96 results on '"Eric A. Price"'
Search Results
2. Beyond Catoni: Sharper Rates for Heavy-Tailed and Robust Mean Estimation.
- Author
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Shivam Gupta 0002, Samuel Hopkins, and Eric C. Price
- Published
- 2024
3. A Systematic Investigation into the Influence of Net Charge on the Biological Distribution of Radiometalated Peptides Using [68Ga]Ga-DOTA-TATE Derivatives
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Shvan J. Raheem, Akam K. Salih, Moralba Dominguez Garcia, Jessica C. Sharpe, Behzad M. Toosi, and Eric W. Price
- Subjects
Pharmacology ,Organic Chemistry ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Biotechnology - Published
- 2023
4. Radiochemical, Computational, and Spectroscopic Evaluation of High-Denticity Desferrioxamine Derivatives DFO2 and DFO2p toward an Ideal Zirconium-89 Chelate Platform
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Elaheh Khozeimeh Sarbisheh, Kelly L. Summers, Akam K. Salih, Julien J. H. Cotelesage, Amanda Zimmerling, Ingrid J. Pickering, Graham N. George, and Eric W. Price
- Subjects
Inorganic Chemistry ,Physical and Theoretical Chemistry - Published
- 2023
5. The Chemistry of Creating Chemically Programmed Antibodies (cPAbs): Site-Specific Bioconjugation of Small Molecules
- Author
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Omozojie P. Aigbogun, Christopher P. Phenix, Ed S. Krol, and Eric W. Price
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Drug Discovery ,Pharmaceutical Science ,Molecular Medicine - Published
- 2023
6. Design, Synthesis, and Evaluation of DFO-Em: A Modular Chelator with Octadentate Chelation for Optimal Zirconium-89 Radiochemistry
- Author
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Akam K. Salih, Shvan J. Raheem, Moralba Dominguez Garcia, William K. Ahiahonu, and Eric W. Price
- Subjects
Inorganic Chemistry ,Physical and Theoretical Chemistry - Abstract
Zirconium-89 has quickly become a favorite radionuclide among academics and clinicians for nuclear imaging. This radiometal has a relatively long half-life, which matches the biological half-life of most antibodies, suitable decay properties for positron emission tomography (PET), and efficient and affordable cyclotron production and purification. The "gold standard" chelator for [
- Published
- 2022
7. 89Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe
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Kimberly Fung, Delphine Vivier, Outi Keinänen, Elaheh Khozeimeh Sarbisheh, Eric W. Price, and Brian M. Zeglis
- Subjects
mucin 1 ,MUC1 ,positron emission tomography ,PET ,AR20.5 ,zirconium-89 ,Organic chemistry ,QD241-441 - Abstract
High expression levels of the tumor-associated antigen MUC1 have been correlated with tumor aggressiveness, poor response to therapy, and poor survival in several tumor types, including breast, pancreatic, and epithelial ovarian cancer. Herein, we report the synthesis, characterization, and in vivo evaluation of a novel radioimmunoconjugate for the immuno-positron emission tomography (immunoPET) imaging of MUC1 expression based on the AR20.5 antibody. To this end, we modified AR20.5 with the chelator desferrioxamine (DFO) and labeled it with the positron-emitting radiometal zirconium-89 (t1/2 ~3.3 d) to produce [89Zr]Zr-DFO-AR20.5. In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [89Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ± 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ± 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [89Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue—including metastatic lesions—with promising tumor-to-background contrast.
- Published
- 2020
- Full Text
- View/download PDF
8. Browser-Based Attacks on Tor.
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Timothy G. Abbott, Katherine J. Lai, Michael R. Lieberman, and Eric C. Price
- Published
- 2007
- Full Text
- View/download PDF
9. Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT
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Brian P. Rempel BSc, PhD, Eric W. Price BSc, PhD, and Christopher P. Phenix BSc, PhD
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Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
Hydrolytic enzymes are a large class of biological catalysts that play a vital role in a plethora of critical biochemical processes required to maintain human health. However, the expression and/or activity of these important enzymes can change in many different diseases and therefore represent exciting targets for the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radiotracers. This review focuses on recently reported radiolabeled substrates, reversible inhibitors, and irreversible inhibitors investigated as PET and SPECT tracers for imaging hydrolytic enzymes. By learning from the most successful examples of tracer development for hydrolytic enzymes, it appears that an early focus on careful enzyme kinetics and cell-based studies are key factors for identifying potentially useful new molecular imaging agents.
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- 2017
- Full Text
- View/download PDF
10. DiPODS: A Reagent for Site-Specific Bioconjugation via the Irreversible Rebridging of Disulfide Linkages
- Author
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Elaheh Khozeimeh Sarbisheh, Yujia Xu, Eric W. Price, Whitney Shannon, Guillaume Dewaele-Le Roi, Brian M. Zeglis, and Sally Tan
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Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,Conjugated system ,01 natural sciences ,Article ,Polyethylene Glycols ,Substrate Specificity ,Sulfone ,chemistry.chemical_compound ,Disulfides ,Sulfhydryl Compounds ,Sulfones ,Bifunctional ,Pharmacology ,chemistry.chemical_classification ,Binding Sites ,Bioconjugation ,010405 organic chemistry ,Organic Chemistry ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,chemistry ,Covalent bond ,Reagent ,Thiol ,Indicators and Reagents ,Amine gas treating ,0210 nano-technology ,Biotechnology - Abstract
Chemoselective reactions with thiols have long held promise for the site-specific bioconjugation of antibodies and antibody fragments. Yet bifunctional probes bearing monovalent maleimides — long the ‘gold standard’ for thiol-based ligations — are hampered by two intrinsic issues: the in vivo instability of the maleimide-thiol bond and the need to permanently disrupt disulfide linkages in order to facilitate bioconjugation. Herein, we present the synthesis, characterization, and validation of DiPODS, a novel bioconjugation reagent containing a pair of oxadiazolyl methyl sulfone moieties capable of irreversibly forming covalent bonds with two thiolate groups while simultaneously re-bridging disulfide linkages. The reagent was synthesized from commercially available starting materials in 8 steps, during which rotamers were encountered and investigated both experimentally and computationally. DiPODS is designed to be modular and can thus be conjugated to any payload through a pendant terminal primary amine (DiPODS–PEG(4)-NH(2)). Subsequently, the modification of a HER2-targeting Fab with a fluorescein-conjugated variant of DiPODS (DiPODS-PEG(4)-FITC) reinforced the site-specificity of the reagent, illustrated its ability to rebridge disulfide linkages, and produced an immunoconjugate with in vitro properties superior to those of an analogous construct created using traditional stochastic bioconjugation techniques. Ultimately, we believe that this work has particularly important implications for the synthesis of immunoconjugates, specifically for ensuring that the attachment of cargoes to immunoglobulins is robust, irreversible, and biologically and structurally benign.
- Published
- 2020
11. Ultrasonic-Assisted Solid-Phase Peptide Synthesis of DOTA-TATE and DOTA-linker-TATE Derivatives as a Simple and Low-Cost Method for the Facile Synthesis of Chelator–Peptide Conjugates
- Author
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Viswas Raja Solomon, Eric W. Price, Shvan J. Raheem, Benjamin W Schmidt, and Akam K Salih
- Subjects
Pharmacology ,DOTA-TATE ,Octreotate ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Biomedical Engineering ,Pharmaceutical Science ,Total synthesis ,Bioengineering ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Yield (chemistry) ,Radionuclide therapy ,Peptide synthesis ,DOTA ,Chelation ,Biotechnology - Abstract
Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [68Ga]Ga-DOTA-TATE (NETSPOT) and [177Lu]Lu-DOTA-TATE (LUTATHERA) received U.S. Food and Drug Administration approval for positron emission tomography (PET) imaging and PRRT of NETs, respectively. However, to the best of our knowledge a well-described synthesis of DOTA-TATE has not been reported in the literature. Herein, we report a fully reoptimized DOTA-TATE synthesis, including the application of a simple ultrasonic bath to greatly improve yields, reduce coupling times, and decrease the amount of reagents required for each coupling step by a half. The most prevalently used cyclizing agents such as iodine, thallium(III) trifluoroacetate, hydrogen peroxide, and dimethyl sulfoxide were compared. On-resin cyclizations using mechanical agitation showed higher yields (23% and 25% using I2 and Tl(III), respectively) than off-resin (1.3% and 11% using DMSO and H2O2, respectively), and the total synthesis time of DOTA-TATE was ∼540 min excluding the cyclization step, with a total synthesis yield of ∼23%. The same manual SPPS methods/reagents were reoptimized with ultrasonic (US) agitation, resulting in an immense reduction in the total synthesis time by ∼8-fold to ∼70 min for DOTA-TATE with a higher yield (∼29% yield), and ∼13-fold to 105 min for DOTA-PEG4-TATE (∼29% yield). Also, the use of US agitation reduces the need for excess molar equivalents of the reagents to a half, which is particularly important when coupling expensive or custom-synthesized groups such as bifunctional chelators and linkers. Finally, the synthesized DOTA-TATE was successfully radiolabeled with [68Ga]Ga3+ (t1/2 = 68 min) with high radiochemical yields (30 min, 95 °C). We believe this work opens the door to the facile and low-cost synthesis of many new chelator-linker-peptide conjugates that were previously cumbersome or cost-prohibitive to produce with manual SPPS.
