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In the study, we report an in situ corrosion and mass transport monitoring method developed using a radionuclide tracing technique for the corrosion study of 316L stainless steel (316L SS) in a NaCl–MgCl 2 eutectic molten salt natural circulation loop. This method involves cyclotron irradiation of a small tube section with 16 MeV protons, later welds at the hot leg of the molten salt flow loop, generating radionuclides 51 Cr, 52 Mn, and 56 Co at the salt–alloy interface. By measuring the activity variations of these radionuclides at different sections along the loop, both the in situ monitoring of the corrosion attack depth of 316L SS and corrosion product transport and its precipitation in flowing NaCl–MgCl 2 molten salt are achieved. While 316L SS is the focus of this study, the technique reported herein can be extended to other structural materials being used in a wide range of industrial applications. In situ corrosion monitoring is essential to unveil corrosion mechanisms and safeguard materials’ health. Here, the authors develop a radionuclide tracing based in situ corrosion monitoring technique that can monitor corrosion attack depth and corrosion product transport in flowing molten salts.

Plasmonic hotspots generate a blinking Surface Enhanced Raman Spectroscopy (SERS) effect that can be processed using Stochastic Optical Reconstruction Microscopy (STORM) algorithms for super-resolved imaging. Furthermore, by imaging through a diffraction grating, STORM algorithms can be modified to extract a full SERS spectrum, thereby capturing spectral as well as spatial content simultaneously. Here we demonstrate SERS and STORM combined in this way for super-resolved chemical imaging using an ultra-thin silver substrate. Images of gram-positive and gram-negative bacteria taken with this technique show excellent agreement with scanning electron microscope images, high spatial resolution at <50 nm, and spectral SERS content that can be correlated to different regions. This may be used to identify unique chemical signatures of various cells. Finally, because we image through as-deposited, ultra-thin silver films, this technique requires no nanofabrication beyond a single deposition and looks at the cell samples from below. This allows direct imaging of the cell/substrate interface of thick specimens or imaging samples in turbid or opaque liquids since the optical path doesn’t pass through the sample. These results show promise that super-resolution chemical imaging may be used to differentiate chemical signatures from cells and could be applied to other biological structures of interest.

BackgroundRadiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (119Sb, t1/2 = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation. A theranostic (therapeutic/diagnostic) pair can be formed with 119Sb’s radioisotopic imaging analogue 117Sb (t1/2 = 2.80 h, Eγ = 158.6 keV, Iγ = 85.9%, β+ = 262.4 keV, Iβ+ = 1.81%).ResultsWithin, we report techniques for sustainable and cost-effective production of pre-clinical quality and quantity, radionuclidically pure 119Sb and 117Sb, novel low energy photon measurement techniques for 119Sb activity determination, and physical yields for various tin target isotopic enrichments and thicknesses using (p, n) and (d, n) nuclear reactions. Additionally, we present a two-column separation providing a radioantimony yield of 73.1% ± 6.9% (N = 3) and tin separation factor of (6.8 ± 5.5) x 105 (N = 3). Apparent molar activity measurements for deuteron produced 117Sb using the chelator TREN-CAM were measured at 42.4 ± 25 MBq 117Sb/µmol (1.14 ± 0.68 mCi/µmol), and we recovered enriched 119Sn target material at a recycling efficiency of 80.2% ± 5.5% (N = 6) with losses of 11.6 mg ± 0.8 mg (N = 6) per production.ConclusionWe report significant steps in overcoming barriers in 119Sb production, chemical isolation and purification, enriched target material recycling, and chelation, helping promote accessibility and application of this promising therapeutic radionuclide. We describe a method for 119Sb activity measurement using its low energy gamma (23.87 keV), negating the need for attenuation correction. Finally, we report the largest yet-measured 119Sb production yields using proton and deuteron irradiation of natural and enriched targets and radioisotopic purity > 99.8% at end of purification.

The present study describes a novel method for the low energy cyclotron production and radiochemical isolation of no-carrier-added 132/135 La 3+ from bulk nat Ba. This separation strategy combines precipitation and single-column extraction chromatography to afford an overall radiochemical yield (92 ± 2%) and apparent molar activity (22 ± 4 Mbq/nmol) suitable for the radiolabeling of DOTA-conjugated vectors. The produced 132/135 La 3+ has a radiochemical and radionuclidic purity amenable for 132 La/ 135 La-based cancer theranostic applications. Longitudinal PET/CT images acquired using the positron-emitting 132 La and ex vivo biodistribution data separately corroborated the accumulation of unchelated 132/135 La 3+ ions in bone and the liver.

