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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 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Influence of calcium nitrate timing on the structural and textural characteristics of mesoporous SiO 2 -CaO nanoparticles

Mesoporous bioactive glass nanoparticles (MBGNPs) are promising materials for drug delivery due to their high pore volume and specific surface area. This study investigates how the timing of calcium nitrate addition affects the structural and textural characteristics of MBGNPs synthesized via a microemulsion-assisted sol-gel method. Delayed calcium nitrate addition reduced calcium incorporation from 14.2 to 9.5 mol% and increased particle size from 178 ± 51 nm to 256 ± 30 nm. The specific surface area values increased with the delayed addition of calcium nitrate, as observed through BET and USAXS/SAXS measurements. The proportion of Q Si n units slightly changed, but no cytotoxicity was observed in osteoblast-like cells. These findings provide valuable insights into optimizing MBGNP synthesis for biomedical applications.

Calcium nitrate tetrahydrate↗
DOE OSTI2023

Application of Cell Painting for chemical hazard evaluation in support of screening-level chemical assessments

‘Cell Painting’ is an imaging-based high-throughput phenotypic profiling (HTPP) method in which cultured cells are fluorescently labeled to visualize subcellular structures (i.e., nucleus, nucleoli, endoplasmic reticulum, cytoskeleton, Golgi apparatus / plasma membrane and mitochondria) and to quantify morphological changes in response to chemicals or other perturbagens. HTPP is a high-throughput and cost-effective bioactivity screening method that detects effects associated with many different molecular mechanisms in an untargeted manner, enabling rapid in vitro hazard assessment for thousands of chemicals. Here, 1201 chemicals from the ToxCast library were screened in concentration-response up to ~100 μM in human U-2 OS cells using HTPP. A phenotype altering concentration (PAC) was estimated for chemicals active in the tested range. PACs tended to be higher than lower bound potency values estimated from a broad collection of targeted high-throughput assays, but lower than the threshold for cytotoxicity. In vitro to in vivo extrapolation (IVIVE) was used to estimate administered equivalent doses (AEDs) based on PACs for comparison to human exposure predictions. AEDs for 18/412 chemicals overlapped with predicted human exposures. Phenotypic profile information was also leveraged to identify putative mechanisms of action and group chemicals. Of 58 known nuclear receptor modulators, only glucocorticoids and retinoids produced characteristic profiles; and both receptor types are expressed in U-2 OS cells. Thirteen chemicals with profile similarity to glucocorticoids were tested in a secondary screen and one chemical, pyrene, was confirmed by an orthogonal gene expression assay as a novel putative GR modulating chemical. Most active chemicals demonstrated profiles not associated with a known mechanism-of-action. However, many structurally related chemicals produced similar profiles, with exceptions such as diniconazole, whose profile differed from other active conazoles. Overall, the present study demonstrates how HTPP can be applied in screening-level chemical assessments through a series of examples and brief case studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles

Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Mitochondrial integration and ovarian cancer chemotherapy resistance

Ovarian cancer has been nicknamed the “silent killer”. Most patients with ovarian cancer are diagnosed at an advanced stage of the disease for the first time because of its insignificant early clinical symptoms. In addition to the difficulty of early screening and delay in diagnosis, the high recurrence rate and relapsed refractory status of patients with ovarian cancer are also important factors for their high mortality. Patients with recurrent ovarian cancer often use neoadjuvant chemotherapy followed by surgery as the first choice. However, this is often accompanied by chemotherapy resistance, leading to treatment failure and a mortality rate of more than 90%. In the past, it was believed that the anti-tumor effect of chemotherapeutics represented by cisplatin was entirely attributable to its irreversible damage to DNA, but current research has found that it can inhibit cell growth and cytotoxicity via nuclear and cytoplasmic coordinated integration. As an important hub and integration platform for intracellular signal communication, mitochondria are responsible for multiple key factors during tumor occurrence and development, such as metabolic reprogramming, acquisition of metastatic ability, and chemotherapy drug response. The role of mitochondria in ovarian cancer chemotherapy resistance is becoming increasingly recognized. In this review, we discuss the cellular interactive regulatory network surrounding mitochondria, elucidate the mechanisms of tumor cell survival under chemotherapy, and discuss potential means of interfering with mitochondrial function as a novel anti-cancer therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Karyopherin beta 1 (Kpnβ1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpnβ1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpnβ1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpnβ1 and its cargoes, NFκB/p65, NFAT and AP-1, and the overexpression of Kpnβ1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpnβ1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