- Published
- 2020
12. A Systematic Evaluation of Antibody Modification and 89Zr-Radiolabeling for Optimized Immuno-PET
- Author
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Elaheh Khozeimeh Sarbisheh, Kimberly J. Edwards, Eric W. Price, Jason S. Lewis, Jonathan M. Glaser, Sai Kiran Sharma, and Akam K Salih
- Subjects
Pharmacology ,Tris ,HEPES ,Biodistribution ,010405 organic chemistry ,Chemistry ,Radioimmunoconjugate ,Organic Chemistry ,Radiochemistry ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,In vitro ,3. Good health ,0104 chemical sciences ,chemistry.chemical_compound ,In vivo ,Specific activity ,0210 nano-technology ,Biotechnology ,Conjugate - Abstract
Immuno-PET using desferrioxamine (DFO)-conjugated zirconium-89 ([89Zr]Zr4+)-labeled antibodies is a powerful tool used for preclinical and clinical molecular imaging. However, a comprehensive study evaluating the variables involved in DFO-conjugation and 89Zr-radiolabeling of antibodies and their impact on the in vitro and in vivo behavior of the resulting radioimmunoconjugates has not been adequately performed. Here, we synthesized different DFO-conjugates of the HER2-targeting antibody (Ab)-trastuzumab, dubbed T5, T10, T20, T60, and T200-to indicate the molar equivalents of DFO used for bioconjugation. Next we radiolabeled the immunoconjugates with ([89Zr]Zr4+) under a comprehensive set of reaction conditions including different buffers (PBS, chelexed-PBS, TRIS/HCl, HEPES; ± radioprotectants), different reaction volumes (0.1-1 mL), variable amounts of DFO-conjugated Ab (5, 25, 50 μg), and radioactivity (0.2-1.0 mCi; 7.4-37 MBq). We evaluated the effects of these variables on radiochemical yield (RCY), molar activity (Am)/specific activity (As), immunoreactive fraction, and ultimately the in vivo biodistribution profile and tumor targeting ability of the trastuzumab radioimmunoconjugates. We show that increasing the degree of DFO conjugation to trastuzumab increased the RCY (∼90%) and Am/As (∼194 MBq/nmol; 35 mCi/mg) but decreased the HER2-binding affinity (3.5×-4.6×) and the immunoreactive fraction of trastuzumab down to 50-64%, which translated to dramatically inferior in vivo performance of the radioimmunoconjugate. Cell-based immunoreactivity assays and standard binding affinity analyses using surface plasmon resonance (SPR) did not predict the poor in vivo performance of the most extreme T200 conjugate. However, SPR-based concentration free calibration analysis yielded active antibody concentration and was predictive of the in vivo trends. Positron emission tomography (PET) imaging and biodistribution studies in a HER2-positive xenograft model revealed activity concentrations of 38.7 ± 3.8 %ID/g in the tumor and 6.3 ± 4.1 %ID/g in the liver for ([89Zr]Zr4+)-T5 (∼1.4 ± 0.5 DFOs/Ab) at 120 h after injection of the radioimmunoconjugates. On the other hand, ([89Zr]Zr4+)-T200 (10.9 ± 0.7 DFOs/Ab) yielded 16.2 ± 3.2 %ID/g in the tumor versus 27.5 ± 4.1 %ID/g in the liver. Collectively, our findings suggest that synthesizing trastuzumab immunoconjugates bearing 1-3 DFOs per Ab (T5 and T10) combined with radiolabeling performed in low reaction volumes using Chelex treated PBS or HEPEs without a radioprotectant provided radioimmunoconjugates having high Am/As (97 MBq/nmol; 17.5 ± 2.2 mCi/mg), highly preserved immunoreactive fractions (86-93%), and favorable in vivo biodistribution profile with excellent tumor uptake.
- Published
- 2020
13. The Impact of Psychotherapeutic Reiki on Anxiety
- Author
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Dee C. Ray, Lindsay C. Webster, Tessa M. Hastings, Eric W. Price, and Janice Miner Holden
- Subjects
Psychiatry and Mental health ,Clinical Psychology ,Psychotherapist ,medicine ,Anxiety ,macromolecular substances ,medicine.symptom ,Reiki ,Psychology ,Mental health - Abstract
Reiki healing is one of several complementary and integrative therapies becoming increasingly prevalent in mental health counseling. It has been identified in the medical field for its usefulness i...
- Published
- 2019
14. Connecting, Coping, and Creating: An Expressive Arts Group for First Year College Students
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Alyssa M. Swan and Eric W. Price
- Subjects
Group psychotherapy ,Psychiatry and Mental health ,Clinical Psychology ,Coping (psychology) ,medicine.medical_treatment ,medicine ,biochemical phenomena, metabolism, and nutrition ,Psychology ,Mental health ,The arts ,Clinical psychology - Abstract
First-year college students are at-risk for mental health concerns that surface or are exacerbated by transition to college academics and new lifestyle. The purpose of this article is to: (a) inves...
- Published
- 2019
15. Computational Prediction of Chemical Tools for Identification and Validation of Synthetic Lethal Interaction Networks
- Author
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Kalpana K, Bhanumathy, Omar, Abuhussein, Frederick S, Vizeacoumar, Andrew, Freywald, Franco J, Vizeacoumar, Christopher P, Phenix, Eric W, Price, and Ran, Cao
- Subjects
Chromosomal Instability ,Neoplasms ,Humans ,Genomics ,Ligands ,Synthetic Lethal Mutations - Abstract
Cancer is one of the leading causes of death and chromosomal instability (CIN) is a hallmark feature of cancer. CIN, a source of genetic variation in either altered chromosome number or structure contributes to tumor heterogeneity and has become a hot topic in recent years prominently for its role in therapeutic responses. Synthetic lethality and synthetic rescue based approaches, for example, advancing CRISPR-Cas9 platform, are emerging as a powerful strategy to identify new potential targets to selectively eradicate cancer cells. Unfortunately, only few of them are further explored therapeutically due to the difficulty in linking these targets to small molecules for pharmacological intervention. This, however, can be alleviated by the efforts to bring chemical, bioactivity, and genomic data together, as well as established computational approaches. In this chapter, we will discuss some of these advances, including established databases and in silico target-ligand prediction, with the aim to navigate through the synthetically available chemical space to the biologically targetable landscape, and eventually, to the chemical modeling of synthetic lethality and synthetic rescue interactions, that are of great clinical and pharmaceutical relevance and significance.
- Published
- 2021
16. The Lived Experiences of GLB College Students Who Feel Supported by their Parents
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Eric W. Price and Elizabeth A. Prosek
- Subjects
Family therapy ,Lived experience ,05 social sciences ,050109 social psychology ,Human sexuality ,Mental health ,Developmental psychology ,Gender Studies ,050902 family studies ,behavior and behavior mechanisms ,Coming out ,0501 psychology and cognitive sciences ,0509 other social sciences ,Lesbian ,Psychology ,reproductive and urinary physiology ,Social Sciences (miscellaneous) - Abstract
Gay and lesbian individuals often wait until moving away to college before they come out to their parents. Individuals who are rejected by their parents often report mental health concerns, whereas...
