Radionuclide Therapy Of Cancer Research Articles

Novel 131-iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform for synergistic sonodynamic/nitric oxide/chemodynamic/radionuclide therapy

Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In −vitro and −vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.

An operational approach for accurate 177Lu and 177mLu activity quantifications to comply with the environmental release criteria: the role of GEANT4 for efficiency curve and True Coincidence Summing effect estimation

The increasing use of 177Lu-labelled agents for targeted radionuclide cancer therapy highlights the radiation protection challenges in the management of radioactive waste due to 177mLu impurities. To ensure safe disposal, compliance with clearance criteria must be verified using calibrated systems, such as Hyper Pure Germanium (HPGe) spectrometers. This work aims to validate a customized GEANT4 model of our HPGe system in Marinelli beaker geometry to propose an operational approach properly quantifying 177Lu and 177mLu in waste samples. The system's efficiency curve was calculated by modelling gamma sources in the energy range of interest and validated by spectra measurements of 177Lu and 99mTc sources. Correction factors accounting for true coincidence summing (TCS) effect were simulated for 177Lu, 177mLu and 99mTc and they were applied to the spectrum measurement of a waste sample model with known activities of 177Lu and 177mLu. Thus, an operational approach for activities quantification was tested comparing the results with the nominal values. No significant differences were observed between simulated and measured efficiency values. TCS correction factors are significant only for 177mLu (1.6 at 112.95 keV and 204.11 keV). Eventually, the proposed framework to quantify 177Lu in a waste sample allowed to estimate the 177Lu and 177mLu component activities within a maximum 16% uncertainty. Results show that the HPGe model could be a powerful resource for a wide range of applications in daily clinical routine and it could be used to build a simple quality assurance program to monitor the detector response constancy in time.

SENTRI: Single-Particle Energy Transducer for Radionuclide Injections for Personalized Targeted Radionuclide Cancer Therapy

IntroductionTargeted radionuclide therapy (TRT), whereby a tumor-targeted molecule is linked to a therapeutic beta- or alpha-emitting radioactive nuclide, is a promising treatment modality for patients with metastatic cancer, delivering radiation systemically. However, patients still progress due to suboptimal dosing, driven by the large patient to patient variability. Therefore, the ability to continuously monitor the real-time dose deposition in tumors and organs at risk (OARs) provides an additional dimension of information during clinical trials that can enable insights into better strategies to personalize TRT. MethodsHere, we present a single beta-particle sensitive dosimeter consisting of a 0.27 mm3 monolithic silicon chiplet, directly implanted into the tumor. To maximize the sensitivity and have enough detection area, minimum size diodes (1 μm2) are arrayed in 64 × 64. Signal amplifiers, buffers, and on chip memories are all integrated in the chip. For verification, PC3-PIP (PSMA+) and PC3-flu (PSMA-) cell lines are injected into the left and right flanks of the mice, respectively. The devices are inserted into each tumor, measure activities at 5 different time points (0-2 hour, 7-9 hour, 12-14 hour, 24-26 hour, and 48-50 hour) post 177Lu-PSMA-617 injections. SPECT/CT scans are used to verify measured data. ResultWith a wide detection range from 0.013 to 8.95 MBq/mL, the system is capable of detecting high tumor uptake, as well as low doses delivered to OARs in real time. The measurement data is highly proportional (R2 > 0.99) to the 177Lu-PSMA-617 activity. The in vivo measurement data agrees well with the SPECT/CT results within acceptable errors (±1.5 %ID/mL). ConclusionGiven the recent advances in clinical use of TRT in prostate cancer, the proposed system is verified in a prostate cancer mouse model using 177Lu-PSMA-617.

