additionally, the MF irradiations induced the highest number of differentially methylated regions in genes associated with DNAm biomarkers of aging, carcinogenesis, and cardiovascular disease. The DNAm profile of the oncogenes and tumor suppressor genes suggests that the fibroblasts manifested a defensive response to the MF α-irradiation. Key DNAm events of ionizing radiation exposure, including changes in methylation levels in mitochondria dysfunction-related genes, were mainly identified in the MF groups. However, these alterations were under-represented, indicating that the mitochondria undergo adaptive mechanisms, aside from DNAm, in response to radiation-induced oxidative stress. CONCLUSIONS: We identified a contrasting methylomic profile in the lung fibroblasts α-irradiated to SF compared with MF exposures. These findings demonstrate that the methylome response of the lung cells to α-radiation is highly dependent on both the total dose and the exposure regimen. They also provide novel insights into potential biomarkers of α-radiation, which may contribute to the development of innovative approaches to detect, prevent, and treat α-particle-related diseases.

Measurement of the intensities of the long-range alpha particles from 212Po.

212Bi partially decays by ß- populating excited levels of 212Po. Some of these excited states of 212Po decay with very low probability by direct alpha-particle emissions instead of a gamma-alpha cascade. This effect was known since the earliest times after the discovery of radioactivity. Emission energies of these long-range alpha particles were measured in the past, but the activity ratios were not accurately determined. Relative intensities for these decays have now been experimentally determined. Results agree with data previously reported. It is the first time that an uncertainty estimate is provided for such experiment.

Experimental Setups for In Vitro Studies on Radon Exposure in Mammalian Cells-A Critical Overview.

Naturally occurring radon and its short lived progeny are the second leading cause of lung cancer after smoking, and the main risk factor for non-smokers. The radon progeny, mainly Polonium-218 (218Po) and Polonium-214 (214Po), are responsible for the highest dose deposition in the bronchial epithelium via alpha-decay. These alpha-particles release a large amount of energy over a short penetration range, which results in severe and complex DNA damage. In order to unravel the underlying biological mechanisms which are triggered by this complex DNA damage and eventually give rise to carcinogenesis, in vitro radiobiology experiments on mammalian cells have been performed using radon exposure setups, or radon analogues, which mimic alpha-particle exposure. This review provides an overview of the different experimental setups, which have been developed and used over the past decades for in vitro radon experiments. In order to guarantee reliable results, the design and dosimetry of these setups require careful consideration, which will be emphasized in this work. Results of these in vitro experiments, particularly on bronchial epithelial cells, can provide valuable information on biomarkers, which can assist to identify exposures, as well as to study the effects of localized high dose depositions and the heterogeneous dose distribution of radon.

Radiation Response of Large-Area 4H-SiC Schottky Barrier Diodes.

We report on the effects of large-area 4H-SiC Schottky barrier diodes on the radiation response to ionizing particles. Two different diode areas were compared: 1 mm × 1 mm and 5 mm × 5 mm. 6LiF and 10B4C films, which were placed on top of the diodes, were used as thermal neutron converters. We achieved a thermal neutron efficiency of 5.02% with a 6LiF thermal neutron converter, which is one of the highest efficiencies reported to date. In addition, a temperature-dependent radiation response to alpha particles was presented. Neutron irradiations were performed in a JSI TRIGA dry chamber and an Am-241 wide-area alpha source was used for testing the alpha response of the 4H-SiC Schottky barrier diodes.

Review of current status of targeted alpha therapy in cancer treatment.

Targeted alpha therapy is an emerging alternative for palliative therapy of a wide range of tumor types. Data from preclinicaland clinical research demonstrates a high potential for the selective killing of tumor cells and minimal toxicity to surroundinghealthy tissues. This article summarizes the developmental stages of alpha-targeted therapy from benchtop to commercialization.It discusses fundamental properties, production pathways, microdosimetry, and possible targeting vectors. Proper coverage hasalso been given to comparing it with other standard treatment procedures while exploring clinical applications of alpha emitters.In the end, like other therapies, the challenges it faces and its future impact on personalized medicine are also illustrated.

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts.

Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with 177lutetium (177Lu)-PSMA-617 represented a pivotal step forward and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include 177Lu, 131iodide (131I), and 67copper (67Cu). Targeted alpha emitters potentially include 225actinium (225Ac), 227thorium (227Th), and 212lead (212Pb). Phase III trials are underway with both 177Lu-PSMA-617 and 177Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with 225Ac-J591 but additional data are need to launch a phase III. Data are promising with 225Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.

Impact of the redox environment on propagation of radiation bystander effects: The modulating effect of oxidative metabolism and oxygen partial pressure.