- Published
- 2019
17. Application of X-ray photoelectron spectroscopy to examine surface chemistry of cancellous bone and medullary contents to refine bone sample selection for nuclear DNA analysis
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Eric W. Price, Reed A. Davis, Janna M. Andronowski, and Amy Z. Mundorff
- Subjects
Medullary cavity ,Chemistry ,Phosphorus ,010401 analytical chemistry ,Radiochemistry ,chemistry.chemical_element ,010501 environmental sciences ,Calcium ,Bone tissue ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Nuclear DNA ,medicine.anatomical_structure ,X-ray photoelectron spectroscopy ,medicine ,Cortical bone ,Cancellous bone ,Spectroscopy ,0105 earth and related environmental sciences - Abstract
The optimum skeletal element and bone tissue type to select for maximum nuclear DNA yield has been recently investigated. We employed X-ray photoelectron spectroscopy (XPS) to evaluate the elemental composition (atomic percentage) of cancellous and cortical bone tissue types to: (1) evaluate the use of XPS for surface chemistry analysis of cancellous bone tissue/medullary contents as a novel approach to discriminate biological tissues from diagenetic infiltrations (e.g., soil) among trabeculae, and (2) present the methodology as a potential tool for refining bone sample selection for nuclear DNA analysis. XPS data from modern bone specimens (n = 46) confirmed that cortical-dominant bones contained higher elemental composition of oxygen (p = 0.012), calcium (p < 0.0001), and phosphorous (p < 0.0001) and lower amounts of carbon (p < 0.0001) relative to cancellous-dominant samples. Data were presented as a ratio of carbon to calcium + phosphorus, revealing higher carbon content and lower calcium/phosphorus in cancellous- versus cortical-dominant bones (ratios of 20.0 ± 11.3 and 8.6 ± 5.6, respectively (p < 0.0001)). Results indicated that primarily cancellous bones contain higher amounts of soft tissue which explains their yielding higher-quality nuclear DNA. We further hypothesized that aluminum is a suitable elemental marker for soil infiltration. One buried donor had visibly soil-stained bones, with a cuneiform exhibiting detectable aluminum content (1.0% versus ∼3.8% in a location-matched soil control). Our results shed new light on the relationship between nuclear DNA yield and cancellous bone/medullary contents, thus informing bone-sample selection for nuclear DNA analysis in forensic contexts.
- Published
- 2019
18. Serial Stimulated Jitter Analysis In Juvenile Myasthenia Gravis
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Shivani Bhatia, Courtney McCracken, Haley Quinlan, Eric W. Price, Lokesh Guglani, and Sumit Verma
- Subjects
0301 basic medicine ,Spirometry ,Vital capacity ,medicine.diagnostic_test ,Orbicularis oculi muscle ,Physiology ,business.industry ,Mean age ,medicine.disease ,Myasthenia gravis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Grip strength ,030104 developmental biology ,0302 clinical medicine ,Physiology (medical) ,Anesthesia ,medicine ,Juvenile ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Jitter - Abstract
Introduction Clinical and electrophysiological studies to measures disease activity in juvenile myasthenia gravis (JMG) are limited. Methods Retrospective review of the clinical profile, Myasthenia Gravis Foundation of America (MGFA) scores, serial stimulated jitter analysis (Stim-JA) of the orbicularis oculi muscle, grip strength, and spirometry of patients with JMG who were followed in a multidisciplinary clinic was performed. Results Thirteen patients with JMG (9 females) with mean age of 13.2 ± 4.8 years and follow-up duration of 25.3 ± 8.3 months (range, 6-39) with ≥ 2 Stim-JA recordings were included. The mean jitter, mean percentage of apparent single-fiber action potentials (%ASFAP) with increased jitter, and mean %ASFAP with blocking at baseline values (77.3 ± 54.7 µs, 64.3% ± 35.8%, 39% ± 38.6%, respectively) and at follow-up (53 ± 45.4 µs, 51.2% ± 34.5%, 17% ± 29.4%, respectively) were abnormal; however, no statistically significant interval difference was noted. The electrophysiological data correlated significantly with Myasthenia Gravis Foundation of America (MGFA) class. Grip strength and spirometry did not correlate with MGFA class. Discussion Stimulated jitter values are sensitive biomarkers in JMG. Muscle Nerve 58: 729-732, 2018.
- Published
- 2018
19. Computational Prediction of Chemical Tools for Identification and Validation of Synthetic Lethal Interaction Networks
- Author
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Eric W. Price, Christopher P. Phenix, Ran Cao, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald, Kalpana Kalyanasundaram Bhanumathy, and Omar Abuhussein
- Subjects
Virtual screening ,chemistry.chemical_compound ,chemistry ,Computer science ,Chromosome instability ,In silico ,Synthetic rescue ,Identification (biology) ,Synthetic lethality ,Computational biology ,Chemical space ,Chemical library - Abstract
Cancer is one of the leading causes of death and chromosomal instability (CIN) is a hallmark feature of cancer. CIN, a source of genetic variation in either altered chromosome number or structure contributes to tumor heterogeneity and has become a hot topic in recent years prominently for its role in therapeutic responses. Synthetic lethality and synthetic rescue based approaches, for example, advancing CRISPR-Cas9 platform, are emerging as a powerful strategy to identify new potential targets to selectively eradicate cancer cells. Unfortunately, only few of them are further explored therapeutically due to the difficulty in linking these targets to small molecules for pharmacological intervention. This, however, can be alleviated by the efforts to bring chemical, bioactivity, and genomic data together, as well as established computational approaches. In this chapter, we will discuss some of these advances, including established databases and in silico target-ligand prediction, with the aim to navigate through the synthetically available chemical space to the biologically targetable landscape, and eventually, to the chemical modeling of synthetic lethality and synthetic rescue interactions, that are of great clinical and pharmaceutical relevance and significance.
- Published
- 2021
20. SNAP: Combine and Map modules for multilocus population genetic analysis.
- Author
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David L. Aylor, Eric W. Price, and Ignazio Carbone
- Published
- 2006
- Full Text
- View/download PDF
21. SNAP: workbench management tool for evolutionary population genetic analysis.
- Author
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Eric W. Price and Ignazio Carbone
- Published
- 2005
- Full Text
- View/download PDF
22. Structural Characterization of the Solution Chemistry of Zirconium(IV) Desferrioxamine: A Coordination Sphere Completed by Hydroxides
- Author
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Amanda Zimmerling, Kelly L. Summers, Ingrid J. Pickering, Elaheh Khozeimeh Sarbisheh, Julien J. H. Cotelesage, Graham N. George, and Eric W. Price
- Subjects
chemistry.chemical_classification ,Denticity ,Aqueous solution ,Coordination sphere ,Extended X-ray absorption fine structure ,010405 organic chemistry ,Chemistry ,Inorganic chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Coordination complex ,Inorganic Chemistry ,chemistry.chemical_compound ,Hydroxide ,Molecule ,Chelation ,Physical and Theoretical Chemistry - Abstract
Positron emission tomography (PET) using radiolabeled, monoclonal antibodies has become an effective, noninvasive method for tumor detection and is a critical component of targeted radionuclide therapy. Metal ion chelator and bacterial siderophore desferrioxamine (DFO) is the gold standard compound for incorporation of zirconium-89 in radiotracers for PET imaging because it is thought to form a stable chelate with [89Zr]Zr4+. However, DFO may not bind zirconium-89 tightly in vivo, with free zirconium-89 reportedly liberated into the bones of experimental mouse models. Although high bone uptake has not been observed to date in humans, this potential instability has been proposed to be related to the unsaturated coordination sphere of [89Zr]Zr-DFO, which is thought to consist of the 3 hydroxamate groups of DFO and 1 or 2 water molecules. In this study, we have used a combination of X-ray absorption spectroscopy and density functional theory (DFT) geometry optimization calculations to further probe the coordination chemistry of this complex in solution. We find the extended X-ray absorption fine structure (EXAFS) curve fitting of an aqueous solution of Zr(IV)-DFO to be consistent with an 8-coordinate Zr with oxygen ligands. DFT calculations suggest that the most energetically favorable Zr(IV) coordination environment in DFO likely consists of the 3 hydroxamate ligands from DFO, each with bidentate coordination, and 2 hydroxide ligands. Further EXAFS curve fitting provides additional support for this model. Therefore, we propose that the coordination sphere of Zr(IV)-DFO is most likely completed by 2 hydroxide ligands rather than 2 water molecules, forming Zr(DFO)(OH)2.
- Published
- 2020
23. A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89
- Author
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Shvan J. Raheem, Eric W. Price, Elaheh Khozeimeh Sarbisheh, Jason S. Lewis, and Akam K Salih
- Subjects
Siderophore ,Zirconium ,Denticity ,010405 organic chemistry ,Chemistry ,chemistry.chemical_element ,Deferoxamine ,010402 general chemistry ,Iron Chelating Agents ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,3. Good health ,Inorganic Chemistry ,Coordination Complexes ,Chelation ,Physical and Theoretical Chemistry ,Density Functional Theory - Abstract
Herein we report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). Our new chelator — DFO2 — was designed and synthesized with the purpose of improving the coordination chemistry and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([(89)Zr]-Zr(4+)) has found wide-usage for positron emission tomography (PET) imaging when coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination number of twelve, which provides theranostic potential for binding large oxophilic metal ions. Following synthesis of the DFO2 chelator and the [(nat)Zr]Zr-DFO2 complex, we performed density functional theory calculations to study its coordination sphere, and zirconium-89 radiolabeling experiments for comparisons with the “gold standard” chelator DFO. DFO (CN = 6) is thought to coordinate with zirconium in a hexadentate fashion leaving two open coordination sites where water is thought to coordinate (total CN = 8). DFO2 (potential CN = 12, dodecadentate) saturated the coordination sphere of zirconium with four hydroxamate groups (CN = 8) with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quantitative radiolabeling with zirconium-89, the preformed [(89)Zr]Zr-(DFO) and [(89)Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of in vitro stability challenges including human blood serum, apo-transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to determine if the increased denticity of DFO2 over DFO imparted improved chelate stability, and another was to determine which of these assays is most relevant to perform with future chelators. In all assays DFO2 showed superior stability with zirconium-89, except for the iron challenge where both DFO2 and DFO were identical. Substantial differences in stability were observed for human blood serum using a precipitation method of analysis, apo-transferrin, hydroxyapatite, and EDTA. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochemisty with even larger radionuclides, which will expand to utility of DFO2 into theranostic applications.
