Publications by authors named "Chris Orvig"

Htrica is a nonadentate chelating ligand intended for coordinating large radiometal ions, such as those used in nuclear medicine. This chelator, featuring a triaza-18-crown-6 macrocycle with three pendant carboxylic acid functional groups, was synthesized and characterized. Complementary nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) studies were used to explore the coordination of Htrica with metal ions such as La, Y (as a model for Tb, and Lu at the bulk scale.

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Superior bifunctional chelating ligands, which can sequester both α-emitting radionuclides (Ac, Bi) and their diagnostic companions (Tb, In), remain a formidable challenge to translating targeted alpha therapy, with complementary diagnostic imaging, to the clinic. HnoneupaX, a chelating ligand with an unusual diametrically opposed arrangement of pendant donor groups, has been developed to this end. HnoneunpaX preferentially complexes Ln and An ions, forming thermodynamically stable (pLa = 17.

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Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of β and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra.

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Hdedpa-,'-pram (HL), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (Hdedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing Ga- and Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related Hdedpa-,'-prpta (HL) platform as a simple structural model for its conjugated systems.

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A new, high-denticity, bifunctional ligand─HTPAN-triazole-Bn-NH─has been synthesized and studied in complexation with [Ac]Ac and [In]In for radiopharmaceutical applications. The bifunctional chelator is readily synthesized, using a high-yielding four-step prep, which is highly adaptable and allows for straightforward incorporation of different covalent linkers using Cu-catalyzed alkyne-azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of HTPAN-triazole-Bn-NH with La and In metal ions show the formation of a single, asymmetric complex with each ion in solution, corroborated by density functional theory (DFT) calculations.

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The nuclear decay characteristics of Ac ( = 5-8 MeV, linear energy transfer (LET) = ∼100 keV/μm, = 9.92 days) are well recognized as advantageous for the treatment of primary and metastatic tumors; however, suitable chelation systems are required, which can accommodate this radiometal. Since Ac does not possess any suitable low-energy, high abundance γ-ray emissions for nuclear imaging, there is a clear need for the development of other companion radionuclides with similar coordination characteristics and comparable half-lives, which can be applied in diagnostics.

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A new, bifunctional chelating ligand for immuno-Positron Emission Tomography (PET) was designed, synthesized, and conjugated to Trastuzumab for a proof-of-concept study with Zr. Hneunox was synthesized from the tris(2-aminoethyl)amine backbone, decorated with 8-hydroxyquinoline moieties, and utilizes a primary amine for functionalization. A maleimide moiety extends the chelator to create Hneunox-mal for antibody conjugation via maleimide-thiol click chemistry.

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Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed.

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A new decadentate chelator, Hampa, was designed to be a potential radiopharmaceutical chelator component. The chelator involves both amide and picolinate functional groups on a large non-macrocyclic, ether-bridged backbone. With its large scaffold, Hampa was paired with [Pb]Pb, [Bi]Bi, and La/[Ac]Ac ions.

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The bisoxine hexadentate chelating ligand, Hglyox was investigated for its affinity for Mn, Cu and Lu ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry. The aqueous coordination chemistry and thermodynamic stability of all three metal complexes were thoroughly investigated by detailed DFT structure calculations and stability constant determination, by employing UV in-batch spectrophotometric titrations, giving pM values (pM = -log[M ] when [M ] = 1 μM, [L] = 10 μM at pH 7.4 and 25 °C) - pCu (25.

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With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, Hamidohox (2,2'-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and HamidoC3hox (2,2'-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 1,3-diaminopropane backbones, respectively.

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With the emergence of [Ac]Ac as a therapeutic radionuclide for targeted α therapy (TAT), access to clinical quantities of the potent, short-lived α-emitter [Bi]Bi ( = 45.6 min) will increase over the next decade. With this in mind, the nonadentate chelator, Hneunpa-NH, has been investigated as a ligand for chelation of [Bi]Bi in combination with [In]In as a suitable radionuclidic pair for TAT and single photon emission computed tomography (SPECT) diagnostics.

