Engineering topics

Wilbur, D. Scott

Publications and source records attributed to Wilbur, D. Scott.

8 records

DOE OSTI2022

Design and synthesis of astatinated benzothiazole compounds for their potential use in Targeted Alpha Therapy (TAT) strategies to treat Alzheimer's disease-associated amyloid plaques

Alzheimer's disease (AD) is a terminal neurodegenerative disease characterized by the buildup of amyloid fibrils, amorphous aggregates and tauopathies. Several treatment modalities, which rely on various biological processes to reduce disease burden, have been largely ineffective at treating Alzheimer's disease. Targeted alpha therapy (TAT) has demonstrated positive results in the treatment of cancer. Benzothiazole derivatives have been successfully shown to target these plaques and are used in several imaging applications. One such derivative, Flutemetamol (Vizamyl TM ) is an FDA approved diagnostic tool for PET imaging of AD-associated plaques. We report the radiolabeling of benzothiazole derivatives with 211 At, a 7.2 h alpha emitting radionuclide, using a copper catalyzed reaction with a boronic acid precursor molecule. In conclusion, our final compound [ 211 At]3'-At-PIB-OMe had a radiochemical yield of 55% and was found to be stable for at least 3 h in phosphate buffered saline.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2022

Oxidation of p-[125I]Iodobenzoic Acid and p-[211At]Astatobenzoic Acid Derivatives and Evaluation In Vivo

The alpha particle-emitting radionuclide astatine-211 (211At) is of interest for targeted radiotherapy; however, low in vivo stability of many 211At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG4-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with 125I and 211At. Oxidization of the [125I]iodo- and [211At]astato-benzamidyl-dPEG4-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized 125I- and 211At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [211At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [211At]NaAtO3 and [125I]NaIO3. Comparison of the tissue concentrations of the isolated material from the oxidized [211At]benzamide derivative with those of [211At]astatate indicated the species obtained after isolation was likely [211At]astatate.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Evaluation of 186 WS 2 target material for production of high specific activity 186 Re via proton irradiation: separation, radiolabeling and recovery/recycling

Enriched tungsten disulfide ( 186 WS 2 ) was evaluated at increasing proton beam currents (20-50 µA) and times (up to 4 h) on a GE PETtrace cyclotron for production of high specific activity (HSA) 186 Re. The HSA 186 Re was separated from the irradiated target as [ 186 Re][ReO 4 ] - by a liquid-liquid extraction method and radiolabeled with a new N 2 S 2 ligand (222-MAMA-N-ethylpropionate). The enriched 186 W was recovered from the extraction process, analyzed for purity and enrichment, and converted back to the disulfide ( 186 WS 2 ). The results demonstrate that the 186 WS 2 is an easily pressed target material that can withstand relatively high currents and can be readily recovered and recycled. The 186 Re produced was isolated in high specific activity and readily formed the radiotracers [ 186 Re][ReO(222-MAMA-N ethylpropionate)] and [ 186 Re][Re(CO) 3 (OH 2 ) 3 ] + .

186Re,N2S2 ligand↗

DOE OSTI2022

Development and biodistribution studies of 77 As-labeled trithiol RM2 bioconjugates for prostate cancer: Comparison of [ 77 As]As-trithiol-Ser-Ser-RM2 vs. [ 77 As]As-trithiol-Glu-Ser-RM2

Recent progress with the production of 72 As (2.49 Mev β + max (64%), 3.33 Mev β + max (16%), 834 keV (81%), t 1/2 : 26 h) and 77 As (0.683 Mev β- max (97%), 239 keV (1.59%), t 1/2 : 38.8 h) has facilitated their evaluation as a potential “theranostic pair” for PET imaging and radiotherapy. Our 3 rd generation trithiol chelate with two carboxylic acid groups was further developed as a bifunctional chelate for radioarsenic. The As complex with the trithiol chelate was synthesized and characterized. No carrier added (nca) [ 77 As][H 2 AsO 4 - ] was used for radiolabeling studies. Here, the trithiol chelate was conjugated to the RM2 peptide (DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH 2 ) via solid phase peptide synthesis with two different linkers, Ser-Ser and Glu-Ser. The trithiol chelate and its RM2 bioconjugates were radiolabeled with nca 77 As, and the RM2 bioconjugates were compared in initial biodistribution studies. The As diacid trithiol complex was characterized by 1 H NMR, 13 C NMR and HR-ESI-MS. The trithiol-RM2 precursor and As trithiol bioconjugates were characterized by HR-ESI-MS and/or LC-ESI-MS. Radiolabeling of the RM2 bioconjugates with 77 As resulted in over 85% radiochemical yield for [ 77 As]As-trithiol-Ser-Ser-RM2 ([ 77 As]8) and 90% for [ 77 As]As-trithiol-Glu-Ser-RM2 ([ 77 As]9). Both radiotracers demonstrated excellent in vitro stability (≥ 90% remaining intact through 24 h in PBS buffer) and were more hydrophilic than previous analogues based on log D 7.4 values. Biodistribution results of the two radiotracers in healthy CF-1 male mice demonstrated blockable pancreatic uptake at 1 h (82% for ([ 77 As]8 and 78% for [ 77 As]9) indicating specific gastrin-releasing peptide receptor (GRPR) uptake. The primary route of excretion was through the gastrointestinal system for both radiotracers. A new trithiol chelate with improved hydrophilicity was successfully conjugated to the RM2 peptide via two linkers, and high radiolabeling yield with nca 77 As was achieved. In vivo biodistribution studies with both radiotracers demonstrated blockable pancreatic uptake suggestive of specific receptor uptake.

