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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,045 records · Page 58
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

How much have adverse occupational health outcomes among construction workers improved over time? Evidence from 25 years of medical screening

Background Construction workers have always had a high risk of occupational illnesses. We used 25 years of data from a medical screening program serving older construction workers to determine how much health outcomes have improved over the past 60 years. Methods We investigated changes in relative risk for chest radiographs consistent with pneumoconiosis, COPD by spirometry, lung cancer mortality, and audiometry-assessed hearing impairment among workers participating in a medical screening program. Results were stratified by decade of first construction employment: before 1960, 1960–1969, 1970–1979, 1980–1989, and after 1990. Poisson and Cox regression analyses assessed relative risk by decade adjusted for age, sex, smoking, and years of construction trade work. Results Subjects were 94% male and, on average, 60 years old with 25 years of construction work. When compared to workers employed before 1960, those first employed after 1990 experienced the following reductions in model-adjusted relative risks: chronic obstructive pulmonary disease, 32%; all pneumoconiosis, 68%; parenchymal abnormalities, 35%; pleural abnormalities, 71%; hearing impairment, 20%; and lung cancer mortality, 48%. Risks started to decline in the 1960s with greatest reductions among workers first employed after 1970. Conclusions This study demonstrates the positive impact that adoption of occupational health protections have had over the past 60 years. The greatest risk reductions were observed for outcomes with strong regulatory and legal incentives to reduce exposures and associated risks, such as those associated with inhalation hazards (asbestos and silica), while lowest improvement was for hearing impairment, for which little regulatory enforcement and few prevention incentives have been adopted.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Breast tumor-targeted drug delivery via polymer nanocarriers: Endogenous and exogenous strategies

Breast cancer, one of the most common types of cancer worldwide, has a high degree of malignancy while lacking efficient treatments. The off-target events frequently occurring in drug administration have been a major obstacle, which causes severe side effects to patients and reduces the therapeutic efficacy. An ideal medication should precisely target the specific site with precise control over concentration and duration. In recent years, there has been immense progress in polymer nanocarriers that demonstrate great potential in the targeted delivery. These nanocarriers are constructed from materials sensitive to a wide range of endogenous (e.g., pH, enzyme, redox) and exogenous stimuli (e.g., light, ultrasound, magnetic waves), driving cargo release to the targeted tissue or cells. Here, we elucidate the mechanism of current targeting strategies and the engineering methods to construct these targeting systems or to improve their targeting efficiency. Here we capture the recent progress in the targeted nanocarriers derived from polymers which span hydrogels and micelles, demonstrating their design and applications in chemo, hyperthermia, immuno, and gene therapies.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Nuclear data for reactor production of 131 Ba and 133 Ba

The newest radioisotope for brachytherapy treatment of prostate cancer is 131 Cs (t 1/2 = 9.69 d, 100% EC). Generated via electron capture decay of 131 Ba (t 1/2 = 11.6 d, 100% EC), 131 Cs has been used in brachytherapy for prostate cancer since 2004. The 131 Ba parent is produced through neutron capture of enriched 130 Ba in a nuclear reactor. For large-scale production of 131 Ba, an accurate knowledge of production and burnup cross sections of 131 Ba are essential. Here, we report two group cross sections (thermal and resonance integrals) for 130 Ba and 131 Ba and a new measure of the half-life of 131 Ba. Targets consisting of milligram quantities of enriched 130Ba (~35%) were irradiated in Oak Ridge National Laboratory's High Flux Isotope Reactor at thermal and resonance neutron fluxes of (1.9–2.1) × 10 15 and (5.8–7.0) × 10 13 neutrons·cm -2 s -1 , respectively, for durations ranging from 3 to 26 days. In addition, cadmium covered samples of 130 Ba were irradiated for 1 hour at 12.6% full reactor power (10.7 MW). The yield of 131 Ba approaches a saturation value of ~60 GBq (~1.6 Ci) per mg of 130 Ba for 20 days irradiation at a thermal neutron flux of 1.8 × 10 15 n·s -1 ·cm -2 , with a thermal/epithermal ratio of ~30. Under the above experimental conditions, the two group cross sections of 130 Ba are 6.9 ± 0.5 b (thermal, σ 0 ) and 173 ± 7 b (resonance, I 0 ). These values represent the sum of cross sections to metastable and ground states of 131 Ba. For 131 Ba, the empirically measured thermal cross section is 200 ± 50 b assuming an I 0 /σ 0 of 10. This cross section is reported for the first time. Further, the half-life of 131 Ba was remeasured to be 11.657 ± 0.008 d. Lastly, this study also resulted in the co-production of 133 Ba (t 1/2 = 10.52 y, 100% EC). The experimental yield of 133 Ba is ~370 MBq (~10 mCi) per mg of 132 Ba (thin target) for one cycle irradiation in the High Flux Isotope Reactor, and measured two-group 132 Ba cross sections are 7.2 ± 0.2 b and 39.9 ± 1.3 b. These values also represent the sum of cross sections to metastable and ground states of 133 Ba.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation

Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fcγ receptors (FcγRs) or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. However, how these competing signals are integrated is poorly understood, raising questions about how to effectively titrate immune responses. Here, we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand over a broad range of absolute molecular densities. Using both endogenous and chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering that ratio reduces FcγR phosphorylation because of inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPα, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Small-molecule allosteric inhibitors of GPX4

Here, encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation

Human uracil DNA-glycosylase (UDG) is the prototypic and first identified DNA glycosylase with a vital role in removing deaminated cytosine and incorporated uracil and 5-fluorouracil (5-FU) from DNA. UDG depletion sensitizes cells to high APOBEC3B deaminase and to pemetrexed (PEM) and floxuridine (5-FdU), which are toxic to tumor cells through incorporation of uracil and 5-FU into DNA. To identify small-molecule UDG inhibitors for pre-clinical evaluation, we optimized biochemical screening of a selected diversity collection of >3,000 small-molecules. We found aurintricarboxylic acid (ATA) as an inhibitor of purified UDG at an initial calculated IC 50 < 100 nM. Subsequent enzymatic assays confirmed effective ATA inhibition but with an IC50 of 700 nM and showed direct binding to the human UDG with a K D of <700 nM. ATA displays preferential, dose-dependent binding to purified human UDG compared to human 8-oxoguanine DNA glycosylase. ATA did not bind uracil-containing DNA at these concentrations. Yet, combined crystal structure and in silico docking results unveil ATA interactions with the DNA binding channel and uracil-binding pocket in an open, destabilized UDG conformation. Biologically relevant ATA inhibition of UDG was measured in cell lysates from human DLD1 colon cancer cells and in MCF-7 breast cancer cells using a host cell reactivation assay. Collective findings provide proof-of-principle for development of an ATA-based chemotype and “door stopper” strategy targeting inhibitor binding to a destabilized, open pre-catalytic glycosylase conformation that prevents active site closing for functional DNA binding and nucleotide flipping needed to excise altered bases in DNA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Immunotargeting of Nanocrystals by SpyCatcher Conjugation of Engineered Antibodies

Inorganic nanocrystals such as quantum dots (QDs) and upconverting nanoparticles (UCNPs) are uniquely suited for quantitative live-cell imaging and are typically functionalized with ligands to study specific receptors or cellular targets. Antibodies (Ab) are among the most useful targeting reagents owing to their high affinities and specificities, but common nanocrystal labeling methods may orient Ab incorrectly, be reversible or denaturing, or lead to Ab-NP complexes too large for some applications. Here, we report that SpyCatcher proteins, which bind and spontaneously form covalent isopeptide bonds with cognate SpyTag peptides, can conjugate engineered Ab to nanoparticle surfaces with control over stability, orientation, and stoichiometry. Compact SpyCatcher-functionalized QDs and UCNPs may be labeled with short-chain variable fragment Ab (scFv) engineered to bind urokinase-type plasminogen activator receptors (uPAR) that are overexpressed in many human cancers. Confocal imaging of anti-uPAR scFv-QD conjugates shows the antibody mediates specific binding and internalization by breast cancer cells expressing uPAR. Time-lapse imaging of photostable scFv-UCNP conjugates shows that Ab binding causes uPAR internalization with a ~20 min half-life on the cell surface, and uPAR is internalized to endolysosomal compartments distinct from general membrane stains and without significant recycling to the cell surface. The controlled and stable conjugation of engineered Ab to NPs enables targeting of diverse receptors for live-cell study of their distribution, trafficking, and physiology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Cric searchable image database as a public platform for conventional pap smear cytology data