- Published
- 2020
24. Ultrasonic-Assisted Solid-Phase Peptide Synthesis of DOTA-TATE and DOTA
- Author
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Shvan J, Raheem, Benjamin W, Schmidt, Viswas Raja, Solomon, Akam K, Salih, and Eric W, Price
- Subjects
Heterocyclic Compounds, 1-Ring ,Ultrasonics ,Peptides ,Solid-Phase Synthesis Techniques ,Chelating Agents - Abstract
Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [
- Published
- 2020
25. 89Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe
- Author
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Elaheh Khozeimeh Sarbisheh, Delphine Vivier, Eric W. Price, Outi Keinänen, Kimberly Fung, and Brian M. Zeglis
- Subjects
positron emission tomography ,Radioimmunoconjugate ,zirconium-89 ,Pharmaceutical Science ,MUC1 ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,lcsh:Organic chemistry ,In vivo ,Drug Discovery ,medicine ,Percent Injected Dose ,Physical and Theoretical Chemistry ,030304 developmental biology ,0303 health sciences ,AR20.5 ,biology ,medicine.diagnostic_test ,Chemistry ,Organic Chemistry ,medicine.disease ,mucin 1 ,PET ,Chemistry (miscellaneous) ,Positron emission tomography ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Molecular Medicine ,Antibody ,Ovarian cancer - Abstract
High expression levels of the tumor-associated antigen MUC1 have been correlated with tumor aggressiveness, poor response to therapy, and poor survival in several tumor types, including breast, pancreatic, and epithelial ovarian cancer. Herein, we report the synthesis, characterization, and in vivo evaluation of a novel radioimmunoconjugate for the immuno-positron emission tomography (immunoPET) imaging of MUC1 expression based on the AR20.5 antibody. To this end, we modified AR20.5 with the chelator desferrioxamine (DFO) and labeled it with the positron-emitting radiometal zirconium-89 (t1/2 ~3.3 d) to produce [89Zr]Zr-DFO-AR20.5. In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [89Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ±, 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ±, 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [89Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue&mdash, including metastatic lesions&mdash, with promising tumor-to-background contrast.
- Published
- 2020
26. A Systematic Evaluation of Antibody Modification and
- Author
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Sai Kiran, Sharma, Jonathan M, Glaser, Kimberly J, Edwards, Elaheh, Khozeimeh Sarbisheh, Akam K, Salih, Jason S, Lewis, and Eric W, Price
- Subjects
Radioisotopes ,Immunoconjugates ,Positron-Emission Tomography ,Zirconium ,Antibodies ,Article - Abstract
Immuno-PET using desferrioxamine (DFO)-conjugated zirconium-89 ([(89)Zr]Zr(4+))-labeled antibodies is a powerful tool used for preclinical and clinical molecular imaging. However, a comprehensive study evaluating the variables involved in DFO-conjugation and (89)Zr-radiolabeling of antibodies, and their impact on the in vitro and in vivo behavior of the resulting radioimmunoconjugates has not been adequately performed. Here, we synthesized different DFO-conjugates of the HER2-targeting antibody (Ab) – trastuzumab – dubbed T5, T10, T20, T60, and T200 – to indicate the molar equivalents of DFO used for bioconjugation. Next we radiolabeled the immunoconjugates with ([(89)Zr]Zr(4+)) under a comprehensive set of reaction conditions including different buffers (PBS, chelexed-PBS, TRIS/HCl, HEPES; ± radioprotectants), different reaction volumes (0.1–1 mL), variable amounts of DFO-conjugated Ab (5, 25, 50 μg) and radioactivity (0.2–1.0 mCi; 7.4–37 MBq). We evaluated the effects of these variables on radiochemical yield (RCY), molar activity (A(m))/ specific activity (A(s)), immunoreactive fraction, and ultimately the in vivo biodistribution profile and tumor targeting ability of the trastuzumab radioimmunoconjugates. We show that increasing the degree of DFO conjugation to trastuzumab increased the RCY (~90%) and A(m); A(s) (~194 MBq/nmol; 35 mCi/mg) but decreased the HER2-binding affinity (3.5x-4.6x) and the immunoreactive fraction of trastuzumab down to 50–64%, which translated to dramatically inferior in vivo performance of the radioimmunoconjugate. Cell-based immunoreactivity assays and standard binding affinity analyses using surface plasmon resonance (SPR) did not predict the poor in vivo performance of the most extreme T200 conjugate. However, SPR-based concentration free calibration analysis yielded active antibody concentration and was predictive of the in vivo trends. Positron emission tomography (PET) imaging and biodistribution studies in a HER2-positive xenograft model revealed activity concentrations of 38.7 ± 3.8 %ID/g in the tumor and 6.3 ± 4.1 %ID/g in the liver for ([(89)Zr]Zr(4+))-T5 (~1.4 ± 0.5 DFOs/Ab) at 120 h after injection of the radioimmunoconjugates. On the other hand, ([(89)Zr]Zr(4+))-T200 (10.9 ± 0.7 DFOs/Ab) yielded 16.2 ± 3.2 %ID/g in the tumor versus 27.5 ± 4.1 %ID/g in the liver. Collectively, our findings suggest that synthesizing trastuzumab immunoconjugates bearing 1–3 DFOs per Ab (T5 and T10) combined with radiolabeling performed in low reaction volumes using chelexed-PBS without a radioprotectant provided radioimmunoconjugates having high A(m); A(s) (97 MBq/nmol; 17.5 ± 2.2 mCi/mg), highly preserved immunoreactive fractions (86–93%), and favorable in vivo biodistribution profile with excellent tumor uptake.
- Published
- 2020
27. Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model
- Author
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Jason S. Lewis, Sean D. Carlin, Wolfgang W. Scholz, Jacob L. Houghton, Eric W. Price, Jeffrey M. Steckler, Freddy E. Escorcia, and Dalya Abdel-Atti
- Subjects
Serum ,Cancer Research ,Biodistribution ,CA-19-9 Antigen ,Radioimmunoconjugate ,Mice, Nude ,Molecular imaging ,Models, Biological ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Antibody ,Radioisotopes ,Bladder cancer ,medicine.diagnostic_test ,business.industry ,Antibodies, Monoclonal ,Cancer ,Zirconium-89 ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Urinary Bladder Neoplasms ,Oncology ,Positron emission tomography ,Positron-Emission Tomography ,030220 oncology & carcinogenesis ,Cancer research ,Autoradiography ,Immuno-PET ,Zirconium ,business ,Ex vivo ,Research Article - Abstract
Purpose Tumor-specific molecular imaging is an important tool for assessing disease burden and treatment response. CA19.9 is an important tumor-specific marker in several malignancies, including urothelial carcinoma. [89Zr]DFO-HuMab-5B1 (MVT-2163) is a CA19.9-specific antibody-based construct that has been validated in preclinical animal models of lung, colorectal, and pancreatic malignancies for positron emission tomography (PET) imaging and is currently in a phase I trial for pancreatic cancer (NCT02687230). Here, we examine whether [89Zr]DFO-HuMab-5B1 may be useful in defining urothelial malignancies. Procedures Surface expression of CA19.9 was confirmed in the human bladder cancer line HT 1197. The radioimmunoconjugate [89Zr]DFO-HuMab-5B1 was injected into mice bearing HT 1197 xenografts, and followed by PET imaging, ex vivo experiments including biodistribution, histology and autoradiography, and analysis of blood samples for shed antigen levels were performed. Results [89Zr]DFO-HuMab-5B1 specifically accumulates in HT 1197 engrafted tumors when imaged with PET. Ex vivo biodistribution of organs and autoradiography of engrafted tumors confirm our construct’s specific tumor binding. The target antigen CA19.9 was not found to be shed in vitro or in vivo. Conclusions [89Zr]DFO-HuMab-5B1 can be used to delineate urothelial carcinomas by PET imaging and may provide tumor-specific information prior to, during, and after systemic therapies.