In vitro assessment of a synergistic combination of gemcitabine and zebularine in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an extremely poor prognosis. Gemcitabine (Gem) is still the mainstay drug for the treatment of PDAC. However, rapid inactivation by cytidine deaminase (CDA) present in pancreatic cancer cells severely limits anticancer efficacy of Gem. In this study, we investigated the effect of a CDA inhibitor - Zebularine (Zeb) on anticancer activity of Gem in pancreatic cancer cell lines MiaPaCa-2, BxPC-3, and Panc-1. Zeb treatment synergistically increased Gem-induced cytotoxicity in all three pancreatic cancer cell lines. The strongest synergistic activity was found at 1:10 M ratio of Gem/Zeb (combination index 0.04–0.4). Additionally, Gem + Zeb treated cells showed marked decreased in the expressions of anti-apoptotic protein including Bcl-2 and survivin while significantly increased the cleaved caspase-3, and loss of mitochondrial membrane potential was observed. Multicellular 3D spheroids of MiaPaCa-2 cells treated with combination showed significant reduction (25–60%) in spheroid size, weight compared to single drug and control group. Live/dead cell imaging showed that Gem + Zeb treated spheroids exhibited a highly distorted surface with significantly higher number of dead cells (red). The results of the present study confirm that this synergistic combination is worthy of future investigations as a potential approach for the treatment of PDAC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Therapeutic targeting of membrane-associated proteins in central nervous system tumors

The activity of the most complex system, the central nervous system (CNS) is profoundly regulated by a huge number of membrane-associated proteins (MAP). A minor change stimulates immense chemical changes and the elicited response is organized by MAP, which acts as a receptor of that chemical or channel enabling the flow of ions. Slight changes in the activity or expression of these MAPs lead to severe consequences such as cognitive disorders, memory loss, or cancer. CNS tumors are heterogeneous in nature and hard-to-treat due to random mutations in MAPs; like as overexpression of EGFRvIII/TGFβR/VEGFR, change in adhesion molecules α5β3 integrin/SEMA3A, imbalance in ion channel proteins, etc. Extensive research is under process for developing new therapeutic approaches using these proteins such as targeted cytotoxic radiotherapy, drug-delivery, and prodrug activation, blocking of receptors like GluA1, developing viral vector against cell surface receptor. The combinatorial approach of these strategies along with the conventional one might be more potential. Henceforth, our review focuses on in-depth analysis regarding MAPs aiming for a better understanding for developing an efficient therapeutic approach for targeting CNS tumors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Antitumor CD8 T cell responses in glioma patients are effectively suppressed by T follicular regulatory cells

Regulatory T (Treg) cells are thought to contribute to tumor pathogenesis by suppressing tumor immunosurveillance and antitumor immunity. T follicular regulatory (Tfr) cells are a recently characterized Treg subset that expresses both the Treg transcription factor (TF) Foxp3 and the T follicular helper (Tfh) TF Bcl-6. The role of Tfr cells in glioma patients remains unclear. In this study, we found that the level of Tfr cells, identified as Foxp3{sup +}Bcl-6{sup +} CD4 T cells, was significantly elevated in tumor-infiltrating CD4 T cells from resected glioma tumors. Both Tfr cells and Treg cells significantly suppressed the proliferation and the cytotoxic capacity of CD8 T cells toward glioma tumor cells, and the suppression was positively associated with the proportion of Tfr cells and Treg cells, respectively. Tfr and Treg cells from glioma tumor samples demonstrated higher suppression potency than those from healthy blood samples and glioma blood samples. Interestingly, canonical CXCR5{sup -} Treg cells could suppress both CXCR5{sup +} and CXCR5{sup -} CD8 T cells, albeit with stronger potency toward CXCR5{sup -} CD8 T cells. However, Tfr cells presented much higher suppression potency toward CXCR5{sup +} CD8 T cells, whereas CXCR5{sup +} CD8 T cells are a potent CD8 T cell subset previously described to have antiviral and antitumor roles. Overall, these data indicate that Tfr cells are enriched in glioma tumors and have suppressive capacity toward CD8 T cell-mediated effector functions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Disruption of adenosine 2A receptor improves the anti-tumor function of anti-mesothelin CAR T cells both in vitro and in vivo