07 ISOTOPE AND RADIATION SOURCES↗

DOE OSTI2020

A reverse 230 U/ 226 Th radionuclide generator for targeted alpha therapy applications

Thorium-226 (half-life 30.6 m) is a radionuclide of interest for use in targeted alpha therapy applications. Additionally, due to its short half-life, 226 Th must be provided through a radionuclide generator system from its parent 230 U (20.8 d). Furthermore, as the half-life of 226 Th is very short, it should be provided in a form that is directly amenable to use in biomedical applications.

226-Th↗

DOE OSTI2020

Crystalline Loading of Lipophilic Coenzyme Q10 Pharmaceuticals within Conjugated Carbon Aerogel Derivatives

Low-density aerogel materials currently are being considered for applications in controlling the rate of release for small-molecule pharmaceuticals in vivo. In particular, silica (SiO2) aerogels are an intriguing platform for controlling both the absolute amount of drug loading, but also the crystalline state of small molecule pharmaceuticals has been shown to affect drug release kinetics. To date, loading silica aerogel materials with crystalline pharmaceuticals typically require dissolving small molecules in a supercritical solvent (i.e., CO2) before drying to recover the aerogel/drug composite. Here we demonstrate a simple and low-cost method for controlling the crystallinity of the model drug coenzyme Q10 (CoQ10) within carbon aerogel materials by rationally controlling the chemical microstructure of the aerogel to exhibit ?-conjugated (sp2) chemical bonding. In particular, both pyrolyzed graphene and nanodiamond aerogels exhibit enhanced intrinsic drug loading capacity and CoQ10 crystallinity over a broad range of sp2 surface-curvature. In contrast, amorphous carbon aerogel materials are observed to load CoQ10 pharmaceuticals with strictly amorphous microstructure.

Lim, Mathew↗

DOE OSTI2020

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226

We report one of the main challenges in targeted alpha therapy is assuring delivery of the α-particle dose to the targeted cells. Thus, it is critical to identify ligands for α-emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium-227 (t 1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed-phased HPLC and gamma spectroscopy. Studies revealed that high 227 Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me-3,2-HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H 4 octapa 3 (65%) and H 4 py4pa 6 (87%). No reaction occurred with H 4 neunpa-p-Bn-NO 2 4, and the chelation reaction with another pa ligand H 4 pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO) 4 1, H 4 octapa 3, and H 4 py4pa 6 had high stability (i.e., 87% of 227 Th still bound to the ligand) in phosphate-buffered saline at room temperature over a 6-day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium-226 (t 1/2 = 30.57 min) when heated to 80°C for 5 min.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2020

A Solid-State Support for Separating Astatine-211 from Bismuth

Increasing access to the short-lived α-emitting radionuclide astatine-211 ( 211 At) has the potential to advance targeted α-therapeutic treatment of disease and to solve challenges facing the medical community. For example, there are numerous technical needs associated with advancing the use of 211 At in targeted α-therapy, e.g., improving 211 At chelates, developing more effective 211 At targeting, and characterizing in vivo 211 At behavior. There is an insufficient understanding of astatine chemistry to support these efforts. The chemistry of astatine is one of the least developed of all elements on the periodic table, owing to its limited supply and short half-life. Increasing access to 211 At could help address these issues and advance understanding of 211 At chemistry in general. Here, we contribute an extraction chromatographic processing method that simplifies 211 At production in terms of purification. It utilizes the commercially available Pre-Filter resin to rapidly (<1.5 h) isolate 211 At from irradiated bismuth targets (Bi decontamination factors ≥876 000), in reasonable yield (68–55%) and in a form that is compatible for subsequent in vivo study. We are excited about the potential of this procedure to address 211 At supply and processing/purification problems.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