Synthesis of 197m/gHg labelled gold nanoparticles for targeted radionuclide therapy

Abstract Meitner-Auger-electron emitters have a promising potential for targeted radionuclide therapy of cancer because of their short range and the high linear energy transfer of Meitner-Auger-electrons (MAE). One promising MAE candidate is 197m/gHg with its half-life of 23.8 h and 64.1 h, respectively, and high MAE yield. Gold nanoparticles (AuNPs) that are labelled with 197m/gHg could be a helpful tool for radiation treatment of glioblastoma multiforme when infused into the surgical cavity after resection to prevent recurrence. To produce such AuNPs, 197m/gHg was embedded into pristine AuNPs. Two different syntheses were tested starting from irradiated gold containing trace amounts of 197m/gHg. When sodium citrate was used as reducing agent, no 197m/gHg labelled AuNPs were formed, but with tannic acid, 197m/gHg labeled AuNPs were produced. The method was optimized by neutralizing the pH (pH = 7) of the Au/197m/gHg solution, which led to labelled AuNPs with a size of 12.3 ± 2.0 nm as measured by transmission electron microscopy. The labelled AuNPs had a concentration of 50 μg (gold)/mL with an activity of 151 ± 93 kBq/mL (197gHg, time corrected to the end of bombardment).

Theranostic Surrogacy of [123I]NaI for Differentiated Thyroid Cancer Radionuclide Therapy.

Precise dosimetry has gained interest for interpreting the response assessments of novel therapeutic radiopharmaceuticals, as well as for improving conventional radiotherapies such as the "one dose fits all" approach. Although radioiodine as same-element isotope theranostic pairs has been used for differentiated thyroid cancer (DTC), there are insufficient studies on the determination of its dosing regimen for personalized medicine and on extrapolating strategies for companion diagnostic radiopharmaceuticals. In this study, DTC xenograft mouse models were generated after validating iodine uptakes via sodium iodine symporter proteins (NIS) through in vitro assays, and theranostic surrogacy of companion radiopharmaceuticals was investigated in terms of single photon emission computed tomography (SPECT) imaging and voxel-level dosimetry. Following a Monte Carlo simulation, the hypothetical energy deposition/dose distribution images were produced as [123I]NaI SPECT scans with the use of 131I ion source simulation, and dose rate curves were used to estimate absorbed dose. For the tumor, a peak concentration of 96.49 ± 11.66% ID/g occurred 2.91 ± 0.42 h after [123I]NaI injection, and absorbed dose for 131I therapy was estimated as 0.0344 ± 0.0088 Gy/MBq. The absorbed dose in target/off-target tissues was estimated by considering subject-specific heterogeneous tissue compositions and activity distributions. Furthermore, a novel approach was proposed for simplifying voxel-level dosimetry and suggested for determining the minimal/optimal scan time points of surrogates for pretherapeutic dosimetry. When two scan time points were set to Tmax and 26 h and the group mean half-lives were applied to the dose rate curves, the most accurate absorbed dose estimates were determined [-22.96, 2.21%]. This study provided an experimental basis to evaluate dose distribution and is expected hopefully to improve the challenging dosimetry process for clinical use.

68Ga]Ga-HBED-CC-FAPI Derivatives with Improved Radiolabeling and Specific Tumor Uptake.

Fibroblast activation protein (FAP) is selectively expressed in tumors and highly important for maintaining the microenvironment in malignant tumors. Radioisotope-labeled FAP inhibitors (FAPIs) were proven to be useful for diagnosis and radionuclide therapy of cancer and are under active clinical investigations. Ga-HBED complex displays a higher in vivo stability constant (log KGaL: 38.5), compared to that of Ga-DOTA (log KGaL: 21.3). Such advantage in stability constant suggests that it may be useful for development of alternative FAPI imaging agents. In this study, previously reported [68Ga]Ga-DOTA-FAPI-02 and -04 were converted to the corresponding [68Ga]Ga-HBED-CC-FAPI-02 and -04 derivatives ([68Ga]Ga-4, [68Ga]Ga-5, [68Ga]Ga-6, and [68Ga]Ga-7). It was found that substituting the DOTA chelating group with HBED-CC led to several unique and desirable tumor-targeting properties: (1) robust, fast, and high yield labeling─readily adaptable to a kit formulation; (2) high stabilities in vitro; (3) excellent FAP binding affinities (IC50 ranging between 4 and 7 nM) and improved cell uptake and retention (in HT1080 (FAP+) cells); and (4) excellent selective in vivo tumor uptake in nude mice bearing U87MG tumor. It appeared that Ga(III) chelation with HBED-CC improved the in vivo kinetics favoring higher tumor uptake and retention compared to the corresponding Ga-DOTA complex. Out of the four tested ligands the new [68Ga]Ga-HBED-CC-FAPI dimer, [68Ga]Ga-6, displayed the best tumor localization properties, and further studies are warranted to demonstrate that it is an alternative FAP imaging agent for cancer patients.

