Energy Beta Particles Research Articles

Demonstration and aging test of a radiation resistant strontium-90 betavoltaic mechanism

In this work, a betavoltaic combined with photovoltaic mechanism using strontium-90 as a radioactive source was built up. A transparent yttrium aluminum garnet ceramic doped with a cerium ion is used as an intermediate conversion layer to avoid direct irradiation to a semiconductor conversion device and translates most of the high energy beta particles into photons. The traditional crystalline silicon conversion device with an N+PP+ junction structure functions as a betavoltaic and photovoltaic conversion device simultaneously. Radiation resistance is demonstrated by a 0.9 MeV electron beam irradiation aging experiment. In the optimized betavoltaic setup with a 0.5 mm transparent yttrium aluminum garnet ceramic, the crystalline silicon conversion device can bear 5 × 1015 e/cm2 by degrading output power less than 15%. Loaded with 1.3 mCi strontium-90, this betavoltaic setup produces a short circuit current of 282 nA, an open circuit voltage of 0.168 V, a fill factor of 0.58, and a total conversion efficiency of 0.32%.

Monte Carlo simulation of the bremsstrahlung X-rays emitted from H-3 and C-14 for the in-vivo imaging of small animals

For the imaging using low energy pure beta-emitting radionuclides, autoradiography is used by slicing the subjects because the range of beta particles is short and thought to be impossible to detect beta particles from outside the subjects. Contrary to this scientific consensus, we recently found that the distributions of C-14 could be measured by detecting the bremsstrahlung X-rays emitted from the solution of C-14 and may also be applicable to lower energy pure beta-emitting radionuclide, H-3. Although the detection of bremsstrahlung X-rays emitted from H-3 and C-14 may be a possible method for in-vivo imaging of small animals, the absorption of the bremsstrahlung X-rays in the subjects are significant because the energy of bremsstrahlung X-rays is relatively low. In addition, the generations of bremsstrahlung X-rays are lower for low energy beta particles. They may make the in-vivo imaging of these beta radionuclides difficult. To clarify these points for the in-vivo imaging of bremsstrahlung X-rays emitted from H-3 and C-14, we used Monte Carlo simulation to calculate the numbers of counts and the energy spectra of the bremsstrahlung X-rays emitted from H-3 and C-14 in water. The simulation results showed that the fraction of detected bremsstrahlung X-rays by a 4 cm × 4 cm detector in all emitted beta particles was 3.5 × 10−6 at 0.1 mm from the source. Thus, with a 10 M Bq of H-3, we will detect ~35 cps at 0.1 mm from the source so in-vivo imaging at surface area will be possible. For C-14, the fraction of detected bremsstrahlung X-rays by the detector without and with collimator were 7.0 × 10−5 and 1.1 × 10−6 at 10 mm from the source, respectively. Thus, with a 10 M Bq of C-14, we will detect ~700 cps and ~11 cps at 10 mm from the source without and with collimator, respectively. The count rate without collimator is easy to form an image in a short time using a low energy X-ray detector. With collimator, in-vivo imaging of distribution of C-14 will be possible. We conclude that in-vivo imaging of small animals by detecting the bremsstrahlung X-rays emitted from H-3 and C-14 is possible and promising for a new molecular imaging technology.

Liver Radioembolization: a New Chapter in Russian Oncology

Recent years have seen an increase in the number of patients with malignant tumours of the liver. In this context, new treatment methods are being actively introduced into practice, one of which is liver radioembolization utilizing microspheres embedded with yttrium-90 (90Y).Aim. To review literature data on the history of radioembolization and its application for liver tumours.Key findings. Annually, over 200 thousand patients with inoperable primary liver cancer and over 270 thousand patients with inoperable metastatic liver cancer are registered globally, for whom radioembolization is considered as the most suitable treatment method. 90Y is a pure beta emitter without its own gamma line, which is characterized by a small average particle path in the tissue of 2.5 mm (the maximum level is 11 mm), a maximum beta particle energy of 2.27 MeV (average energy of 0.937 MeV) and a half-life of 64.1 hours. Clinical research into microspheres containing 90Y has been actively conducted since 1977 all over the world. However, it was only in 2004 that the US FDA authorized the clinical use of glass microspheres containing 90Y for the treatment of hepatocellular cancer and liver colorectal cancer metastases. Until recently, radioembolization has not been applied in Russia. In 2018, the joint efforts of the A. Tsyb Medical Radiological Research Centre (MRRC) — branch of the National Medical Research Radiological Centre and BEBIG LLC resulted in the production of Russian microspheres containing yttrium-90, which were subsequently introduced into routine clinical practice. The first liver embolization in Russia using microspheres containing domestic yttrium-90 (BEBIG LLC) to a patient with hepatocellular cancer was carried out by V.V. Kucherov and A.P. Petrosyan at the A. Tsyb RMMC on April, 25 in 2019.Conclusion. The production of microspheres containing 90Y in Russia, as well as a technical improvement of the procedure, will facilitate the introduction of liver radioembolization into the routine management of patients with malignant liver tumours.

Investigation of nickel‐63 radioisotope‐powered GaN betavoltaic nuclear battery

This work describes the theoretical and experimental investigation of an in-house produced 63Ni radioisotope-powered GaN-based direct conversion (betavoltaic) nuclear battery. GaN p-n junction device with 1-mm2 area was fabricated and irradiated by the 63Ni plate source. Short-circuit current and open-circuit voltage of the battery were measured, and current-voltage curves were plotted. The energy stored in battery, maximum power, and efficiency parameters were calculated. Monte Carlo modelling was used to investigate radioisotope's self-absorption effect, the optimization of semiconductor and source thickness, transport, and penetration of beta particles in semiconductor junction. A large fraction of beta particle energy emitted from 63Ni source is absorbed within 1 μm of the semiconductor junction on the basis of the simulation results. Epitaxial growth of GaN was performed using metal-organic chemical vapour deposition (MOCVD) system. Monte Carlo simulation with MCNPX was used to determine optimum 63Ni radioactive film thickness. 63Ni film was electroplated on one face of 1-mm2 copper plate and mounted 1 mm over the semiconductor device. A 63Ni source with an apparent activity of 0.31 mCi produced 0.1 ± 0.001 nA short-circuit current (Isc), 0.65 V ± 0.0022 open-circuit voltage (Voc), and 0.016 nW ± 0.0002 maximum power (Pmax) in the semiconductor device. The filling factor (FF) of the betavoltaic cell was 25%, and the conversion efficiency (ɳ) was 0.05%. Finally, experimental results were compared with theoretical calculations.

PenNuc: Monte Carlo simulation of the decay of radionuclides

The Fortran subroutine package PenNuc that performs Monte Carlo simulation of the decay of radioactive nuclides is described. The adopted nuclear decay characteristics (possible disintegration modes and branching ratios, energies and half-lives of nuclear energy levels, types and energies of emitted particles) are from the nucleide evaluated database ( http://www.nucleide.org/DDEP_WG/DDEPdata.htm) in the specific format PenNuc. The initial energies of electrons and positrons emitted in beta disintegrations are sampled from their continuous spectra by means of the RITA (rational inverse transform with aliasing) algorithm, which is described in the Appendix. Electronic relaxation of the residual ion after electron capture and internal conversion is simulated by using the data and sampling methods of the penelope code system. At each call the subroutines deliver a list of state variables of the particles (photons, electrons, positrons and alphas) emitted in a random decay path of the considered radionuclide down to a metastable level or to the ground state of the daughter nucleus. The distribution package includes a main program that simulates the emission spectrum of a radionuclide and, optionally, produces a list of particles emitted in a prescribed number of decays. Program summaryProgram Title: PenNucProgram Files doi:http://dx.doi.org/10.17632/dy28h8xmkv.1Licensing provisions: CC by NC 3.0Programming language: Fortran 90/95Nature of problem:PenNuc simulates the emission of energetic particles in random decay pathways of radionuclides. The initial state of a particle is described by the following variables: type of particle (photon, electron, positron, or alpha), energy, direction, and emission time relative to the start of the decay. For each decay the program provides a list of initial states of the particles emitted with energies higher than the adopted cutoff ECNUC, which is set to 200 eV in the original source file.Solution method: The nuclear disintegration mode and the subsequent de-excitation of the daughter nucleus are simulated by using decay information from the nucleide evaluated databases. De-excitation of ions produced in electron capture and internal conversion is simulated by using atomic transition data and sampling methods from the Monte Carlo code system penelope [1]. The energy of beta particles is sampled using the RITA (rational inverse transform with aliasing) algorithm, which optimizes both simulation speed and accuracy.Additional comments: Although PenNuc can describe several radionuclides simultaneously, the selection of the active nuclide (appropriate to the characteristics of the radioactive source) must be done in the main program. The subroutines provide the complete set of particles emitted with energies higher than the cutoff ECNUC in each nuclear decay, including x rays and Auger electrons.[1] F. Salvat, penelope-2014: A code System for Monte Carlo Simulation of Electron and Photon Transport, OECD/NEA Data Bank, Issy-les-Moulineaux, France, 2015. Available from http://www.nea.fr/lists/penelope.html.

Experimental production and theoretical assessment of 67Cu via neutron induced reaction

The 67Cu therapeutic radionuclides emitting medium energy beta particle can be used in radioimmunotherapy, imaging, and tracer kinetic studies. In this work, the experimental and theoretical production yield of 67Cu from the natZnO and natZnONPs targets were investigated. The irradiations of targets were done at Tehran Research Reactor for 0.5 h within 1.4 × 1013 n.cm−2.s−1 fast neutron flux. The nuclear codes of MCNPX and TALYS-1.8 were used to calculate the neutron distribution function and the average cross section of this reaction. The achieved results were compared with each other.

Possibility analysis of bremsstrahlung x-ray imaging of C-14 radionuclide using a LaGPS radiation imaging system

The in-vivo imaging of C-14 is thought to be impossible because it is a pure beta-emitting radionuclide and the energy of beta particles is low. However, beta particles emit bremsstrahlung x-rays in subjects that may be imaged from the outside subjects. Thus, we imaged bremsstrahlung x-rays from a C-14 solution using a high resolution Ce-doped (Gd, La)2Si2O7 (LaGPS) radiation imaging system. With a LaGPS radiation imaging system, we conducted bremsstrahlung x-ray imaging from a C-14 solution in a plastic container with 37 MBq radioactivity with and without a parallel hole collimator. Without it, images were obtained with a spatial resolution of ∼1 mm FWHM in less than 1 min of acquisition time. The energy spectrum of the bremsstrahlung x-rays from a C-14 solution showed a broad distribution with an average energy of ∼30 keV. With a parallel hole collimator, images of the C-14 solutions were also possible although the detected counts decreased to 2.4% of those without a collimator. The measured sensitivities of the LaGPS imaging system without and with a collimator for bremsstrahlung x-rays from C-14 solutions in a plastic container were 3.5 × 10−5 and 8.5 × 10−7, respectively. We conclude that the imaging of bremsstrahlung x-rays from C-14 might be a new method for the in-vivo distribution imaging of small animals or plants.

Determination of 18F positron range in PET imaging using Monte Carlo simulation - Geant4 code

Objective: To determine the distribution of the positron range of radionuclide 18F using Monte Carlo Simulation. Method: 18F is widely available for routine clinical use. In this work, we perform a theoretical calculation of the distribution of the 18F positron range using Monte Carlo (MC) simulation. To collect a statistically significant sample of distance values between the beta emitter point and the Line Of Response (LOR), approximately50000 tracks in water were generated and propagated until annihilation. The radial cumulative probability distribution G2 D(δ) as a function of was adjusted and the analytical formulae was obtained. Finding: The maximum, mean and 1D values of the positron range for 18F simulated and propagated in water are calculated and compared with other studies. The application of Monte Carlo simulation for positron range calculation emphasizes the adoption of this calculation for the radionuclide properties and their propagated medium. The calculation results of beta particle energy loss are in good agreement with many studies that dealt with the same matter having the same energy range. The bin size, source shape, simulation code and propagation medium are the main parameters responsible on the slight differences in the positron range calculation results. Application: It is well known from most existing studies that PET resolution blurring is coupled to the positron range and that it is important to take this range into account in the image reconstruction process. In this study, we calculated the positron range of 18F in water, which is not an obvious affect and it is related to the values of Emean and Emax of 18F 0.250 MeV and 0.635MeV, respectively. These values will cause positron particles to propagate in the medium with a range not exceeding 2 mm with an FWHM(px) is 0.16 mm and FWTM(px) is 1.05 mm. Keywords: Geant4 Code, Positron Emission Tomography, Positron Range

Cherenkov luminescence imaging of shallow sources in semitransparent media.

.We experimentally investigated the Cherenkov luminescence imaging (CLI) of the isotopes with different beta particles energies (, , , , and ) in semitransparent biological equivalent media. The main focus of this work is to characterize the CLI when the sources are at the depth comparable with the range of beta particles. The experimental results were compared with Monte Carlo (MC) simulation results to fine tune the simulation parameters to better model the phantom materials. This approach can be applied to estimate the CLI performance for different phantom materials and isotopes. This work also demonstrates some unique properties of high energy beta particles that can be beneficial for CLI, including the possibility to utilize the betas escaped from the object for imaging purposes.

Design Principles of Narrow and Wide Bandgap-Based Betavoltaic Batteries

A Monte Carlo electron transport code PENELOPE was used to analyze beta particle energy deposition in semiconductors for titanium tritide and beryllium tritide. The source thickness was incorporated into the model in order to take into account the self-absorption of beta particles in the source material. Furthermore, an isotropic source was modeled with the full beta energy spectrum of tritium to make the beta particle transport method more realistic. The simulated results for a 0.4- $\mu \text{m}$ -thick titanium tritide source with silicon carbide agreed well with the experimental results. The simulated results obtained for an optimized 2.5- $\mu \text{m}$ -thick beryllium tritide source with silicon carbide was about two times higher than the power for a 0.4- $\mu \text{m}$ -thick titanium tritide source with silicon carbide. An approximately two times higher short-circuit current density was obtained for beryllium tritide with silicon compared to silicon carbide. However, the power output density was about $10\times $ higher for silicon carbide. The width of the depletion region for a p-type dopant concentration of $\textsf {1} \times \textsf {10}^{\textsf {19}}/\textsf {cm}^{\textsf {3}}$ and an n-type dopant concentration of $\textsf {5} \times \textsf {10}^{\textsf {14}}/\textsf {cm}^{\textsf {3}}$ is about 1.4 and $2.5~\mu \text{m}$ in silicon and silicon carbide, respectively. The estimated beta particle penetration depth is about 1.48 ± 0.015 and $\textsf {1.03} \pm \textsf {0.015}~\mu \text{m}$ in silicon and silicon carbide, respectively. This suggests that the proper choice of dopant concentrations will achieve greater energy deposition in the depletion region, which in turn will increase the power output.

Corrigendum to “Beta particle energy spectra shift due to self-attenuation effects in environmental sources” [Nucl. Eng. Technol. 49 (7) 1483–1488

Corrigendum to “Beta particle energy spectra shift due to self-attenuation effects in environmental sources” [Nucl. Eng. Technol. 49 (7) 1483–1488

Development of ultrahigh resolution radiation imaging detector using 1 mm channel size Si-PM array combined with 0.2 mm × 0.2 mm pixelated GAGG plate

For precise distribution measurements of gamma photons or beta particles, high resolution radiation imaging detectors are required. Reducing the size of the photodetectors combined with small pixel scintillators is a possible method to improve the spatial resolution of the scintillator based radiation imaging detectors. In this paper, we used a 1mm channel size silicon photomultiplier (Si-PM) array combined with a small pixel scintillator array and evaluated the performance for gamma photons and beta particles. For the radiation imaging detector, a Si-PM array with 1mm × 1mm channel size arranged in 8 × 8 (Hamamatsu, S13615-1025N-08) was optically coupled to a 0.2 mm × 0.2 mm pixelated GAGG plate. For 662 keV high energy gamma photons, 0.2mm GAGG pixels were clearly resolved in the position histogram. The peak to valley ratio (P/V) of the position histogram was not improved when only photo-peak events were used while it was improved when the events lower energy than the Compton edge was used. We could also resolve the position histograms for both 122 keV and 60 keV gamma photons. For beta particles, although the position histogram showed good separation for relatively low energy beta particles of Ca-45 (245 keV max), separation became worse for higher energy beta particles from Sr-Y-90 (545keV and 2280keV max). The separation of the position histogram for Sr-Y-90 improved when only lower energy events were used. Using 1mm size Si-PM array, high resolution detectors was realized for low energy gamma photons and beta particle but the spatial resolution was decreased for high energy beta particles from Sr-Y-90.

Beta particle transport and its impact on betavoltaic battery modeling

Simulation of beta particle transport from a Ni-63 radioisotope in silicon using the Monte Carlo N-Particle (MCNP) transport code for monoenergetic beta particle average energy, monoenergetic beta particle maximum energy, and the more precise full beta energy spectrum of Ni-63 were demonstrated. The beta particle penetration depth and the shape of the energy deposition varied significantly for different transport approaches. A penetration depth of 2.25±0.25µm with a peak in energy deposition was found when using a monoenergetic beta particle average energy and a depth of 14.25±0.25µm with an exponential decrease in energy deposition was found when using a full beta energy spectrum and a 0° angular variation. For a 90° angular variation, i.e. an isotropic source, the penetration depth was decreased to 12.75±0.25µm and the backscattering coefficient increased to 0.46 with 30.55% of the beta energy escaping when using a full beta energy spectrum. Similarly, for a 0° angular variation and an isotropic source, an overprediction in the short circuit current and open circuit voltage solved by a simplified drift-diffusion model was observed when compared to experimental results from the literature. A good agreement in the results was found when self-absorption and isotope dilution in the source was considered. The self-absorption effect was 15% for a Ni-63 source with an activity of 0.25mCi. This effect increased to about 28.5% for a higher source activity of 1mCi due to an increase in thickness of the Ni-63 source. Source thicknesses of approximately 0.1µm and 0.4µm for these Ni-63 activities predicted about 15% and 28.5% self-absorption in the source, respectively, using MCNP simulations with an isotropic source. The modeling assumptions with different beta particle energy inputs, junction depth of the semiconductor, backscattering of beta particles, an isotropic beta source, and self-absorption of the radioisotope have significant impacts in betavoltaic battery design.

Experimental and Simulation Analysis of Radiation of the Beta Emitting Sources in a Magnetic Field.

Objective:The behavior of beta particles under the magnetic field was investigated both theoretically and experimentally based on the assumption of reducing the damage to the normal tissues created by using magnetic field in radionuclide therapy.Methods:A water-filled spherical medium and a beta particle source was formed by using Geant4 simulation software for the theoretical study. After applying a homogenous magnetic field, the volume of points at which the particles interact with the medium was calculated by determining particle range. The range of beta particles was examined using yttrium-90 source and Gafchromic films for the experimental study. The setup was kept in normal room conditions and in the magnetic resonance imaging device. Then the irradiated films were analyzed by creating isodose curves.Results:With the increase of the magnetic field, the number of hits at the center was increased, but the number of hits at the outer boundaries decreased inversely proportional to the strength of the magnetic field. The change perpendicular to the magnetic field was greater as compared to the change parallel to the magnetic field. The volume of hits of beta particles got smaller with the increase of the magnetic field.Conclusion:When magnetic field is increased, the decrease in the number of interactions at the outer boundaries became more pronounced in the perpendicular direction to the magnetic field. The effect of magnetic field was more apparent for higher energy beta particles than lower energy particles.

Beta particle energy spectra shift due to self-attenuation effects in environmental sources

In order to predict and control the environmental and health impacts of ionising radiation in environmental sources such as groundwater, it is necessary to identify the radionuclides present. Beta-emitting radionuclides are frequently identified by measuring their characteristic energy spectra. The present work shows that self-attenuation effects from volume sources result in a geometry-dependent shift in the characteristic spectra which needs to be taken into account in order to correctly identify the radionuclides present. These effects are shown to be compounded due to the subsequent shift in the photon spectra produced by the detector, in this case an inorganic solid scintillator (CaF2:Eu) monitored using a Silicon Photomultiplier (SiPM). Using tritiated water as an environmentally relevant, and notoriously difficult to monitor case study, analytical predictions for the shift in the energy spectra as a function of depth of source have been derived. These predictions have been validated using Geant4 simulations and experimental results measured using bespoke instrumentation.

In-situ formation of holmium oxide in pores of Mesoporous Carbon Nanoparticles as substrates for neutron-activatable radiotherapeutics

Radionuclide therapy with nano-sized carriers is a very promising approach to treat various types of cancer. The preparation of radioactive nanocarriers can be achieved with minimum handling using a neutron-activation approach. However, the nanocarrier material must possess certain characteristics such as low density, heat-resistance, high metal adsorption, easy surface modification and low toxicity in order to be useful. Mesoporous Carbon Nanoparticles (MCNs) in which holmium oxide is formed in their pores by a wet-impregnation process are investigated as a suitable material for this application. Holmium (165Ho) has a natural abundance of 100% and possesses a large cross-section for capturing thermal neutrons. After irradiation of Ho-containing MCNs in a neutron flux, 166Ho, which emits therapeutic high energy beta particles as well as diagnostic low energy gamma photons that can be imaged externally, is produced. The wet impregnation process (16 w/w% Ho loading) is shown to completely prevent the leaching of radioactive holmium from the MCNs without compromising their structural integrity. In vitro studies showed that the MCNs containing non-radioactive holmium do not exhibit toxicity and the same formulation with radioactive holmium (166Ho) demonstrated a tumoricidal effect. Post-irradiation PEGylation of the MCN surfaces endows dispersibility and biocompatibility.

Application of the Böhm chamber for reference beta dose measurements and the calibration of personal dosimeters

Abstract Thermoluminescent dosimeters (TLDs) currently used in personal and area dosimetry are often utilized to measure doses of ionizing radiation in fields with a more complex structure and therefore they should be calibrated in relation to different radiation types. The results of such calibration presented for UD-813 TLDs allowed for evaluation of their capability in relation to different radiation types like the beta and photon radiation of different energies and neutron radiation generated by the 241Am-Be source. The detector response for 60 keV photons was 10% higher than for the 662 keV gamma radiation of 137Cs. There were also response differences in relation to photon and beta radiation between detectors with an enhanced concentration of lithium 6Li and boron 10B and detectors containing a natural level of these isotopes. Measurements of the reference beta doses were performed with the help of the Böhm chamber. This method is relatively more complicated compared to determining the reference photon and neutron doses and is described thoroughly in this paper. The corrected current measured by the Böhm chamber for the chosen parameters was a linear function for an entire available range of the chamber depths. The percentage of errors related to the evaluated reference beta doses were below 2% despite a rather large number of corrections that should be taken into account. The calibration distances varied from 11 cm to 50 cm. For this range and beta particle energy, the absorption of radiation in the air was negligible and their attenuation had a predominantly geometric character.

Determination of Beta Radiation Dose to the Thyroid Gland from the Ingestion of <sup>131</sup>I by Patients

Total activities due to the ingestion of 131I were evaluated in different compartments of the human body of patients. It has been shown that the 131I activity in urine of patients increases when the 131I uptake decreases which could represent a source of radiation for their relatives when they leave hospitals. A new dosimetric model based on the specific beta-dose concept was developed for evaluating committed equivalent doses to thyroid due to 131I uptake by different age groups of patients. Data obtained are in good agreement with those obtained by using the ICRP model for iodine. Committed equivalent dose to the thyroid gland is influenced by the mass of thyroid, 131I uptake and energy of the emitted beta particles. In addition, 131I uptake was measured by using a gamma camera and committed equivalent doses to the thyroid gland of female patients from the ingestion of 131I for the treatment of hyperthyroidism diseases were evaluated. Data obtained by using our model and the ICRP ingestion dose coefficients are in good agreement with each other.

Beta response of CaSO4:Dy based thermoluminescent dosimeter badge and its angular dependence studies for personnel monitoring applications

Studies on the response of 0.4 mm and 0.8 mm thick Teflon embedded CaSO4:Dy discs are carried out using different beta sources having energy ranging from 0.224 to 3.54 MeV. Angular dependence of the response for 0.4 and 0.8 mm thick thermoluminescence (TL) discs was also studied for 85 Kr and 90 Sr/90 Y beta sources. The ratio of the response of the open disc to that under 1.5 mm thick Perspex filter (DOpen/DPerspex) was estimated for 0.4 and 0.8 mm thick TL discs in the energy range from 0.689 to 3.54 MeV. The evaluation of (DOpen/DPerspex) ratio is necessary as same is used to estimate the energy of beta particles and to apply appropriate correction factor while evaluating beta dose. In addition to above, the optical density and transmission characteristics for 0.4 and 0.8 mm thick Teflon and CaSO4:Dy Teflon embedded discs are also reported.

A Novel Bispecific CD38 Antibody Eradicates Multiple Myeloma in a Mouse Model Following Yttrium-90-DOTA Capture

BACKGROUNDDespite high rates of initial response to immunomodulatory agents and proteasome inhibitors, the vast majority patients living with multiple myeloma (MM) will ultimately die of progressive disease that is a function of persistent MM cell clones. The radiosensitivity of malignant plasma cells is well documented in clinical settings, and we have previously reported the therapeutic efficacy of a streptavidin-biotin (SAB) pretargeted radioimmunotherapy (PRIT) system delivering the β-emitter 90Y to CD38 antigen targets (Green, et al. Cancer Res. 2014). While SAB-PRIT is capable of disease eradication in mouse models, SA immunogenicity and interference by endogenous biotin may complicate clinical translation of these findings into human trials. METHODSTo prospectively address these potential limitations and to further enhance therapeutic efficacy of PRIT, we engineered an anti-human CD38 xanti-chelated radiometal fusion protein (FP) specifically designed to trap second-step radiolabeled ligand (Y-DOTA) using a very high affinity anti-Y-DOTA scFv (C825). The bispecific anti-CD38 FP construct (028Fc-C825) expressed in CHO cells was affinity purified, assessed by gel filtration chromatography and binding specificity to both CD38 and Y-DOTA was confirmed. In vivo experiments showed the absence of toxicity of the bispecific construct at a dose range of 0.14-2.8 nmol per mouse (n=5/group). Biodistribution studies were performed in athymic nude mice (n=5/group) bearing s.c. luciferase transduced NCI-H929Luc human MM xenograft tumors. Animals received 2.8 nmol (420 µg) of either 028-Fc-C825 (anti-CD38 FP) or an irrelevant matched negative control bi-specific FP 2H7-Fc-C825 (anti-CD20 FP) with the same modular IgG-scFv structure (NCI-H929Luc are CD20 negative). The bispecific FP was administered 23 hours prior to a synthetic DOTAY-Dextran clearing agent (CA; 5 µg) and 24 hours prior to administration of trace labeled 90Y-DOTA (2 µg). In therapy studies, athymic nude mice (n=10/group) bearing s.c. NCI-H929Luc human MM xenograft tumors received 2.8 nmol of either 028-Fc-C825 (anti-CD38 FP) or 2H7-Fc-C825 (anti-CD20 FP) 23 hours prior to synthetic DOTAY-Dextran CA and 24 hrs prior to 90Y-DOTA (2 µg; 1200 µCi per mouse). An activity range of 800 µCi to 1200 µCi was previously identified as optimal in a MM xenograft model using the high energy beta particle emitter 90Y (t1/2 = 64 hours) [Green, et al. Cancer Res. 2014]. RESULTSSelective tumor targeting of 90Y ligand to CD38+ xenografts was observed following administration of the bispecific anti-CD38 FP. Blood, tumor and nonspecific organ uptakes of 028-Fc-C825 demonstrated tumor-to-normal organ absorbed ratios that were 15:1; 17:1; 9:1; and 13:1, respectively for blood, lung, liver and kidney; compared to 0.7:1; 1:1; 1:1 and 0.5:1, respectively, in mice pretargeted with 2H7-Fc-C825 (control). The bispecific anti-CD38 FP also resulted in tumor-to-normal organ ratios of absorbed radioactivity that were superior to those measured in animals receiving anti-CD38 SAB-PRIT (OKT10-SA chemical conjugate) in the same study (5:1; 8:1; 5:1 and 2:1 for blood, lung, liver and kidney respectively). In therapy studies, no animal in any group lost >7% of initial body weight and by day 11 anti-CD38 bispecific FP treated animals were 102.4% ± 3.4% of baseline weight. All mice in the control bispecific FP group experienced exponential MM tumor growth and 100% of these control animals required euthanasia within 27 days. All mice pretargeted with 028-Fc-C825 (anti-CD38 bispecific FP) demonstrated tumor response by day 6. After 45 days, 100% of the anti-CD38 bispecific FP treated animals remained alive (Figure A) and objective remissions were observed within 18 days in 100% of the mice treated with 028-Fc-C825 followed by 1200 µCi of 90Y-DOTA, including 90% complete remissions (no detectable tumor in 028Fc-C825 treated mice) compared to tumors that were 2040 ± 1389% of initial tumor volume [p<0.0001, Student's t-test] in untreated control animals by day 12 (Figure B). CONCLUSIONBiodistribution studies demonstrate MM tumor specific targeting after anti-CD38 xanti-chelated radiometal FP with minimal levels of yttrium-90 radioactivity detected in normal organs. Tumor responses are very encouraging in this MM xenograft model and results support clinical evaluation of bispecific anti-CD38 FP PRIT in MM. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.