Chimeric antigen receptor (CAR) T cells have been successfully used for the treatment of hematological malignancies including acute and chronic lymphoblastic leukemia. However, results of CAR T cell projects in solid tumors have been less impressive to date, partly because of immunosuppressive tumor microenvironment (TME). It is widely known that high adenosine production is an important factor causing tumor-induced immunosuppression in TME, and adenosine mediates the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Previous studies have shown that adenosine generated by cancer cells significantly inhibits T cell anti-tumor activity through binding and then activating adenosine 2A receptors (A2aRs) of T cells. Based on the previous work, in our study, we evaluated whether A2aR disruption by shRNA could enhance the anti-tumor function of anti-mesothelin (MSLN) CAR T cells both in vitro and in vivo. For this goal above, we used MSLN-positive human ovarian serous carcinoma cells (SKOV3) and human colon cancer cells (HCT116) as target cancer cells while MSLN-negative human ovarian cancer cells (ES2) as non-target cancer cells. We observed that targeting cell-intrinsic A2aR through shRNA overexpression caused significant A2aR disruption in CAR T cells and profoundly increased CAR T cell efficacy in both CAR T cell cytokine production and cytotoxicity towards MSLN-positive cancer cells in vitro. More importantly, in SKOV3 xenograft mouse models, anti-MSLN CAR-T cells significantly reduced the tumor burden compared with non-transduced T cells, and the anti-tumor activity of A2aR-disrupted anti-MSLN CAR-T cells was stronger than that of wild-type anti-MSLN CAR-T cells. Altogether, our study showed enhanced anti-tumor efficacy caused by shRNA-mediated A2aR disruption in anti-MSLN CAR T cells both in vitro and in vivo, which proved that shRNA-mediated modification of gene expression might be an excellent strategy for improving CAR T cell function in immunosuppressive tumor microenvironment (TME) and could potentially improve the outcome of treatment in clinical trials.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Prenol production in a microbial host via the “Repass” Pathways

Prenol and isoprenol are promising advanced biofuels and serve as biosynthetic precursors for pharmaceuticals, fragrances, and other industrially relevant compounds. Despite engineering improvements that circumvent intermediate cytotoxicity and lower energy barriers, achieving high titer ‘mevalonate (MVA)-derived’ prenol has remained elusive. Difficulty in selective prenol production stems from the necessary isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP) as well as the intrinsic toxicity of these diphosphate precursors. Here, the expression of specific isopentenyl monophosphate kinases with model-guided enzyme substitution of diphosphate isomerases and phosphatases enabled selective cycling of monophosphates and diphosphates, dramatically improving prenol titers and selectivity in Escherichia coli. Pairing this approach with the canonical MVA pathway resulted in 300 mg/L prenol at a 30:1 ratio with isoprenol. Further pairing with the “IPP-Bypass” pathway resulted in 526 mg/L prenol at a 72:1 ratio with isoprenol, the highest and purest MVA-derived prenol titer to date. Additionally, modifying this “IPP-Repass” for DMAPP production and coexpressing the prenyltransferase acPT1 yielded 48.3 mg/L of the potential therapeutic precursor drupanin from p-coumarate. These novel repass pathways establish a unique strategy for tuning diphosphate precursors to drive isoprenoid biosynthesis and prenylation reactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Zwitterion Moieties in Polypeptides Synergistically Enhance the Release of Cellulose and Amorphous Polysaccharides from Plant Cell Walls

This study demonstrated that covalently localized zwitterionic moieties in zwitterionic polypeptides (ZIPs) effectively disrupt hydrogen bonds in cellulosic substrates, including filter paper and plant cell wall materials, without significant cytotoxicity. ZIPs with varying densities of zwitterionic side chains were synthesized via the postpolymerization modification of histidinecontaining oligopeptides. The newly developed ZIPs predominantly comprised repeating units with zwitterionically converted side chains. Such ZIPs can cleave multiple hydrogen bonds by anchoring the zwitterionic structure at specific sites, thereby partially dissociating the polysaccharide chains in the cell wall. They are especially effective in dissolving amorphous cellulose, even at low concentrations in aqueous solutions. Importantly, this effect was achieved with minimal cellular toxicity, harnessing the advantages of ionic liquid-like properties while mitigating their high-toxicity limitations. This biofriendly approach to cell wall denaturation highlights a novel method for controlling hydrogen bond networks in polysaccharides and cell walls. These findings indicate a new approach for reducing biomass recalcitrance and developing next-generation biobased materials and fuels derived from plant cell walls.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Synthesis, Characterization, and Biological Activity of Hybrid Thiosemicarbazone–Alkylthiocarbamate Metal Complexes

A series of hybrid ligands (H 2 L 1 –H 2 L 3 ) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O-alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (4–6), nickel (7–9), and zinc (10–12) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the Cu II/I reduction potential of ~160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates 4–12 were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives 4 and 6 were found to have potent and cancer-selective antiproliferative effects, with GI 50 values less than 100 nM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 nonmalignant lung fibroblasts. In comparison, the nickel complexes were much less active and had little cancer-selectivity. Varying by ligand, the zinc complexes were less potent or had comparable activity compared to that of the corresponding copper complex. UV–visible spectroscopy indicated that zinc complex 10 was transmetalated in the presence of equimolar copper, whereas nickel complex 7 was not. Copper complexes 4 and 6 were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, 4 and 6 were substantially more active against A549 cancer cells than Cu(ATSM) and were more cancer-selective (for A549 compared to IMR-90) than Cu(GTSM). Finally, our results suggest that hybrid thiosemicarbazone–alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor

Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Self-Assembly Interactions in Magnetite-Coated Cellulose Nanocrystals: Implications for Magnetic Hyperthermia Applications

Magnetic cellulose nanocrystal (MCNC) nanocomposites are promising sustainable and biocompatible platforms for magnetic hyperthermia; however, the molecular mechanisms governing Fe 3 O 4 adsorption and deposition onto CNCs remain poorly understood. Here, sulfated (S-CNC) and TEMPO-oxidized CNCs (T-CNC) were used to prepare nanocomposites at 1:2 and 1:4 CNC:Fe 3 O 4 mass ratios, enabling a systematic evaluation of how surface chemistry and nanoparticle loading dictate interfacial interactions and magneto-colloidal behavior. Bare magnetite nanoparticles were 21 ± 5 nm by TEM but grew to 144 ± 18 in the DLS measurement at pH 7. The S-CNC nanocomposites had hydrodynamic sizes between 144 and 210 nm, not much larger than the 140 nm long CNC rods, suggesting an enhanced dispersion stability compared to Fe3O4 alone. X-ray photoelectron spectroscopy combined with density functional theory revealed that −OH and −COOH groups drive electrostatic adsorption with charge transfer from Fe 3 O 4 to the CNC surface, while T-CNCs showed more favorable adsorption energies and evidence of covalent Fe−O bonding. Vibrating sample magnetometry demonstrated superparamagnetic behavior for all samples, with S-CNC/Fe 3 O 4 1:4 and 1:2 displaying saturation magnetizations of 78 and 77 emu/g-Fe 3 O 4 , close to the 83 emu/g of bare magnetite. The T-CNC composites showed lower (60 and 66 emu/g-Fe3O4) saturation magnetizations. Zero-field-cooled/field-cooled measurements resulted in a blocking temperature of 112 K for all samples, except T-CNC/Fe 3 O 4 1:2 (100 K). Magnetic hyperthermia studies revealed that specific absorption rate (SAR) increased with field strength and Fe 3 O 4 content; however, S-CNC/Fe 3 O 4 (1:2) achieved the highest intrinsic SAR per gram of Fe 3 O 4 (649 W/g-Fe 3 O 4 ) likely due to its anisotropy and fast magnetic relaxation. Cytotoxicity assays confirmed that all nanocomposites were nontoxic toward mammalian cells. These results establish quantitative structure−property relationships between CNC surface chemistry, interfacial bonding mechanisms, and magnetic heating performance, providing a foundation for rational design of biocompatible magnetic nanocomposites for hyperthermia and related applications.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Fitness Landscape-Guided Engineering of Locally Supercharged Virus-like Particles with Enhanced Cell Uptake Properties