- Published
- 2018
28. Development of a pharmacodynamic biomarker to measure target engagement from inhibition of the NGF–TrkA pathway
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Shawn J. Stachel, Kausik K. Nanda, Darrell A. Henze, Eric A. Price, and Alicja Krasowska-Zoladek
- Subjects
Male ,0301 basic medicine ,animal structures ,Biopsy ,Pain ,Enzyme-Linked Immunosorbent Assay ,Pilot Projects ,Human skin ,Tropomyosin receptor kinase B ,Biology ,Tropomyosin receptor kinase A ,Tropomyosin receptor kinase C ,Biomarkers, Pharmacological ,03 medical and health sciences ,0302 clinical medicine ,Nerve Growth Factor ,Animals ,Humans ,Receptor, trkB ,Receptor, trkC ,Phosphorylation ,Receptor, trkA ,Receptor ,Skin ,Analgesics ,General Neuroscience ,Brain ,Middle Aged ,Macaca mulatta ,Rats ,Biomarker (cell) ,Disease Models, Animal ,030104 developmental biology ,nervous system ,biology.protein ,Female ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction ,Neurotrophin - Abstract
Background NGF signaling through TrkA triggers pathways involved in a wide range of biological effects. Clinical trials targeting either NGF or TrkA are ongoing to treat various diseases in the areas of oncology, neuroscience, and for pain, but there is no described measure of target engagement of TrkA in these studies. New method We have developed custom ELISA assays to measure NGF-induced phosphorylation of TrkA specific for rodent and human receptors. Optimized tissue processing methods allow for detection in both the brain and in skin. In addition, TrkB and TrkC assays have been in established to evaluate selectivity against other neurotrophin receptors. Results In a preclinical NGF-induced pain model, we show that pre-dosing with a TrkA inhibitor prevents phosphorylation of TrkA in the skin at a dose that is efficacious in reversal of thermal hypersensitivity. In addition, we show data in non-human primate and human skin supporting the potential use of this approach to enable translational target engagement. Comparison with existing methods: Existing methods involve animal models expressing TrkA tumors or injection of over-expressing TrkA recombinant cells into animals. Our method can measure target engagement in both normal and disease tissues in preclinical animal models and human skin. Conclusions We have developed methods to assess target engagement for drug programs aimed at disrupting NGF-induced TrkA signaling. This includes preclinical determination of selectivity against other neurotrophin receptors and estimation of functional peripheral restriction. Preliminary data supports this method can be translated into a clinical pharmacodynamic readout using human skin biopsies.
- Published
- 2017
29. The Radiopharmaceutical Chemistry of the Radioisotopes of Lutetium and Yttrium
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Elaheh Khozeimeh Sarbisheh and Eric W. Price
- Subjects
chemistry.chemical_classification ,Radionuclide ,Denticity ,Aqueous solution ,Chemistry ,Radiochemistry ,Radionuclide therapy ,chemistry.chemical_element ,Yttrium ,Nuclide ,Lutetium ,Coordination complex - Abstract
When harnessing radiometals for medical applications, both the aqueous chemistry of the metal ion (e.g. its coordination number, Lewis acidity, solvent activation, pKa) and the properties of the chelator (e.g. donor atoms, denticity, charge, polarity) should be carefully considered to ensure the stable in vivo sequestration of the radionuclide. The decay properties of the radiometal—including its radioactive half-life as well as the type, yield, and energy of its emissions—must also be matched to the biomolecular vector as well as the intended medical application. The most medically relevant radionuclides of lutetium and yttrium are lutetium-177 ([177Lu]Lu3+), yttrium-86 ([86Y]Y3+), and yttrium-90 ([90Y]Y3+). In this chapter, we will discuss the radioactive properties of these nuclides as well as their fundamental coordination chemistry. In addition, we will address the most effective chelators for each radiometal, the biological factors relating to their use in medicine, prominent examples of 177Lu- and 86/90Y-labeled radiopharmaceuticals, potential pitfalls in their use, and tips for radiolabeling with these radionuclides.
- Published
- 2019
30. ATS Core Curriculum 2016: Part III. Pediatric Pulmonary Medicine
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Dawn M. Simon, Jennifer A. Wambach, Jade Tam-Williams, Debra Boyer, Sharon D. Dell, Jonathan H. Rayment, Robyn T. Cohen, Carey C. Thomson, Jordan S. Rettig, Christopher D. Baker, Ruobing Wang, Devika R. Rao, Deborah R. Liptzin, Elizabeth D. Duncan, Christopher M Oermann, Paul E. Moore, Alvin Singh, Eric W. Price, and Fei Jamie Dy
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Pediatrics ,Core curriculum ,Part iii ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Respiratory failure ,030225 pediatrics ,Pulmonary medicine ,Pulmonary Medicine ,Humans ,Medicine ,Education, Medical, Continuing ,Curriculum ,Child ,business ,Intensive care medicine ,ATS Core Curriculum - Published
- 2016
31. Differences in Emotion Dysregulation and Symptoms of Depression and Anxiety among Illicit Substance Users and Nonusers
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Rachel McCullough, Elliott S. Woehler, Eric W. Price, Elizabeth A. Prosek, and Amanda L. Giordano
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Male ,medicine.medical_specialty ,Health (social science) ,Adolescent ,Substance-Related Disorders ,Emotions ,030508 substance abuse ,Medicine (miscellaneous) ,Anxiety ,Affect (psychology) ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,mental disorders ,Medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Students ,Depression (differential diagnoses) ,Illicit Substance ,business.industry ,Depression ,Public Health, Environmental and Occupational Health ,Mental health ,Psychiatry and Mental health ,Case-Control Studies ,Female ,medicine.symptom ,Substance use ,0305 other medical science ,business ,Stress, Psychological - Abstract
Illicit substance users may rely on mind-altering substances to regulate affect, especially when mental health symptoms are present.In light of the prevalence of illicit substance use and symptoms of depression and anxiety among college students, as well as the affect regulation properties of illicit substances, we sought to examine whether differences in emotion dysregulation, depression, anxiety, and stress exist between illicit substance users and non-users.At a large Southwestern U.S. university, we examined differences in emotion dysregulation, depression, anxiety, and stress among college students who used illicit substances in the past 30 days (n = 92, 34.5%) and those who did not (n = 175, 65.5%). Data were collected in 2016 using two measures: the Difficulties in Emotion Regulation Scale (DERS; GratzRoemer, 2004) and the Depression Anxiety Stress Scales (DASS21; LovibondLovibond, 1995).Results from the Descriptive Discriminate Analysis (DDA) indicated that significant differences existed between the two groups. Anxiety, difficulty clarifying emotions, difficulty employing goal-directed behaviors, and stress accounted the most for the group differences. Conclusion/Importance: Mental health differences between illicit substance users and nonusers exist. Specifically, illicit substance users reported more anxiety, stress, and difficulties with emotion regulation.
- Published
- 2018
32. Development of a MUC1-targeting PET probe for ovarian cancer
- Author
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Brian M. Zeglis, K. Fung, Delphine Vivier, and Eric W. Price
- Subjects
Cancer Research ,business.industry ,Cancer research ,Molecular Medicine ,Medicine ,Radiology, Nuclear Medicine and imaging ,business ,Ovarian cancer ,medicine.disease ,MUC1 - Published
- 2019
33. 89Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection
- Author
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Eric W. Price, Yelena Y. Janjigian, Kathryn E. Carnazza, Elisa de Stanchina, Kimberly J. Edwards, Kuntal K. Sevak, Jason S. Lewis, Sean Carlin, Jonathan M. Glaser, and Andrew Cho
- Subjects
0301 basic medicine ,Biodistribution ,biology ,Chemistry ,Cancer ,Rilotumumab ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,In vivo ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Cancer research ,Immunohistochemistry ,Radiology, Nuclear Medicine and imaging ,Hepatocyte growth factor ,Antibody ,Ex vivo ,medicine.drug - Abstract
The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a 89Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated 89Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. Methods: The chelator p-SCN-Bn-DFO was conjugated to AMG102, radiolabeling with 89Zr was performed in high radiochemical yields and purity (>99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Results: Tumor uptake of 89Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 ± 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 ± 1.3 %ID/g and a control of nonspecific human IgG 89Zr-DFO-IgG in U87MG tumors was 11.5 ± 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of 89Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that 89Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. Conclusion: The new immuno-PET imaging agent 89Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that 89Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes.