This dissertation investigates production, chemical isolation, and radiopharmaceutical incorporation of the therapeutic radionuclide 119Sb (119Sb, t1/2 = 38.19 22 h, EC=100%) and its radioisotopic imaging analogue 117Sb (t1/2 = 2.80 1 h, EC = 100%, Eγ = 158.562 15 keV, Iγ = 85.9%, Eβ+ = 262.4 4 keV, Iβ+ = 1.81 11 %). For decades, researchers have predicted 119Sb to be one of the most promising Auger electron-emitting radionuclides for therapeutic application because of its high electron yield (~24 electrons per decay), optimal emitted internal conversion electron energies (20 – 30 keV), and low co-emission of photons (Emax = 29.1 keV, I = 2.18 7 %). Barriers in 119Sb production, chemical isolation from target material, and stable radiometal complexation with a bifunctional chelator have limited exploration of 119Sb’s therapeutic potential to in silico studies. This work begins by developing production and chemical isolation techniques, electroplating tin targets suitable for low energy proton and deuteron irradiation and separating Sb from Sn using column chromatography and liquid extraction. We discovered target recycling techniques compatible with our column-based Sn(II)/Sb(III) separation, allowing us to sustainably irradiate 96.3% isotopically enriched 119Sn to make radionuclidically pure 119Sb. With collaborators in inorganic chemistry, we found two chelators capable of bifunctionalization for complexing radioantimony—a trithiol chelator for complexing Sb(III) and a tris-catechol chelator (TREN-CAM) for Sb(V). Using spectroscopy, in vitro, in vivo, and ex vivo techniques, we characterized [nat/1XXSb]Sb-trithiol-diacid and [nat/1XXSb]Sb-TREN-CAM complexes, reported X-ray crystal structures, and analyzed complex stability. [nat/1XXSb]Sb-trithiol-diacid was stable in serum, but upon conjugation to a targeting moiety, the complexes decomposed in PBS. We collected the first in vivo PET and SPECT images of a chelator complexed radioactive antimony to prove [nat/1XXSb]Sb-TREN-CAM complex’s stability.

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by Y, Lu, and Ac as unbound radionuclides and when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 /Treg ratios increased in tumors 7 days after Y- and Lu-NM600 and day 21 after Ac-NM600. Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

The dynamic field of radiopharmaceuticals is currently experiencing an explosion of growth due in part to excitement over the emerging field of theranostics (therapy and diagnostics). Radiopharmaceuticals use physiological targeting methods to deliver radionuclides with medically relevant decay properties to disease biomarkers for diagnosis and treatment, offering opportunities for early disease imaging and radiation therapy treatment in disease pathologies that are inoperable or refractory to other forms of radiotherapy. Sustaining this rapidly growing field depends heavily on the continued design and production of novel, effective radiopharmaceuticals. Effective therapeutic radiopharmaceuticals cause complex and varied cellular responses, and to choose radionuclides that maximize therapeutic response, researchers must understand radiation biology. Cellular radiation response depends heavily on factors including linear energy transfer (LET), dose, dose rate, targeted location, direct or indirect energy deposition mechanisms, the broader cellular matrix, cellular stress signaling pathways, and endogenous radiation protection mechanisms. Because of the extensive application of low-LET external beam radiation on clinical cancer treatments, biological responses to low-LET form the basis of radiation biology and are generally considered transferable to high-LET radiopharmaceuticals. However, increased focus on high-LET, radiopharmaceutical therapy-specific radiation biology is motivated by differences between low- and high-LET radiation, external beam versus radiopharmaceutical therapy-induced biological response, and the observed varied clinical responses to radiopharmaceutical therapies. This review article summarizes historical understanding of low- and high-LET radiation responses within cells, with emphasis on radiopharmaceutical-specific responses when available, and discusses current gaps in understanding in the radiation biology of radiotheranostic pharmaceuticals.

The present study describes a novel method for the low energy cyclotron production and radiochemical isolation of no-carrier-added La from bulk Ba. This separation strategy combines precipitation and single-column extraction chromatography to afford an overall radiochemical yield (92 ± 2%) and apparent molar activity (22 ± 4 Mbq/nmol) suitable for the radiolabeling of DOTA-conjugated vectors. The produced La has a radiochemical and radionuclidic purity amenable for La/ La-based cancer theranostic applications. Longitudinal PET/CT images acquired using the positron-emitting La and ex vivo biodistribution data separately corroborated the accumulation of unchelated La ions in bone and the liver.