Fundamentals of Rhenium-188 Radiopharmaceutical Chemistry.

The β- emitter, rhenium-188 (188Re), has long been recognized as an attractive candidate for targeted cancer radionuclide therapy (TRNT). This transition metal shares chemical similarities with its congener element technetium, whose nuclear isomer technetium-99m (99mTc) is the current workhorse of diagnostic nuclear medicine. The differences between these two elements have a significant impact on the radiolabelling methods and should always receive critical attention. This review aims to highlight what needs to be considered to design a successful radiopharmaceutical incorporating 118Re. Some of the most effective strategies for preparing therapeutic radiopharmaceuticals with 188Re are illustrated and rationalized using the concept of the inorganic functional group (core) and a simple ligand field theoretical model combined with a qualitative definition of frontiers orbitals. Of special interest are the Re(V) oxo and Re(V) nitrido functional groups. Suitable ligands for binding to these cores are discussed, successful clinical applications are summarized, and a prediction of viable future applications is presented. Rhenium-188 decays through the emission of a high energy beta particle (2.12 MeV max energy) and a half-life of 16.9 h. An ideal biological target would therefore be a high-capacity target site (transporters, potential gradients, tumour microenvironment) with less emphasis on saturable targets such as overexpressed receptors on smaller metastases.

Targeting Copper in Cancer Imaging and Therapy: A New Theragnostic Agent

Copper is required for cancer cell proliferation and tumor angiogenesis. Copper-64 radionuclide (64Cu), a form of copper chloride (64CuCl2), is rapidly emerging as a diagnostic PET/CT tracer in oncology. It may also represent an interesting alternative to gallium-68 (68Ga) as a radionuclide precursor for labelling radiopharmaceuticals used to investigate neuroendocrine tumors and prostate cancer. This emerging interest is also related to the nuclear properties of 64CuCl2 that make it an ideal theragnostic nuclide. Indeed, 64CuCl2 emits β+ and β- particles together with high-linear-energy-transfer Auger electrons, suggesting the therapeutic potential of 64CuCl2 for the radionuclide cancer therapy of copper-avid tumors. Recently, 64CuCl2 was successfully used to image prostate cancer, bladder cancer, glioblastoma multiforme (GBM), and non-small cell lung carcinoma in humans. Copper cancer uptake was related to the expression of human copper transport 1 (hCTR1) on the cancer cell surface. Biodistribution, toxicology and radiation safety studies showed its radiation and toxicology safety. Based on the findings from the preclinical research studies, 64CuCl2 PET/CT also holds potential for the diagnostic imaging of human hepatocellular carcinoma (HCC), malignant melanoma, and the detection of the intracranial metastasis of copper-avid tumors based on the low physiological background of radioactive copper uptake in the brain.

Monte Carlo Code Calculation for the Characterization of 10nm Nano-Layers Coated 50nm 90Y Radionuclide Nanospheres Radiation in the Liver Radionuclide Therapy

Purpose: Cancer radionuclide therapy is an effective, beneficial, and crucial method of cancer treatment that uses unsealed radioactivated radionuclides sources that are attached to a targeting vector to deliver therapeutic radiation doses from the ionizing radiation source to specific disease sites either for curative intent or for disease control and palliation for the patient pain decreasing. For this aim, Monte Carlo N–Particle 5 (MCNP5) MC computational code was employed for simulations and calculations as well as radiation transport.
 Materials and Methods: 50nm 90Y radionuclide nanosphere was modelled coated by a 10nm coating layer with some non-toxic high and low Z materials. Physical interactions, such as β-ray and the simulated coating materials were studied and radiological parameters were scored by the used MC code. Attenuation of β-ray, and production of the bremsstrahlung X-ray photons and other phenomena were simulated by the code and analyzed. MC code estimated the effect of the simulated coating materials, such as Gold, Platinum, Gaddolonium, Silver, and Epoxy-Resin on the radiation characteristics around the modelled nano-radionuclide per 2nm from the radiation source surface to 1µm distance. Produced bremsstrahlung X-ray by the source coating material and tissue atoms, emitted β-particle number, flux over the surfaces (per 2nm), radiation fluence of photon and β- ray, deposited energy per gr of the cell medium, and average dose to the cells around the 500nm and 1µm distance from the radionuclide source surface also was derived.
 Results: Our results showed that coating the radionuclide with the materials especially high Z (Gold and Platinum) materials may produce a dual emitter radiation source, X-ray photon and β- ray and is capable of killing the cancer cells more than the source with not-coated source.
 Conclusion: Our conclusion was that coating the β- ray emitter radionuclides, especially high-energy β- ray, enhances its therapeutical capability with X-ray and β- ray emission. The studied coated sources in our study were performed as a dual radiation source; produced X-ray and β-ray, which increases the therapeutic efficiency of the source.