Redox modulated pathways play important roles in out-of-field effects of ionizing radiation. We investigated how the redox environment impacts the magnitude of propagation of stressful effects from irradiated to bystander cells. Normal human fibroblasts that have incorporated [3H]-thymidine were intimately co-cultured with bystander cells in a strategy that allowed isolation of bystander cells with high purity. The antioxidant glutathione peroxidase (GPX) was maintained either at wild-type conditions or overexpressed in the bystanders. Following 24 h of coculture, levels of stress-responsive p21Waf1, p-Hdm2, and connexin43 proteins were increased in bystander cells expressing wild-type GPX relative to respective controls. These levels were significantly attenuated when GPX was ectopically overexpressed, demonstrating by direct approach the involvement of a regulator of intracellular redox homeostasis. Evidence of participation of pro-oxidant compounds was generated by exposing confluent cell cultures to low fluences of 3.7 MeV α particles in presence or absence of t-butyl hydroperoxide. By 3 h post-exposure to fluences wherein only ∼2% of cells are traversed through the nucleus by a particle track, increases in chromosomal damage were greater than expected in absence of the drug (p < 0.001) and further enhanced in its presence (p < 0.05). While maintenance and irradiation of cell cultures at low oxygen pressure (pO2 3.8 mm Hg) to mimic in vivo still supported the participation of bystander cells in responses assessed by chromosomal damage and stress-responsive protein levels (p < 0.001), the effects were attenuated compared to ambient pO2 (155 mm Hg) (p < 0.05). Together, the results show that bystander effects are attenuated at below ambient pO2 and when metabolic oxidative stress is reduced but increased when the basal redox environment tilts towards oxidizing conditions. They are consistent with bystander effects being independent of radiation dose rate.

Optimisation of radioligand therapy in neuroendocrine tumours: Current and evolving evidence.

Treatment of neuroendocrine tumours (NETs) with radioligand therapy (RLT) for example, 177 Lu-DOTATATE is generally well-tolerated and prolongs time to progression in most patients. However, approximately 20% of patients are nonresponders. In addition, complete responses are rare (<5% of patients), and durable responses beyond 3-4 years are uncommon. This article will discuss factors which may improve the outcomes of PRRT by using biomarkers to identify patients at high risk to be nonresponders (imaging and liquid biomarkers) and will examine mechanisms to potentially improve/optimise current RLT treatment strategies. These include mechanisms to potentiate the effects of RLT, increase tumour absorbed dose, overcoming radio-resistance and upregulation of somatostatin receptors, although larger studies will be required to demonstrate which techniques are going to be most efficacious in clinical practice.

Dosimetry in Radiopharmaceutical Therapy.

The application of radiopharmaceutical therapy for the treatment of certain diseases is well established, and the field is expanding. New therapeutic radiopharmaceuticals have been developed in recent years, and more are in the research pipeline. Concurrently, there is growing interest in the use of internal dosimetry as a means of personalizing, and potentially optimizing, such therapy for patients. Internal dosimetry is multifaceted, and the current state of the art is discussed in this continuing education article. Topics include the context of dosimetry, internal dosimetry methods, the advantages and disadvantages of incorporating dosimetry calculations in radiopharmaceutical therapy, a description of the workflow for implementing patient-specific dosimetry, and future prospects in the field.

Exosome secretion and cellular response of DU145 and PC3 after exposure to alpha radiation.

Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival. Studies investigating exosomes isolated from cells exposed to photon radiation commonly used in conventional radiotherapy demonstrate the influence of this type of radiation on exosome characteristics and secretion. There is currently no research investigating the effects of densely ionizing particles such as protons and alpha radiation on exosomes. Thus we have evaluated the cellular response of human prostate cancer cells exposed to 0, 2, and 6 Gy of alpha radiation emitted from the Am-241 source. Irradiated PC3 and DU145 cell lines, characterized by differences in radiosensitivity, were studied using apoptosis, LDH, and IL-6 assays. Additionally, the corresponding concentration and size of isolated exosomes were measured using NTA. We found that exposure to ionizing radiation resulted in gross changes in viability and cell damage. There were increased amounts of apoptotic or necrotic cells as a function of radiation dose. We demonstrated that irradiated PC3 cells secrete higher quantities of exosomes compared to DU145 cells. Additionally, we also found no statistical difference in exosome size for control and irradiated cells.

Radiopharmaceutical Treatments for Cancer Therapy, Radionuclides Characteristics, Applications, and Challenges.

Advances in the field of molecular biology have had an impact on biomedical applications, which provide greater hope for both imaging and therapeutics. Work has been intensified on the development of radionuclides and their application in radiopharmaceuticals (RPS) which will certainly influence and expand therapeutic approaches in the future treatment of patients. Alpha or beta particles and Auger electrons are used for therapy purposes, and each has advantages and disadvantages. The radionuclides labeled drug delivery system will deliver the particles to the specific targeting cell. Different radioligands can be chosen to uniquely target molecular receptors or intracellular components, making them suitable for personal patient-tailored therapy in modern cancer therapy management. Advances in nanotechnology have enabled nanoparticle drug delivery systems that can allow for specific multivalent attachment of targeted molecules of antibodies, peptides, or ligands to the surface of nanoparticles for therapy and imaging purposes. This review presents fundamental radionuclide properties with particular reference to tumor biology and receptor characteristic of radiopharmaceutical targeted therapy development.

Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe.

Introduction: Radium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level. Methods: We evaluated the effects of 223Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics. Results: 223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe. Conclusions: These results suggest that 223Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization.