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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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All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Simultaneous Separation of Protactinium-230 and Uranium-230 Isotopes from a Proton-Irradiated Thorium Matrix

The use of radioisotopes in cancer therapy is becoming increasingly important. As a potential candidate for targeted alpha therapy, 230 U (t 1/2 = 20.8 d), the decay daughter of 230 Pa (t 1/2 = 17.4 d) is currently being investigated for cancer treatment. For radioisotopes to be used in biomedicine, they must be radiochemically pure and free from carrier interference. This can be challenging given their short half-life. Thus, in this study, radiological separation methods for harvesting isotopes for use in biomedicine must be simple, fast, and capable of obtaining the required purity levels. Herein, we demonstrate a new rapid method for the separation of 230 U and 230 Pa from a proton-irradiated 232 Th metal target and from coproduced fission products with high recovery and purity. A dual-column approach was used, in which the first column was an anion exchange (AX) column and the second column was a DGA column. The MP-1 AX resin was used for the primary separation of the three major components (U, Pa, and Th, as well as fission products), and the DGA column was used for further purification of the separated 230 U. The method is simple and allows for straightforward separation of U, Pa, Th, and fission products; also, the entire process from target dissolution to shipment of 230 U could be completed in 3 days with an overall 230 U recovery yield of 96 ± 3%. Additionally, separated 230 Pa fractions can be used to harvest ingrown 230 U after initial separation.

DGA resin↗
DOE OSTI2025

Synthesis and Evaluation of a Bifunctional Chelator for Thorium-227 Targeted Radiotherapy

Thorium-227 (227Th) is an α-emitting radionuclide currently under investigation for targeted alpha therapy. Available chelators used for this isotope suffer from challenging multistep syntheses. Here, we present the synthesis and preclinical evaluation of a novel bifunctional chelator, p-SCN-Bn-DOTHOPO, which contains an isothiocyanate group that is suitable for conjugation to biological molecules. This bifunctional chelator was prepared with a 26% overall yield in four steps and conjugated to the human epidermal growth factor receptor 2 targeting antibody, trastuzumab. The resulting immunoconjugate was labeled with [227Th]ThIV (pH 5.5, room temperature, 60 min) with ≥95% radiochemical yield and purity. The conjugate was also labeled with zirconium-89 (89Zr), which can be used for positron emission tomography imaging. The radiometal complexes were subsequently investigated for their biological stability. The results described here provide insight into ligand design strategies and optimization of chelators for the development of the next generation of 89Zr and 227Th radiopharmaceuticals.

Thorium↗
DOE OSTI2021

Regulatory Considerations in the Development of Radiation-Drug Combinations

Radiation therapy remains a fundamental treatment for patients with cancer. Despite an increasing number of targeted molecular therapies that are US Food and Drug Administration (FDA)-approved for the treatment of patients with metastatic disease, there has been very little progress made in terms of drugs used concurrently with radiation. This article reviews the existing regulatory framework in which cancer drugs may be developed for use in combination with radiation therapy from the perspective of the FDA. To briefly summarize: (1) nonclinical studies are a critical first step to ensure that drugs are safe for use in humans; however, additional nonclinical studies of a drug with radiation may not be required before a clinical trial in combination with radiation as long as the safety profile of the drug has been characterized in humans. The FDA determines the quality of evidence required before studying a drug in combination with radiation on a case-by-case basis. (2) Although often impractical to consider late toxicities during dose-escalation, late adverse events should be captured and taken into consideration when determining the final dose and schedule to take forward during drug development. (3) There are a number of expedited programs for cancer drug development, including accelerated approval, a conditional approval that allows for use of earlier clinical endpoints when the data suggests a clinically meaningful improvement over available therapy. (4) The Agency encourages sponsors to discuss their development plan with the appropriate FDA review division in formal regulatory meetings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

CD46 targeted 212 Pb alpha particle radioimmunotherapy for prostate cancer treatment

We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212 Pb, an in vivo generator of alpha-emitting 212 Bi and 212 Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212 Pb-TCMC-YS5. We characterized 212 Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212 Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212 Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212 Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212 Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.

212Pb↗
DOE OSTI2026

Toward Rapid Actinium-225 Purification via Membrane Adsorbers with Covalently Tethered Diglycolamide Ligands

Extractive diglycolamide (DGA) resins are used in several state-of-the-art techniques for purifying 225 Ac, a promising radiometal for targeted alpha therapy. Unfortunately, separation processes that rely on resins are often limited to slow flow rates, high elution volumes, and long processing times. Membrane adsorbers functionalized with DGA ligands are an alternative separation material that may overcome these challenges. This work presents (1) the synthesis of an aminated tetrahexyldiglycolamide ligand, (2) the covalent tethering of the ligand to electrospun poly(vinylbenzyl chloride) fiber mats, and (3) the adsorption and desorption of La(III) and 225 Ac. Chemical and physical characterization supports the covalent tethering of the ligand to the fiber mat, as well as the preservation of the fiber surface area and porosity after functionalization. Equilibrium adsorption experiments were performed with stable La(III) and radioactive 225 Ac. Trends in affinity are consistent between commercial resins and the synthesized membrane adsorbers; however, the Langmuir constants and the maximum binding capacity of the membrane adsorbers were generally lower than the resins. Despite these differences, the modeled selectivity for an equimolar solution of La(III)/ 225 Ac in 10 M nitric acid is 57. Furthermore, 225 Ac is rapidly desorbed from the fibers in 10 M nitric acid (<20 min). The La(III)/ 225 Ac selectivity and rapid 225 Ac desorption indicate this class of materials is promising for rapid radioanalytical separations.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2021

Peripheral Blood Transcript Signatures after Internal 131 I-mIBG Therapy in Relapsed and Refractory Neuroblastoma Patients Identifies Early and Late Biomarkers of Internal 131 I Exposures

131 I-metaiodobenzylguanidine ( 131 I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early 131 I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with 131 I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after 131 I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after 131 I-mIBG exposure, with mean log2 fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after 131I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after 131 I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after 131 I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal 131 I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal 131 I.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
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 OSTI2026

Accelerating actinium-225 purification by high-pressure ion chromatography

Actinium-225 (t1/2 = 9.92 days) is an important radioisotope for targeted alpha therapy applications. The limited supply obtained through the decay of thorium-229 has motivated accelerator-based production routes, including irradiation of thorium targets. Irradiated targets can produce useful quantities of actinium-225, but the product requires final purification from chemically similar lanthanide contaminants. This work describes an automated high-pressure ion chromatography method for this final polishing step. The method uses a reusable strong-acid cation-exchange column bearing sulfonic acid functional groups. α-Hydroxyisobutyric acid (α-HIBA), adjusted to pH 4.3 with lithium hydroxide, complexes and elutes lanthanides, a dilute hydrochloric acid matrix-exchange step removes residual α-HIBA, and concentrated hydrochloric acid then elutes retained actinium(III). The protocol purified actinium-225 to >99% radiopurity across tracer-level samples and samples containing >150 µCi (5.6 MBq) of activity. A 10 min, 0.1 M hydrochloric acid matrix exchange substantially reduced organic eluent carryover, and in-line sodium iodide detection enabled real-time monitoring of actinium and lanthanide elution. The developed method can be completed in <1 h and provides a basis for automated purification workflows for accelerator-produced actinium-225.

Gaddis, Kevin [ORNL] (ORCID:0000000183398314)↗
DOE OSTI2020

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD 50 . The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Late Life Supplementation of 25‐Hydroxycholesterol Reduces Aortic Stiffness and Cellular Senescence in Mice

ABSTRACT Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age‐related aortic stiffening is driven, in part, by cellular senescence—a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25‐hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice. Old (22–26 months) p16‐3MR mice, a transgenic model allowing for genetic clearance of p16‐positive senescent cells with ganciclovir (GCV), were administered vehicle, 25HC, or GCV to compare the efficacy of the experimental 25HC senolytic versus genetic clearance of senescent cells. We found that short‐term (5d) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity (p = 0.002) to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16‐3MR GCV‐treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells. Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen‐1 abundance and higher α‐elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB‐regulated senescent cell anti‐apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age‐related aortic stiffness.

Cell Biology↗
DOE OSTI2021

NRG Oncology/RTOG Consensus Guidelines for Delineation of Clinical Target Volume for Intensity Modulated Pelvic Radiation Therapy in Postoperative Treatment of Endometrial and Cervical Cancer: An Update

Accurate target definition is critical for the appropriate application of radiation therapy. In 2008, the Radiation Therapy Oncology Group (RTOG) published an international collaborative atlas to define the clinical target volume (CTV) for intensity modulated pelvic radiation therapy in the postoperative treatment of endometrial and cervical cancer. The current project is an updated consensus of CTV definitions, with removal of all references to bony landmarks and inclusion of the para-aortic and inferior obturator nodal regions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Radioisotope production at the Spallation Neutron Source: Design concept of isotope production target

Upon completion of the Second Target Station (STS) Project in the mid 2030s, the Spallation Neutron Source accelerator at Oak Ridge National Laboratory will deliver a 2.7 MW proton beam to the neutron production targets. In the post-STS phase, the accelerator will have a reserve beam power capacity of at least 100 kW beyond what the two neutron production targets will receive, which could potentially be ramped up to 300 kW. In this paper, a design concept for a radioisotope production target that could utilize 250 kW of the reserve beam power capacity is presented. The target consists of thorium discs encapsulated in 316L austenitic steel shells that are cooled by water. The estimated post-irradiation activity of Ac-225 and Ra-225, critical medical radioisotopes used in targeted alpha therapy cancer treatment, is calculated at the end of bombardment after a 14 day long irradiation time. Thermal and structural analyses are performed on the basis of calculated nuclear heating data. The technical feasibility of a high-power target under a 250-kW beam load with an extremely low duty factor of $3.5\cdot 10^{-6}$ is presented from thermal, structural and fatigue lifetime perspectives.

Lee, Yong Joong [ORNL] (ORCID:0000000298381723)↗
DOE OSTI2020

PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.

BRCA1↗
DOE OSTI2022

Examination of Ac-225 production from Ra-226 using fast reactor JOYO

In this study, the authors investigated the method of producing the radionuclide Ac{sup 225} used for targeted alpha therapy (TAT). Currently, Ac{sup 225} is mainly generated from ORNL's Th{sup 229} generator, and the annual production amount is limited to about 63 GBq, and methods for generating it using accelerators are under development in each country. The method using an accelerator has the advantage of being able to generate Ac{sup 225} from a small amount of target nuclides with high efficiency but has the disadvantage of not being able to irradiate a large amount of target nuclides at once due to the small irradiation area. Therefore, the authors investigated a method to generate Ac{sup 225} by neutron irradiation of Ra{sup 226} as a target nuclide using the experimental fast reactor JOYO, which has abundant neutrons and a large loading region. Irradiation of Ra{sup 226} with fast neutrons causes a (n, 2n) reaction to generate Ra{sup 225}, and then decay to produce Ac{sup 225}. In addition, although harmful Ac{sup 227} is also produced at the same time by the (n,γ) reaction, first of all the actinium isotope is chemically separated and eliminated. Since the remaining Ra{sup 225} collapses and Ac{sup 225} is produced, pure Ac{sup 225} can be extracted by performing chemical separation again. As a result of the analysis, 1 g of Ra{sup 226} is irradiated with JOYO for 60 days, and milking is performed 4 times every 17.5 days. By doing these three times a year, it was found that about 50 GBq of Ac{sup 225} was generated. (authors)

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2021

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [ 223 Ra]RaCl 2 is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [ 223 Ra]Ra 2+ localizes. To specifically direct [ 223 Ra]Ra 2+ to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [223Ra]Ra2+ for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [ 223 Ra]Ra 2+ was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [ 223 Ra]Ra 2+ under these conditions. [ 223 Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [ 223 Ra]RaCl 2 , signifying that [ 223 Ra][Ra(macropa)] remains intact in vivo. Upon conjugation of macropa to a single amino acid b-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for 223 Ra, complexing >95% of Ra 2+ in solution. Furthermore, [ 223 Ra][Ra(macropa-b-alanine)] was rapidly cleared from mice and showed low 223 Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability in vivo for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the b-alanine conjugate with 223 Ra and its subsequent stability in vivo establishes for the first time the possibility of delivering [ 223 Ra]Ra 2+ to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.

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

Photonuclear cross sections for the 197 Au ⁢(𝛾, 𝑝⁢𝑛)⁢ 195⁢𝑚 Pt reaction near threshold

Platinum radioisotopes are of growing interest for targeted cancer therapy and diagnostic imaging because their decay delivers highly localized radiation doses in tissue, herewith enabling precise DNA damage through Auger-electron emission. Developing production technologies that provide platinum isotopes with high specific activity is essential in radioisotope therapy. Photonuclear reactions on stable nuclei offer a viable accelerator-based route for isotope production when supported by reliable cross-section data. We report photonuclear cross-section measurements for the 197 Au(γ, pn) 195m Pt reaction at incident γ-ray energies of 27, 29, and 31 MeV using the activation method. The measurements were performed by irradiating a stack of concentric-ring gold targets with a quasi-monoenergetic γ-ray beam provided by the High Intensity Gamma-ray Source (HI γS). The induced 195m Pt activity was quantified using off-line γ-ray spectroscopy. These data provide the first experimental constraints on the 197 Au(γ, pn) 195m Pt cross section in the near-threshold region. Furthermore, the comparison of the measured excitation function to PHITS and TALYS calculations indicates that the reaction becomes measurable only near 30 MeV and that substantially higher bremsstrahlung end-point energies are required for practically meaningful production.

190 ≤ A ≤ 219↗
DOE OSTI2023

Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223 Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223 Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra 2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223 Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra 2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba 2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223 Ra and 224 Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra 2+ . A moderate log K ML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra 2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223 Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Furthermore, although macropa-XL could effectively bind 223 Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra 2+ ion and contributes to the small, but growing, number of chelator development efforts for 223 Ra-based TAT.

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

Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells

Abstract In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In this review, we summarize the current understanding of CSCs and their role in cancer progression, and provide an overview of epigenetic alterations seen in CSCs. Importantly, we focus on primary cancer therapies that target the epigenetic modification of CSCs by the use of specific chemical inhibitors, such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors and microRNA‐based (miRNA‐based) therapeutics.

Zhang, Shunhao↗