Recent Advances in Cancer Imaging with 64CuCl2 PET/CT.

Copper is required for cancer cell proliferation and tumor angiogenesis. Radioactive copper-64 chloride (64CuCl2) is a useful radiotracer for cancer imaging with position emission tomography (PET) based on increased cellular uptake of copper mediated by human copper transporter 1 (hCtr1) expressed on cancer cell membrane. Significant progress has been made in research of using 64CuCl2 as a radiotracer for cancer imaging with PET. Radiation dosimetry study in humans demonstrated radiation safety of 64CuCl2. Recently, 64CuCl2 was successfully used for PET imaging of prostate cancer, bladder cancer, glioblastoma multiforme (GBM), and non-small cell lung carcinoma in humans. Based on the findings from the preclinical research studies, 64CuCl2 PET/CT also holds potential for diagnostic imaging of human hepatocellular carcinoma (HCC), malignant melanoma, and detection of intracranial metastasis of copper-avid tumors based on low physiological background of radioactive copper uptake in the brain. Copper-64 radionuclide emits both β+ and β- particles, suggesting therapeutic potential of 64CuCl2 for radionuclide cancer therapy of copper-avid tumors. Recent progress in production of therapeutic copper-67 radionuclide invites clinical research in use of theranostic pair of 64CuCl2 and 67CuCl2 for cancer imaging and radionuclide therapy.

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics.

Rationale: Fibroblast activation protein (FAP) targeted molecular imaging radiotracers have shown promising preclinical and clinical results in tumor diagnosis. However, rapid clearance and inadequate tumor retention of these molecules have hindered them for further clinical translation in cancer therapy. In this study, we aimed to develop a series of albumin binder-truncated Evans blue (EB) modified FAP targeted radiotracers, and optimize the pharmacokinetic (PK) characteristics to overcome the existing limitations in order to apply in the radionuclide therapy of cancer.Methods: A series of compounds with the general structure of EB-FAPI-Bn were synthesized based on a FAP inhibitor (FAPI) variant (FAPI-02) and radiolabeled with 177LuCl3. To verify the binding affinity and FAP targeting specificity of these tracers in vitro, U87MG cell uptake and competition assays were performed. Preclinical PK was evaluated in U87MG tumor-bearing mice using SPECT imaging and biodistribution studies. The lead compound EB-FAPI-B1 was selected and cancer therapeutic efficacy of 177Lu-EB-FAPI-B1 was assessed in U87MG tumor-bearing mice.Results: 177Lu-EB-FAPI-B1, B2, B3, B4 were stable in PBS (pH 7.4) and saline for at least 24 h. EB-FAPI-B1 showed high binding affinity (IC50 = 16.5 nM) to FAP in vitro, which was comparable with that of FAPI-02 (IC50 = 10.9 nM). SPECT imaging and biodistribution studies of 177Lu-EB-FAPI-B1, B2, B3, B4 have proved their prominently improved tumor accumulation and retention at 96 h post-injection, especially for 177Lu-EB-FAPI-B1, high tumor uptake and low background signal make it the optimal compound. Compared to the saline group, noteworthy tumor growth inhibitions of 177Lu-EB-FAPI-B1 have been observed after administration of different dosages.Conclusion: In this study, several EB modified FAPI-02 related radiopharmaceuticals have been synthesized successfully and evaluated. High binding affinity and FAP targeting specificity were identified in vitro and in vivo. Remarkably enhanced tumor uptake and retention of EB-FAPI-B1 were found over the unmodified FAPI-02. 177Lu-EB-FAPI-B1 showed remarkable tumor growth suppression in U87MG tumor model with negligible side effects, indicating that 177Lu-EB-FAPI-B1 is promising for clinical application and transformation.