- Published
- 2017
34. What a Difference a Carbon Makes: H4octapa vs H4C3octapa, Ligands for In-111 and Lu-177 Radiochemistry
- Author
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Jason S. Lewis, Brian M. Zeglis, Michael J. Adam, Jacqueline F. Cawthray, Eric W. Price, and Chris Orvig
- Subjects
Radioisotopes ,Denticity ,Molecular Structure ,Chemistry ,Ligand ,Radiochemistry ,Indium Radioisotopes ,Lutetium ,Ligands ,Article ,Carbon ,3. Good health ,Inorganic Chemistry ,Proton NMR ,Organometallic Compounds ,Molecule ,Chelation ,Physical and Theoretical Chemistry ,Isomerization ,Heteronuclear single quantum coherence spectroscopy ,Group 2 organometallic chemistry ,Chelating Agents ,Hydrogen - Abstract
The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In3+ and Lu3+, which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work., New ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized and compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes.
- Published
- 2014
35. H6phospa-trastuzumab: bifunctional methylenephosphonate-based chelator with89Zr,111In and177Lu
- Author
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Eric W. Price, Brian M. Zeglis, Michael J. Adam, Jason S. Lewis, and Chris Orvig
- Subjects
Mice, Nude ,Lutetium ,Conjugated system ,Isotope dilution ,Antibodies, Monoclonal, Humanized ,Indium ,Article ,Inorganic Chemistry ,Mice ,chemistry.chemical_compound ,Organophosphorus Compounds ,Cell Line, Tumor ,Animals ,Humans ,Chelation ,Bifunctional ,Chelating Agents ,Ovarian Neoplasms ,Radioisotopes ,Chemistry ,Ovary ,Radiochemistry ,Trastuzumab ,In vitro ,Immunoconjugate ,Biochemistry ,Isotope Labeling ,Positron-Emission Tomography ,Monoclonal ,Female ,Zirconium ,Conjugate - Abstract
The acyclic chelator H6phospa and the bifunctional derivative p-SCN-Bn-H6phospa have been synthesized using nosyl protection chemistry and evaluated with (89)Zr, (111)In, and (177)Lu. The p-SCN-Bn-H6phospa derivative was successfully conjugated to trastuzumab with isotopic dilution assays indicating 3.3 ± 0.1 chelates per antibody and in vitro cellular binding assays indicating an immunoreactivity value of 97.9 ± 2.6%. Radiolabeling of the H6phospa-trastuzumab immunoconjugate was achieved with (111)In in 70-90% yields at room temperature in 30 minutes, while (177)Lu under the same conditions produced more inconsistent yields of 40-80%. Stability experiments in human serum revealed the (111)In-phospa-trastuzumab complex to be 52.0 ± 5.3% intact after 5 days at 37 °C, while the (177)Lu-phospa-trastuzumab to be only 2.0 ± 0.3% intact. Small animal SPECT/CT imaging using mice bearing subcutaneous SKOV-3 ovarian cancer xenografts was performed, and it was found that (111)In-phospa-trastuzumab successfully identified and delineated small (~2 mm in diameter) tumors from surrounding tissues, despite visible uptake in the kidneys and bone due to moderate chelate instability. As predicted from stability assays in serum, the (177)Lu-phospa-trastuzumab conjugate served as a negative control and displayed no tumor uptake, with high uptake in bones indicating rapid and complete radiometal dissociation and suggesting a potential application of H6phospa in transient lanthanide chelation for bone-delivery. Radiolabeling with (89)Zr was attempted, but even with elevated temperatures of 37 °C, the maximum observed radiometal incorporation over 18 hours was 12%. It can be concluded from this work that H6phospa is not superior to the previously studied H4octapa for use with (111)In and (177)Lu, but improvements in (89)Zr radiolabeling were observed over H4octapa, suggesting H6phospa to be an excellent starting point for elaboration of (89)Zr-based radiopharmaceutical development. To our knowledge, H6phospa is the best desferrioxamine alternative for (89)Zr radiolabeling to be studied to date.
- Published
- 2014
36. Matching chelators to radiometals for radiopharmaceuticals
- Author
-
Chris Orvig and Eric W. Price
- Subjects
Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,Chemistry ,Sarcosine ,Nanotechnology ,General Chemistry ,Chlorobenzenes ,Molecular Imaging ,Heterocyclic Compounds, 1-Ring ,Heterocyclic Compounds ,Positron emission tomography ,Positron-Emission Tomography ,medicine ,Molecular targets ,Thermodynamics ,Bifunctional chelator ,Radiopharmaceuticals ,Molecular imaging ,Experimental methods ,Chelating Agents - Abstract
Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g.(67)Ga, (99m)Tc, (111)In, (177)Lu) and positron emission tomography (PET, e.g.(68)Ga, (64)Cu, (44)Sc, (86)Y, (89)Zr), as well as therapeutic applications (e.g.(47)Sc, (114m)In, (177)Lu, (90)Y, (212/213)Bi, (212)Pb, (225)Ac, (186/188)Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.
- Published
- 2014
37. Modular syntheses of H4octapa and H2dedpa, and yttrium coordination chemistry relevant to86Y/90Y radiopharmaceuticals
- Author
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Eric W. Price, Michael J. Adam, Jacqueline F. Cawthray, and Chris Orvig
- Subjects
chemistry.chemical_classification ,Ligand ,Inorganic chemistry ,Potentiometric titration ,Picolinic acid ,Combinatorial chemistry ,Coordination complex ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Stability constants of complexes ,Trifluoroacetic acid ,Chemical stability ,Density functional theory - Abstract
The ligands H2dedpa, H4octapa, p-SCN-Bn-H2dedpa, and p-SCN-Bn-H4octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H2dedpa and p-SCN-Bn-H2dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H4octapa has recently been shown to be a very promising 111In and 177Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y3+ are described to assess its potential for use with 86Y/90Y. The solution chemistry of H4octapa with Y3+ is shown to be suitable via solution NMR studies of the [Y(octapa)]− complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In3+ and Lu3+ complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu3+ and Y3+ complexes of octapa4−, and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log KML) with Y3+ of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future 86Y/90Y radiopharmaceutical applications.
- Published
- 2014
38. Linking computational, spectroscopic, and radiochemical methods to design the next-generation of radiometal chelators
- Author
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A. Khozeimeh and Eric W. Price
- Subjects
Cancer Research ,Molecular Medicine ,Radiology, Nuclear Medicine and imaging - Published
- 2019
39. A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal (90)Y
- Author
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Kathryn E. Carnazza, Kimberly J. Edwards, Eric W. Price, Brian M. Zeglis, Michael J. Adam, Jason S. Lewis, Chris Orvig, and Sean Carlin
- Subjects
Cancer Research ,Pyridines ,medicine.medical_treatment ,Pharmacology ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Trastuzumab ,In vivo ,Isothiocyanates ,Cell Line, Tumor ,medicine ,Ethylamines ,Animals ,Radiology, Nuclear Medicine and imaging ,Chelation ,Tissue Distribution ,Yttrium Radioisotopes ,skin and connective tissue diseases ,neoplasms ,Chelating Agents ,Chemistry ,business.industry ,Pentetic acid ,Pentetic Acid ,Radioimmunotherapy ,medicine.disease ,In vitro ,3. Good health ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Isotope Labeling ,Positron-Emission Tomography ,Molecular Medicine ,CHX-A''-DTPA ,Female ,Ovarian cancer ,Nuclear medicine ,business ,medicine.drug - Abstract
Objectives To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H 4 octapa with the therapeutic radiometal 90 Y. Methods The bifunctional chelators p -SCN-Bn-H 4 octapa and p -SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with 90 Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer. Results High radiochemical yields (>95%) were obtained with 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab after 15min at room temperature. Both 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for 90 Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for 90 Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, 90 Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that 90 Y-CHX-A″-DTPA-trastuzumab and 90 Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls. Conclusions Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H 4 octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring 90 Y.
- Published
- 2016
40. H4octapa: An Acyclic Chelator for 111In Radiopharmaceuticals
- Author
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Chris Orvig, Cara L. Ferreira, Michael J. Adam, Eszter Boros, Gwendolyn A. Bailey, Jacqueline F. Cawthray, and Eric W. Price
- Subjects
Models, Molecular ,Biodistribution ,Denticity ,Stereochemistry ,Metal ions in aqueous solution ,Potentiometric titration ,Biochemistry ,Catalysis ,Heterocyclic Compounds, 1-Ring ,Mice ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Animals ,DOTA ,Tissue Distribution ,Chelation ,Chelating Agents ,Chemistry ,Indium Radioisotopes ,General Chemistry ,Pentetic Acid ,Carbon-13 NMR ,Stability constants of complexes ,Thermodynamics ,Female ,Radiopharmaceuticals ,Nuclear chemistry - Abstract
This preliminary investigation of the octadentate acyclic chelator H(4)octapa (N(4)O(4)) with (111)In/(115)In(3+) has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N(4)O(4)) and DTPA (N(3)O(5)). The ability of H(4)octapa to radiolabel quantitatively (111)InCl(3) at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the (111)In complex of H(4)octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [(111)In(octapa)](-) has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [(111)In(DOTA)](-), demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. (1)H/(13)C NMR studies of the [In(octapa)](-) complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)](2-) and [In(DOTA)](-) under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)](-) complex to be log K(ML) = 26.8(1). Through the same set of analyses, the [(111/115)In(decapa)](2-) complex was found to have nonoptimal stability, with H(5)decapa (N(5)O(5)) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H(4)octapa to be a valuable alternative to the macrocycle DOTA for use with (111)In, and a significant improvement to the acyclic chelator DTPA.