Amidst the current health crisis and social distancing, telemedicine has become an important part of mainstream of healthcare, and building and deploying computational tools to support screening more efficiently is an increasing medical priority. The early identification of cervical cancer precursor lesions by Pap smear test can identify candidates for subsequent treatment. However, one of the main challenges is the accuracy of the conventional method, often subject to high rates of false negative. While machine learning has been highlighted to reduce the limitations of the test, the absence of high-quality curated datasets has prevented strategies development to improve cervical cancer screening. The Center for Recognition and Inspection of Cells (CRIC) platform enables the creation of CRIC Cervix collection, currently with 400 images (1,376 × 1,020 pixels) curated from conventional Pap smears, with manual classification of 11,534 cells. This collection has the potential to advance current efforts in training and testing machine learning algorithms for the automation of tasks as part of the cytopathological analysis in the routine work of laboratories.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Structure and regulation of human epithelial cell transforming 2 protein

Epithelial cell transforming 2 (Ect2) protein activates Rho GTPases and controls cytokinesis and many other cellular processes. Dysregulation of Ect2 is associated with various cancers. Here, we report the crystal structure of human Ect2 and complementary mechanistic analyses. The data show the C-terminal PH domain of Ect2 folds back and blocks the canonical RhoA-binding site at the catalytic center of the DH domain, providing a mechanism of Ect2 autoinhibition. Ect2 is activated by binding of GTP-bound RhoA to the PH domain, which suggests an allosteric mechanism of Ect2 activation and a positive-feedback loop reinforcing RhoA signaling. Furthermore this bimodal RhoA binding of Ect2 is unusual and was confirmed with Förster resonance energy transfer (FRET) and hydrogen–deuterium exchange mass spectrometry (HDX-MS) analyses. Several recurrent cancer-associated mutations map to the catalytic and regulatory interfaces, and dysregulate Ect2 in vitro and in vivo. Together, our findings provide mechanistic insights into Ect2 regulation in normal cells and under disease conditions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan’s effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs

Improper regulation of translation initiation, a vital checkpoint of protein synthesis in the cell, has been linked to a number of cancers. Overexpression of protein subunits of eukaryotic translation initiation factor 3 (eIF3) is associated with increased translation of mRNAs involved in cell proliferation. In addition to playing a major role in general translation initiation by serving as a scaffold for the assembly of translation initiation complexes, eIF3 regulates translation of specific cellular mRNAs and viral RNAs. Mutations in the N-terminal Helix-Loop-Helix (HLH) RNA-binding motif of the EIF3A subunit interfere with Hepatitis C Virus Internal Ribosome Entry Site (IRES) mediated translation initiation in vitro . Here we show that the EIF3A HLH motif controls translation of a small set of cellular transcripts enriched in oncogenic mRNAs, including MYC . We demonstrate that the HLH motif of EIF3A acts specifically on the 5' UTR of MYC mRNA and modulates the function of EIF4A1 on select transcripts during translation initiation. In Ramos lymphoma cell lines, which are dependent on MYC overexpression, mutations in the HLH motif greatly reduce MYC expression, impede proliferation and sensitize cells to anti-cancer compounds. These results reveal the potential of the EIF3A HLH motif in eIF3 as a promising chemotherapeutic target.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A perfused multi-well bioreactor platform to assess tumor organoid response to a chemotherapeutic gradient