Towards Radionuclide Cancer Therapy with High Purity 177Lu from Enriched 176Yb Samples

A method was developed to estimate the isotopic compositions of enriched 176Yb sample required for producing radionuclide 177Lu used for cancer therapy, with high radionuclide purity in accelerators.

Аналоги соматостатина, меченные радионуклидами, для терапии онкологических заболеваний. Обзор

Currently, a specific action on tumor cells with minimal toxicity to healthy tissues is the main re-quirement for radionuclide therapy of cancer. The molecular target of selective antitumor therapy is determined by somatostatin receptors (SSTR) overexpression in various tumors and its metas-tases. Natural somatostatin cannot be used as a vector molecule for radionuclide delivery due to its short half-life in blood (1-3 min). Synthetic peptide somatostatin analogs labeled with thera-peutic radionuclides (radiopeptides) also have high affinity to SSTR and better pharmacokinetics compared to somatostatin and therefore they are of great interest for targeted cancer therapy, al-so called peptide-receptor radionuclide therapy (PRRT). The data about the most important to date somatostatin analogs labeled with In-111, Y-90, Lu-177 radionuclides for therapy of tumors over-expressing SSTR is presented. The results of treatment efficacy and toxicity profile of PRRT, which is administered with various generations of targeting SSTR radiopharmaceuticals, includ-ing the randomized controlled trial NETTER-1, is reviewed. In addition, some strategies for opti-mization of PRRT such as tandem therapy, intra-arterial administration of radiopharmaceuticals, their modification for better pharmacokinetic properties, and the development of new compounds containing alfa-emitting radionuclides or SSTR antagonist analogs are discussed.

Multifunctional Cyanine-Based Theranostic Probe for Cancer Imaging and Therapy.

Cancer is one of the leading causes of death in the world. A cancer-targeted multifunctional probe labeled with the radionuclide has been developed to provide multi-modalities for NIR fluorescence and nuclear imaging (PET, SPECT), for photothermal therapy (PTT), and targeted radionuclide therapy of cancer. In this study, synthesis, characterization, in vitro, and in vivo biological evaluation of the cyanine-based probe (DOTA-NIR790) were demonstrated. The use of cyanine dyes for the selective accumulation of cancer cells were used to achieve the characteristics of tumor markers. Therefore, all kinds of organ tumors can be targeted for diagnosis and treatment. The DOTA-NIR790 labeled with lutetium-111 could detect original or metastatic tumors by using SPECT imaging and quantify tumor accumulation. The β-emission of 177Lu-DOTA-NIR790 can be used for targeted radionuclide therapy of tumors. The DOTA-NIR790 enabled imaging by NIR fluorescence and by nuclear imaging (SPECT) to monitor in real-time the tumor accumulation and the situation of cancer therapy, and to guide the surgery or the photothermal therapy of the tumor. The radionuclide-labeled heptamethine cyanine based probe (DOTA-NIR790) offers multifunctional modalities for imaging and therapies of cancer.

Utilization of nanotechnology in targeted radionuclide cancer therapy: monotherapy, combined therapy and radiosensitization

Abstract The rapid progress of nanomedicine field has a great influence on the different tumor therapeutic trends. It achieves a potential targeting of the therapeutic agent to the tumor site with neglectable exposure of the normal tissue. In nuclear medicine, nanocarriers have been employed for targeted delivery of therapeutic radioisotopes to the malignant tissues. This systemic radiotherapy is employed to overcome the external radiation therapy drawbacks. This review overviews studies concerned with investigation of different nanoparticles as promising carriers for targeted radiotherapy. It discusses the employment of different nanovehicles for achievement of the synergistic effect of targeted radiotherapy with other tumor therapeutic modalities such as hyperthermia and photodynamic therapy. Radiosensitization utilizing different nanosensitizer loaded nanoparticles has also been discussed briefly as one of the nanomedicine approach in radiotherapy.

The electron affinity of astatine

One of the most important properties influencing the chemical behavior of an element is the electron affinity (EA). Among the remaining elements with unknown EA is astatine, where one of its isotopes, 211At, is remarkably well suited for targeted radionuclide therapy of cancer. With the At− anion being involved in many aspects of current astatine labeling protocols, the knowledge of the electron affinity of this element is of prime importance. Here we report the measured value of the EA of astatine to be 2.41578(7) eV. This result is compared to state-of-the-art relativistic quantum mechanical calculations that incorporate both the Breit and the quantum electrodynamics (QED) corrections and the electron–electron correlation effects on the highest level that can be currently achieved for many-electron systems. The developed technique of laser-photodetachment spectroscopy of radioisotopes opens the path for future EA measurements of other radioelements such as polonium, and eventually super-heavy elements.

Pharmacokinetic Properties of 68Ga-labelled Folic Acid Conjugates: Improvement Using HEHE Tag.

The folate receptor (FR) is a promising cell membrane-associated target for molecular imaging and radionuclide therapy of cancer (FR-α) and potentially also inflammatory diseases (FR-β) through use of folic acid-based radioconjugate. FR is often overexpressed by cells of epithelial tumors, including tumors of ovary, cervix, endometrium, lungs, kidneys, etc. In healthy tissues, FR can be found in small numbers by the epithelial cells, mainly in the kidneys. Extremely high undesired accumulation of the folate radioconjugates in the renal tissue is a main drawback of FR-targeting concept. In the course of this work, we aimed to reduce the undesirable accumulation of folate radioconjugates in the kidneys by introducing a histidine/glutamic acid tag into their structure. Two folic acid based compounds were synthesized: NODAGA-1,4-butanediamine-folic acid (FA-I, as control) and NODAGA-[Lys-(HE)2]-folic acid (FA-II) which contains a (His-Glu)2 fragment. In vitro studies with FR (+) cells (KB and others) showed that both compounds have specificity for FR. Introduction of (HE)2-tag does not affect FR binding ability of the conjugates. In vivo biodistribution studies with normal laboratory animals, as well as with KB tumor bearing animals, were carried out. The results showed that introduction of the (HE)2 tag into the structure of folate radioconjugates can significantly reduce the accumulation of these compounds in non-target tissues and important organs (the accumulation in the kidneys is reduced 2–4 times), leaving the accumulation in tumor at least at the same level, and even increasing it.

Capabilities of JSC “SSC RIAR” in Producing 227ThCl4

227Th is considered to be one of the promising radionuclides for target radionuclide therapy of cancer. Its advantages are chemical properties which are good for the synthesis of the complexes with chelating agents and emission of five alpha particles with complete decay of one 227Th nucleus. The apparent disadvantage is the presence of 223Ra among daughter products the chemical properties of which are fundamentally different from thorium that can cause its redistribution in the human body. A rather big half-life of 227Th (18.7 days), on the one hand, is good for the preparation production and shipment, and on the other hand, it specifies high-level requirements to the preparation stability in the human body. In addition to using 227Th for radiopharmaceutical synthesis, it can be applied in manufacturing 223Ra generators. While such generators have a rather small period of use, they have a number of advantages over 227Ac/223Ra generators. In particular, there is no need to check every batch for the 227Ac content, and there are no long-lived radioactive wastes. JSC “SSC RIAR” performs experiments to produce trial samples of 227Th by generating from long-lived parent radionuclide 227Ac extracted from the 226Ra targets irradiated during 20-25 days in the SM reactor neutron trap. To separate 227Th and 227, thorium is sorbed on BioRad AG 18 (NO3-) strongly basic anion-exchange resin from 8M HNO3 with further elution using 0.1-0.5 HNO3 or HCl. To produce the preparation of desired radionuclide purity, the purification process must be carried out at least twice. The key challenge in producing 227Th is determination of the 227Ac content. It is not possible to directly determine 227Ac by its own alpha radiation at its activity of less than 1% of the 227Th activity. The yield of alpha radiation in 227Ac decay is only 1.38 %, and its peak in the spectrum is on the low-energy tail of 227Th and its daughter products. 227Th conversion electrons and beta radiation of the daughter products, namely 211Pb and 211Bi, are obstacles in measuring the 227Ac activity by beta radiation. The presentation discusses possible methods to check the content of 227Ac with its preliminary chemical extraction from a preparation aliquot and gives the characteristics of 227Th experimental samples.

Monte Carlo single-cell dosimetry using Geant4-DNA: the effects of cell nucleus displacement and rotation on cellular S values.

Investigation of biological effects of low-dose ionizing radiation at the (sub-) cellular level, which is referred to as microdosimetry, remains a major challenge of today's radiobiology research. Monte Carlo simulation of radiation tracks can provide a detailed description of the physical processes involved in dimensions as small as the critical substructures of the cell. Hereby, in the present study, microdosimetric calculations of cellular S values for mono-energetic electrons and six Auger-emitting radionuclides were performed in single-cell models of liquid water using Geant4-DNA. The effects of displacement and rotation of the nucleus within the cell on the cellular S values were studied in spherical and ellipsoidal geometries. It was found that for the examined electron energies and radionuclides, in the case of nucleus cross-absorption where the radioactivity is either localized in the cytoplasm of the cell or distributed on the cell surface, rotation of the nucleus within the cell affects cellular S values less than displacement of the nucleus. Especially, the considerable differences observed in S(nucleus ← cell surface) values between an eccentric and a concentric cell-nucleus configuration in spherical and ellipsoidal geometries (up to 63% and up to 44%, respectively) suggests that the approximation of concentricity should be used with caution, at least for localized irradiation of the cell membrane by an Auger-emitter in targeted radionuclide cancer therapy. The obtained results, which are based on a more realistic modeling of the cell than was done before, provide more accurate information about nuclear dose. This can be useful for theranostic applications.

Modeling Cell and Tumor-Metastasis Dosimetry with the Particle and Heavy Ion Transport Code System (PHITS) Software for Targeted Alpha-Particle Radionuclide Therapy.

The use of targeted radionuclide therapy for cancer is on the rise. While beta-particle-emitting radionuclides have been extensively explored for targeted radionuclide therapy, alpha-particle-emitting radionuclides are emerging as effective alternatives. In this context, fundamental understanding of the interactions and dosimetry of these emitted particles with cells in the tumor microenvironment is critical to ascertaining the potential of alpha-particle-emitting radionuclides. One important parameter that can be used to assess these metrics is the S-value. In this study, we characterized several alpha-particle-emitting radionuclides (and their associated radionuclide progeny) regarding S-values in the cellular and tumor-metastasis environments. The Particle and Heavy Ion Transport code System (PHITS) was used to obtain S-values via Monte Carlo simulation for cell and tumor metastasis resulting from interactions with the alpha-particle-emitting radionuclides, lead-212 (212Pb), actinium-225 (225Ac) and bismuth-213 (213Bi); these values were compared to the beta-particle-emitting radionuclides yttrium-90 (90Y) and lutetium-177 (177Lu) and an Auger-electron-emitting radionuclide indium-111 (111In). The effect of cellular internalization on S-value was explored at increasing degree of internalization for each radionuclide. This aspect of S-value determination was further explored in a cell line-specific fashion for six different cancer cell lines based on the cell dimensions obtained by confocal microscopy. S-values from PHITS were in good agreement with MIRDcell S-values (cellular S-values) and the values found by Hindié et al. (tumor S-values). In the cellular model, 212Pb and 213Bi decay series produced S-values that were 50- to 120-fold higher than 177Lu, while 225Ac decay series analysis suggested S-values that were 240- to 520-fold higher than 177Lu. S-values arising with 100% cellular internalization were two- to sixfold higher for the nucleus when compared to 0% internalization. The tumor dosimetry model defines the relative merit of radionuclides and suggests alpha particles may be effective for large tumors as well as small tumor metastases. These results from PHITS modeling substantiate emerging evidence that alpha-particle-emitting radionuclides may be an effective alternative to beta-particle-emitting radionuclides for targeted radionuclide therapy due to preferred dose-deposition profiles in the cellular and tumor metastasis context. These results further suggest that internalization of alpha-particle-emitting radionuclides via radiolabeled ligands may increase the relative biological effectiveness of radiotherapeutics.