- Published
- 2012
41. Cisterna magna cannulated repeated CSF sampling rat model – effects of a gamma-secretase inhibitor on Aβ levels
- Author
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Eric A. Price, Adam J. Simon, Jennifer S. Shapiro, Sethu Sankaranarayanan, Mark Stiteler, and Guoxin Wu
- Subjects
Pathology ,medicine.medical_specialty ,Amyloid beta ,Central nervous system ,Enzyme-Linked Immunosorbent Assay ,Pharmacology ,Cisterna magna ,Antibodies ,Catheterization ,Rats, Sprague-Dawley ,Cerebrospinal fluid ,Cisterna Magna ,medicine ,Animals ,Enzyme Inhibitors ,Gamma secretase ,Cerebrospinal Fluid ,Amyloid beta-Peptides ,biology ,business.industry ,General Neuroscience ,Reproducibility of Results ,Cannula ,Peptide Fragments ,Pathophysiology ,Rats ,Peripheral ,medicine.anatomical_structure ,Data Interpretation, Statistical ,Occipital Bone ,biology.protein ,Amyloid Precursor Protein Secretases ,business - Abstract
Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Aβ) lowering agent. The surgically implanted cisterna magna cannula was patent over a period of 1-2 weeks and enabled repeated sampling of CSF (volume of ∼30-50μL/sample) from each rat. CSF Aβ40 levels showed good intra-animal variability across time points and inter-animal variability within a time point. Peripheral treatment with a gamma-secretase inhibitor (GSI) led to a rapid and robust decline in CSF Aβ40 levels that returned to baseline over 24-96h after dosing. Terminal brain, CSF and plasma Aβ levels measured at 24h after dosing demonstrated robust Aβ lowering and showed excellent correlation across these compartments. These results are the first pharmacological validation of the repeated CSF sampling rat model for Aβ lowering agents. This model can have broad applicability in pharmacological evaluation for diverse CNS targets.
- Published
- 2012
42. Strands, Networks, and Continents from Polystyrene Dewetting at the Air−Water Interface: Implications for Amphiphilic Block Copolymer Self-Assembly
- Author
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Eric W. Price, Matthew G. Moffitt, and Saman Harirchian-Saei
- Subjects
Materials science ,Nanostructure ,Surfaces and Interfaces ,Condensed Matter Physics ,Solvent ,chemistry.chemical_compound ,chemistry ,Chemical engineering ,Amphiphile ,Polymer chemistry ,Electrochemistry ,Copolymer ,General Materials Science ,Polystyrene ,Dewetting ,Self-assembly ,Spectroscopy ,Macromolecule - Abstract
We demonstrate that nanoscale aggregates similar to those formed via amphiphilic block copolymer self-assembly at the air-water interface, including strands, networks, and continents, can be generated by the simple spreading of PS homopolymer solutions on water. Two different PS homopolymers of different molecular weight (PS-405k, M(n) = 405 000 g mol(-1) and PS-33k, M(n) = 33 000 g mol(-1)) are spread at the air-water interface at various spreading concentrations ranging from 0.25 to 3.0 mg/mL. Aggregate formation is driven by PS dewetting from water as the spreading solvent evaporates. We propose that a high spreading concentration or a high molecular weight lead to chain entanglements that restrict macromolecular mobility in the solution, enabling the kinetic trapping of nanostructures associated with early and intermediate stages of PS dewetting. Comparison of PS-405k with a mainly hydrophobic PS-b-PEO block copolymer of similar molecular weight (PSEO-392k, M(n) = 392 000 g mol(-1), 2.0 wt % PEO) allows the effect of a relatively short surface active block on aggregate formation to be investigated. We show that whereas the PEO block is not a required component for the formation of strands and other nonglobular aggregates, it does increase the number of these aggregates at a given spreading concentration and decreases the minimum spreading concentration at which these aggregates are observed, along with decreasing the dimensions and polydispersity of specific surface features. The results provide supporting evidence for the role of PS dewetting in the generation of multiple PS-b-PEO aggregate morphologies at the air-water interface, as originally described in earlier paper from our group.
- Published
- 2010
43. Acyclic Chelate with Ideal Properties for 68Ga PET Imaging Agent Elaboration
- Author
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Michael J. Adam, Eszter Boros, Cara L. Ferreira, Brian O. Patrick, Jacqueline F. Cawthray, Dennis W. Wester, Chris Orvig, and Eric W. Price
- Subjects
Biodistribution ,Molecular Structure ,Stereochemistry ,Ligand ,Gallium Radioisotopes ,General Chemistry ,Pet imaging ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Heterocyclic Compounds, 1-Ring ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Heterocyclic Compounds ,Positron-Emission Tomography ,Animals ,Humans ,DOTA ,Molecule ,Chelation ,Ideal (ring theory) ,Bifunctional ,Chelating Agents - Abstract
We have investigated novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA (N(3)O(3)) or DOTA (N(4)O(4)) for application of radioisotopes of Ga to diagnostic nuclear medicine and have found that the linear N(4)O(2) chelate H(2)dedpa coordinates (67)Ga quantitatively to form [(67)Ga(dedpa)](+) after 10 min at RT. Concentration-dependent coordination to H(2)dedpa of either (68)Ga or (67)Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10(-7) M. With (68)Ga, specific activities as high as 9.8 mCi nmol(-1) were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [(67)Ga(dedpa)](+) showed no decomposition. Two bifunctional versions of H(2)dedpa are also described, and these both coordinate to (67)Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the (67)Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA.
- Published
- 2010
44. Acute γ-Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β Production to Alternative APP Fragments without Amyloid-β Rebound
- Author
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Eric A. Price, Gene G. Kinney, Randall J. Bateman, Maria S. Michener, Marie A. Holahan, Parker Mathers, Adam J. Simon, Kristin R. Wildsmith, Guoxin Wu, David B. Gilberto, Kevin E. Yarasheski, Mark S. Shearman, Jennifer X. Wang, and Jacquelynn J. Cook
- Subjects
Male ,Time Factors ,Amyloid beta ,Article ,Amyloid beta-Protein Precursor ,Species Specificity ,In vivo ,mental disorders ,Amyloid precursor protein ,Extracellular ,Animals ,Humans ,Carbon Radioisotopes ,Beta (finance) ,Gamma secretase ,Amyloid beta-Peptides ,Cross-Over Studies ,biology ,General Neuroscience ,P3 peptide ,Brain ,Macaca mulatta ,nervous system diseases ,Cell biology ,Kinetics ,Spinal Cord ,Biochemistry ,Isotope Labeling ,Models, Animal ,biology.protein ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase - Abstract
The accumulation of amyloid β (Aβ) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Aβ species and extracellular plaque formation in the brain. Multiple Aβ-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Aβ, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Aβ physiology. To this end, we report the translation of the humanin vivostable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a γ-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Aβ (β- and γ-secretase) is that precursors of Aβ may accumulate and cause a rapid increase in Aβ production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction within vivostable-isotope-labeling, and dose-dependently reduced newly generated CNS Aβ. In contrast to systemic Aβ metabolism, CNS Aβ production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Aβ, including C-terminal truncated forms of Aβ: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during γ-secretase inhibition.
- Published
- 2010
45. Block Copolymer Strands with Internal Microphase Separation Structure via Self-Assembly at the Air−Water Interface
- Author
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Chih-Wei Wang, Eric W. Price, Yunyong Guo, and Matthew G. Moffitt
- Subjects
Materials science ,Morphology (linguistics) ,Ethylene oxide ,Evaporation ,Surfaces and Interfaces ,Condensed Matter Physics ,chemistry.chemical_compound ,chemistry ,Chemical engineering ,Transmission electron microscopy ,Amphiphile ,Polymer chemistry ,Electrochemistry ,Copolymer ,General Materials Science ,Self-assembly ,Nanoscopic scale ,Spectroscopy - Abstract
Block copolymer microphase separation in the bulk is coupled to amphiphilic block copolymer self-assembly at the air-water interface to yield hierarchical Langmuir-Blodgett (LB) structures combining organization at the meso- and nanoscales. A blend of polystyrene-b-poly(ethylene oxide) (PS-b-PEO) (Mn=141K, 11.4 wt % PEO) and polystyrene-b-poly(butadiene) (PS-b-PB) (Mn=31.9K, 28.5 wt % PB) containing a PS-b-PB weight fraction of f=0.75 was deposited at the air-water interface, resulting in the spontaneous generation of aggregates with multiscale organization, including nanoscale cylinders in mesoscale strands, via evaporation of the spreading solvent. The resulting features were characterized in LB films via AFM and TEM and at the air-water interface via Langmuir compression isotherms. Blends containing lower PS-b-PB contents formed mesoscale aggregate morphologies of continents and strands (f=0.50) or mesoscale continents with holes (f=0.25), but without the internal nanoscale organization found in the f=0.75 blend. The interfacial self-assembly of pure PS-b-PB at the air-water interface (f=1) yielded taller and more irregularly shaped aggregates than blends containing PS-b-PEO, indicating the integral role of the amphiphilic copolymer in regulating the mesoscale organization of the hierarchically structured features.
- Published
- 2009
46. First Demonstration of Cerebrospinal Fluid and Plasma Aβ Lowering with Oral Administration of a β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor in Nonhuman Primates
- Author
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Janet Lineberger, Matthew G. Stanton, Amy S. Espeseth, Beth Pietrak, Min Xu, Katherine Tugusheva, Harold G. Selnick, Dennis Colussi, Guy R. Seabrook, John Swestock, Jason Kahana, Ming-Chih Crouthamel, Viswanath Devanarayan, Keala X. Tyler, Guoxin Wu, Daria J. Hazuda, Shaun R. Stauffer, Joan D. Ellis, Marie A. Holahan, Joseph P. Vacca, Philippe G. Nantermet, Melissa A. Steinbeiser, Georgia B. McGaughey, Eric A. Price, Jerome Hochman, Hemaka A. Rajapakse, Sethu Sankaranarayanan, Adam J. Simon, Samuel L. Graham, Keith P. Moore, M. Katharine Holloway, Ming-Tain Lai, Lixia Jin, Adam Gates, Xiao-Ping Shi, Jacky Wong, Jacquelynn J. Cook, and Allison R. Gregro
- Subjects
medicine.medical_specialty ,Membrane permeability ,Mice, Transgenic ,Pharmacology ,Transfection ,Cisterna magna ,Amyloid beta-Protein Precursor ,Mice ,Cerebrospinal fluid ,Pharmacokinetics ,Oral administration ,In vivo ,Internal medicine ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Enzyme Inhibitors ,Infusions, Intravenous ,biology ,Macaca mulatta ,Endocrinology ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase - Abstract
beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.
- Published
- 2008
47. Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase
- Author
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Kenneth E. Rittle, Dorothy Levorse, James C. Barrow, Eric A. Price, Katherine Tugusheva, Ming Tain Lai, Abigail Wolfe, Dennis Colussi, Paul Zuck, Shaun R. Stauffer, Adam J. Simon, Samuel L. Graham, M. Katharine Holloway, Zhi Qiang Yang, Georgia B. McGaughey, Amy S. Espeseth, Phung L. Ngo, Beth Pietrak, Min Xu, Qian Huang, Joseph P. Vacca, Sethu Sankaranarayanan, Daria J. Hazuda, Sanjeev Munshi, and Harold G. Selnick
- Subjects
Models, Molecular ,chemistry.chemical_classification ,Molecular Structure ,biology ,Molecular model ,Bicyclic molecule ,Chemistry ,Stereochemistry ,Drug Evaluation, Preclinical ,Hydrogen Bonding ,Crystal structure ,Crystallography, X-Ray ,Imidazolidines ,Chemical synthesis ,Cocrystal ,Structure-Activity Relationship ,Enzyme ,Piperidines ,Enzyme inhibitor ,Drug Discovery ,biology.protein ,Amyloid precursor protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Enzyme Inhibitors - Abstract
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.
- Published
- 2008
48. In Vivo β-Secretase 1 Inhibition Leads to Brain Aβ Lowering and Increased α-Secretase Processing of Amyloid Precursor Protein without Effect on Neuregulin-1
- Author
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Guoxin Wu, Craig A. Coburn, Lixia Jin, Joan D. Ellis, Adam J. Simon, Xiao-Ping Shi, Eric A. Price, Ming-Chih Crouthamel, Jason Kahana, Katherine Tugusheva, Keala X. Tyler, Sethu Sankaranarayanan, Thomas G. Steele, and Shawn J. Stachel
- Subjects
medicine.medical_specialty ,Amyloid beta ,Neuregulin-1 ,Transgene ,Down-Regulation ,Mice, Transgenic ,Amyloid beta-Protein Precursor ,Mice ,In vivo ,Internal medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Neuregulin 1 ,Mice, Knockout ,Pharmacology ,Gene knockdown ,Amyloid beta-Peptides ,biology ,P3 peptide ,Brain ,Up-Regulation ,Mice, Inbred C57BL ,Endocrinology ,Biochemistry ,biology.protein ,Molecular Medicine ,Neuregulin ,Amyloid Precursor Protein Secretases - Abstract
beta-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid beta peptide Abeta42, the putative neurotoxic species in Alzheimer's disease. Recent studies have shown that BACE1 knockdown leads to hypomyelination, putatively caused by a decline in neuregulin (NRG)-1 processing. In this study, we have tested a potent cell-permeable BACE1 inhibitor (IC(50) approximately 30 nM) by administering it directly into the lateral ventricles of mice, expressing human wild-type (WT)-APP, to determine the consequences of BACE1 inhibition on brain APP and NRG-1 processing. BACE1 inhibition, in vivo, led to a significant dose- and time-dependent lowering of brain Abeta40 and Abeta42. BACE1 inhibition also led to a robust brain secreted (s)APPbeta lowering that was accompanied by an increase in brain sAPPalpha levels. Although an increase in full-length NRG-1 levels was evident in 15-day-old BACE1 homozygous knockout (KO) (-/-) mice, in agreement with previous studies, this effect was also observed in 15-day-old heterozygous (+/-) mice, but it was not evident in 30-day-old and 2-year-old BACE1 KO (-/-) mice. Thus, BACE1 knockdown led to a transient decrease in NRG-1 processing in mice. Pharmacological inhibition of BACE1 in adult mice, which led to significant Abeta lowering, was without any significant effect on brain NRG-1 processing. Taken together, these results suggest that BACE1 is the major beta-site cleavage enzyme for APP and that its inhibition can lower brain Abeta and redirect APP processing via the potentially nonamyloidogenic alpha-secretase pathway, without significantly altering NRG-1 processing.
- Published
- 2007
49. Nanometer Distance Measurements in RNA Using Site-Directed Spin Labeling
- Author
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Kálmán Hideg, Eric A. Price, Peter Z. Qin, Qi Cai, Ian S. Haworth, and Ana Karin Kusnetzow
- Subjects
Models, Molecular ,Nitroxide mediated radical polymerization ,Biophysics ,Crystal structure ,Biophysical Phenomena ,Nucleic Acids ,Molecule ,Nanotechnology ,Computer Simulation ,Nucleic acid structure ,chemistry.chemical_classification ,Oligoribonucleotides ,Base Sequence ,Molecular Structure ,Biomolecule ,Electron Spin Resonance Spectroscopy ,RNA ,Site-directed spin labeling ,Crystallography ,chemistry ,Helix ,Nucleic Acid Conformation ,Thermodynamics ,Nitrogen Oxides ,Spin Labels - Abstract
The method of site-directed spin labeling (SDSL) utilizes a stable nitroxide radical to obtain structural and dynamic information on biomolecules. Measuring dipolar interactions between pairs of nitroxides yields internitroxide distances, from which quantitative structural information can be derived. This study evaluates SDSL distance measurements in RNA using a nitroxide probe, designated as R5, which is attached in an efficient and cost-effective manner to backbone phosphorothioate sites that are chemically substituted in arbitrary sequences. It is shown that R5 does not perturb the global structure of the A-form RNA helix. Six sets of internitroxide distances, ranging from 20 to 50Å, were measured on an RNA duplex with a known X-ray crystal structure. The measured distances strongly correlate (R2=0.97) with those predicted using an efficient algorithm for determining the expected internitroxide distances from the parent RNA structure. The results enable future studies of global RNA structures for which high-resolution structural data are absent.
- Published
- 2007
- Full Text
- View/download PDF
50. The Chemistry of Inorganic Nuclides (86Y,68Ga,64Cu,89Zr,124I)
- Author
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Eric W. Price and Chris Orvig
- Subjects
Chemistry ,Radiochemistry ,Nuclide - Published
- 2014
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