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Hpypa is a nonadentate nonmacrocyclic chelator, which previously demonstrated high affinity for scandium-44, lutetium-177, and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the nonradioactive complex was synthesized and characterized in detail using high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared with the structure of [Fe(Hpypa)].

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Article Synopsis
  • Hepatocellular carcinoma (HCC) is a serious global health issue with few effective treatments for advanced stages, prompting research into targeted therapies like α-therapy which involves delivering α-particle-emitting radionuclides, such as Th, specifically to cancer cells.
  • The study focuses on developing a Th-labeled antibody (Th-octapa-αGPC3) that targets Glypican-3 (GPC3), a protein often overexpressed in HCC, showing high efficiency in labeling and maintaining stability in vitro.
  • In preclinical tests involving mice with HCC, Th-octapa-αGPC3 effectively accumulated in tumors while sparing normal tissue, leading to a significant tumor reduction at specific
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8-Hydroxyquinoline (8-HQ, oxine) is a small, monoprotic, bicyclic aromatic compound and its relative donor group orientation imparts impressive bidentate metal chelating abilities that have been exploited in a vast array of applications over decades. 8-HQ and its derivatives have been explored in medicinal applications including anti-neurodegeneration, anticancer properties, and antimicrobial activities. One long established use of 8-HQ in medicinal inorganic chemistry is the coordination of radioactive isotopes of metal ions in nuclear medicine.

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Targeted α-therapy (TAT) is an emerging powerful tool treating late-stage cancers for which therapeutic options are limited. At the core of TAT are targeted radiopharmaceuticals, where isotopes are paired with targeting vectors to enable tissue- or cell-specific delivery of α-emitters. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DTPA (diethylenetriamine pentaacetic acid) are commonly used to chelate metallic radionuclides but have limitations.

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HHBEDpa, a new octadentate chelator inspired by the 1960s ligand HBED of Arthur E. Martell, has been investigated for a selection of trivalent metal ions useful in diagnostic and therapeutic applications (Sc, Fe, Ga, In, and Lu). Complex formation equilibria were thoroughly investigated using combined potentiometric and UV-vis spectrophotometric titrations which revealed effective chelation and high metal-sequestering capacity, in particular for Fe, log = 36.

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Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [Pb]Pb ions for potential radiopharmaceutical applications. H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The H NMR spectrum of [Pb(DTPAm)] revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)] and [Pb(ampam)], both of which showed fewer spectral changes indicative of less static behaviour.

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A new versatile chelating ligand for intermediate size and softness radiometals [Cu]Cu and [In]In, Hpyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu, La, and In demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu, In, and La.

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A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)pharmaceuticals. Three ligands (Hphospa, Hdipedpa, Heppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of Hphospa and Hdipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions.

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Purpose: The purpose of this study was to evaluate the efficacy and toxicity of a novel lanthanum compound, La(XT), in an ovariectomized (OVX) rat model of osteoporosis.

Methods: Twenty-four ovariectomized female Sprague Dawley rats were divided into 3 groups receiving a research diet with/without treatment compounds (alendronate: 3 mg/kg; La(XT) 100 mg/kg) for three months. At the time of sacrifice, the kidney, liver, brain, lung and spleen were collected for histological examination.

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A comparative investigation of two structurally related potentially nonadentate chelating ligands, Hneunpa-NH and Hnoneunpa, has been undertaken to examine the influence of bifunctionalization on their coordination chemistry and metal ion selectivity. Significantly improved synthetic routes for each compound have been developed, employing straightforward high-yielding strategies. Radiolabeling studies with [Sc]Sc, [In]In, [Lu]Lu, and [Ac]Ac revealed a sharp contrast between the affinity of each chelator for large radiometal ions.

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Advances in nuclear medicine depend on chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. A new potentially decadentate ligand, Hdecaox, was synthesised to incorporate two 8-hydroxyquinoline moieties on either end of a diethylenetriamine backbone decorated with three carboxylic acids, one at each N atom of the backbone. Metal complexation was assessed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) with In, Zr and La.

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Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins with anti-apoptotic activity. It plays a key role in the regulation of the intrinsic pathway of apoptosis. Moreover, Mcl-1 is correlated with the progression and drug-resistance of various cancers.

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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 = 18.

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