Protein-based nanoparticles are useful models for the study of self-assembly and attractive candidates for drug delivery. Virus-like particles (VLPs) are especially promising platforms for expanding the repertoire of therapeutics that can be delivered effectively as they can deliver many copies of a molecule per particle for each delivery event. However, their use is often limited due to poor uptake of VLPs into mammalian cells. In this study, we use the fitness landscape of the bacteriophage MS2 VLP as a guide to engineer capsid variants with positively charged surface residues to enhance their uptake into mammalian cells. By combining mutations with positive fitness scores that were likely to produce assembled capsids, we identified two key double mutants with internalization efficiencies as much as 67-fold higher than that of wtMS2. Internalization of these variants with positively charged surface residues depends on interactions with cell surface sulfated proteoglycans, and yet, they are biophysically similar to wtMS2 with low cytotoxicity and an overall negative charge. Additionally, the best-performing engineered MS2 capsids can deliver a potent anticancer small-molecule therapeutic with efficacy levels similar to antibody-drug conjugates. Through this work, we were able to establish fitness landscape-based engineering as a successful method for designing VLPs with improved cell penetration. These findings suggest that VLPs with positive surface charge could be useful in improving the delivery of small-molecule- and nucleic acid-based therapeutics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Synthesis and Characterization of Radio-Halogenated Talazoparib Analogues for Imaging and Radioligand Therapy

Abstract Talazoparib (TZ) is a potent poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that uniquely traps PARP complexes at sites of single-strand DNA damage thereby offering opportunities for targeted radioligand therapy. Radiolabeled halogenated TZ derivatives were synthesized using boronic ester precursors to enable incorporation of diagnostic and therapeutic radionuclides: 18F for PET imaging, 77Br for Auger electron radiotherapy, and 211At for targeted alpha radiotherapy. Copper-mediated radio-halogenation afforded racemic 18F-TZ, 77Br-TZ, and 211At-TZ in sufficient radiochemical yields (4.3 ± 2.6%, n = 33; 29.0 ± 12.0%, n = 4; 3.6 ± 3.8%, n = 9, respectively), ∼99% radiochemical purity and proven stability under formulation conditions. Molecular dynamics simulations of halo-TZ derivatives predicted an inverse relationship between halogen size and PARP1 binding affinity. Indeed, cell uptake of radio-halogenated TZ analogues indicated selective uptake in a panel of cell types that correlated with PARP1 levels but was inversely related to the atomic radii of the halogen series. Despite modest specific activity and specific uptake, 77Br-TZ showed significant cytotoxicity. Further investigation of 18F-TZ with 77Br-TZ as a radiotheranostic pair will be facilitated by the synthetic schemes herein.

Muzzioli, Riccardo [The University of Texas MD And↗
DOE OSTI2023

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer’s disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. In this work, results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

36 MATERIALS SCIENCE↗
DOE OSTI2024

Performance Evaluation of a High Salinity Produced Water Treatment Train: Chemical Analysis and Aryl Hydrocarbon Activation

Water scarcity and increased energy demands have put a strong focus on improving industries at the heart of the water–energy nexus. Treatment of oil and gas produced water (PW) can help reduce freshwater consumption during hydraulic fracturing, especially in arid regions, while also removing harmful contaminants from entering the environment. However, it is also difficult to treat because PW contains high concentrations of many environmentally toxic contaminants, which require complex and expensive treatment processes to achieve their removal. To demonstrate the possibility of PW treatment and reuse in the O&G industry, a comprehensive environmental toxicity and water quality analysis throughout a five-process treatment train was performed on high salinity (>120 g/L) Permian basin raw PW. Here, the concentrations of naturally occurring radioactive materials were reduced by over 99%, total organic carbon was reduced by 93%, and inorganic constituents, including total dissolved solids, were reduced by over 99%. Compounds that induced the aryl hydrocarbon receptor and caused cytotoxicity in MCF-7 cells were also removed. Overall, the results of this study show that a short treatment train (five distinct unit processes) can be effective in treating PW to a level suitable for use outside of the oil industry.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