There is an urgent need to develop new therapies for colorectal cancer that has metastasized to the liver and, more fundamentally, to develop improved preclinical platforms of colorectal cancer liver metastases (CRCLM) to screen therapies for efficacy. To this end, we developed a multi-well perfusable bioreactor capable of monitoring CRCLM patient-derived organoid response to a chemotherapeutic gradient. CRCLM patient-derived organoids were cultured in the multi-well bioreactor for 7 days and the subsequently established gradient in 5-fluorouracil (5-FU) concentration resulted in a lower IC 50 in the region near the perfusion channel versus the region far from the channel. We compared behaviour of organoids in this platform to two commonly used PDO culture models: organoids in media and organoids in a static (no perfusion) hydrogel. The bioreactor IC 50 values were significantly higher than IC 50 values for organoids cultured in media whereas only the IC 50 for organoids far from the channel were significantly different than organoids cultured in the static hydrogel condition. Using finite element simulations, we showed that the total dose delivered, calculated using area under the curve (AUC) was similar between platforms, however normalized viability was lower for the organoid in media condition than in the static gel and bioreactor. Our results highlight the utility of our multi-well bioreactor for studying organoid response to chemical gradients and demonstrate that comparing drug response across these different platforms is nontrivial.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology. Our GL pipeline integrates experimental and predicted structures to efficiently discover leads, allowing early-structure and early-testing (ESET) experiments by many laboratories. By employing an efficient VS protocol to examine protein-protein interfaces (PPIs) and allosteric interactions, we identify ligand binding sites beyond active sites, leveraging in silico advances for molecular docking and modeling to screen PPIs and multiple targets. A diverse 3,174 compound ESET library combines Diamond Light Source DSI-poised, Protein Data Bank fragments, and FDA-approved drugs to span relevant chemotypes and facilitate downstream hit evaluation efficiency for academic laboratories. Two VS per library and multiple ranked ligand binding poses enable target testing for several DDR targets. This GL library and protocol can thus strategically probe multiple DDR network targets and identify readily available compounds for early structural and activity testing to overcome bottlenecks that can limit timely breakthrough drug discoveries. By testing accessible compounds to dissect multi-functional DDRs and suggesting inhibitor mechanisms from initial docking, the GL approach may enable more groups to help accelerate discovery, suggest new sites and compounds for challenging targets including emerging biothreats and advance cancer biology for future precision medicine clinical trials.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Synthesis of DOTA-Based 43 Sc Radiopharmaceuticals Using Cyclotron-Produced 43 Sc as Exemplified by [ 43 Sc]Sc-PSMA-617 for PSMA PET Imaging

The implementation of theranostics in oncologic nuclear medicine has exhibited immense potential in improving patient outcomes in prostate cancer with the implementation of [ 68 Ga]Ga-PSMA-11 PET and [ 177 Lu]Lu-PSMA-617 into clinical practice. However, the correlation between radiopharmaceutical biodistributions seen with [ 68 Ga]Ga-PSMA-11 PET imaging and downstream [ 177 Lu]Lu-PSMA-617 therapy remains imperfect. This suggests that prostate cancer theranostics could potentially be further refined through the implementation of true theranostics, tandem pairs of diagnostic and therapeutic radiopharmaceuticals that utilize the same ligand and element, thus yielding identical pharmacokinetics. The radioscandiums are one such group of true theranostic radiopharmaceuticals. The radioscandiums consist of two β+ emitting scandium isotopes ( 43 Sc/ 44 Sc), as well as a β − emitting therapeutic isotope ( 47 Sc), which can all conjugate with PSMA-targeting PSMA-617. This potential has led to extensive investigations into the production of the radioscandiums as well as pre-clinical assessments with several ligands; however, there is a lack of literature extensively describing the complete synthesis of scandium radiopharmaceuticals. which therefore limits the accessibility of radioscandium research in theranostics. As such, this work aims to present an easily translatable protocol for the synthesis of [ 43 Sc]Sc-PSMA-617 from a [ 42 Ca]CaCO 3 starting material, including target formation, nuclear production via 42 Ca(d,n) 43 Sc reaction, chemical separation, radiolabeling, solvent reformulation, and target recycling.

62 RADIOLOGY AND NUCLEAR MEDICINE↗