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Nicolas Galland - One of the best experts on this subject based on the ideXlab platform.
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advances in the chemistry of Astatine and implications for the development of radiopharmaceuticals
Accounts of Chemical Research, 2021Co-Authors: François Guérard, Jean-françois Gestin, Gilles Montavon, Lu Liu, Clemence Maingueneau, Romain Eychenne, Nicolas GallandAbstract:ConspectusAstatine (At) is the rarest on Earth of all naturally occurring elements, situated below iodine in the periodic table. While only short-lived isotopes (t1/2 ≤ 8.1 h) are known, 211At is the object of growing attention due to its emission of high-energy alpha particles. Such radiation is highly efficient to eradicate disseminated tumors, provided that the radionuclide is attached to a cancer-targeting molecule. The interest in applications of 211At in nuclear medicine translates into the increasing number of cyclotrons able to produce it. Yet, many challenges related to the minute amounts of available Astatine are to be overcome in order to characterize its physical and chemical properties. This point is of paramount importance to develop synthetic strategies and solve the labeling instability in current approaches that limits the use of 211At-labeled radiopharmaceuticals. Despite its discovery in the 1940s, only the past decade has seen a significant rise in the understanding of Astatine's basic chemical and radiochemical properties, thanks to the development of new analytical and computational tools.In this Account, we give a concise summary of recent advances in the determination of the physicochemical properties of Astatine, putting in perspective the duality of this element which exhibits the characteristics both of a halogen and of a metal. Striking features were evidenced in the recent determination of its Pourbaix diagram such as the identification of stable cationic species, At+ and AtO+, contrasting with other halogens. Like metals, these species were shown to form complexes with anionic ligands and to exhibit a particular affinity for organic species bearing soft donor atoms. On the other hand, Astatine shares many characteristics with other halogen elements. For instance, the At- species exists in water, but with the least range of EH-pH stability in the halogen series. Astatine can form molecular interactions through halogen bonding, and it was only recently identified as the strongest halogen-bond donor. This ability is nonetheless affected by relativistic effects, which translate to other peculiarities for this heavy element. For instance, the spin-orbit coupling boosts Astatine's propensity to form charge-shift bonds, catching up with the behavior of the lightest halogens (fluorine, chlorine).All these new data have an impact on the development of radiolabeling strategies to turn 211At into radiopharmaceuticals. Inspired by the chemistry of iodine, the chemical approaches have sparsely evolved over the past decades and have long been limited to electrophilic halodemetalation reactions to form astatoaryl compounds. Conversely, recent developments have favored the use of the more stable At- species including the aromatic nucleophilic substitution with diaryliodonium salts or the copper-catalyzed halodeboronation of arylboron precursors. However, it is clear that new bonding modalities are necessary to improve the in vivo stability of 211At-labeled aryl compounds. The tools and data gathered over the past decade will contribute to instigate original strategies for overcoming the challenges offered by this enigmatic element. Alternatives to the C-At bond such as the B-At and the metal-At bonds are typical examples of exciting new axes of research.
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Astatine facing janus halogen bonding vs charge shift bonding
Molecules, 2021Co-Authors: Serigne Sarr, Gilles Montavon, Julien Pilme, Jeanyves Le Questel, Nicolas GallandAbstract:The nature of halogen-bond interactions was scrutinized from the perspective of Astatine, potentially the strongest halogen-bond donor atom. In addition to its remarkable electronic properties (e.g., its higher aromaticity compared to benzene), C6At6 can be involved as a halogen-bond donor and acceptor. Two-component relativistic calculations and quantum chemical topology analyses were performed on C6At6 and its complexes as well as on their iodinated analogues for comparative purposes. The relativistic spin–orbit interaction was used as a tool to disclose the bonding patterns and the mechanisms that contribute to halogen-bond interactions. Despite the stronger polarizability of Astatine, halogen bonds formed by C6At6 can be comparable or weaker than those of C6I6. This unexpected finding comes from the charge-shift bonding character of the C–At bonds. Because charge-shift bonding is connected to the Pauli repulsion between the bonding σ electrons and the σ lone-pair of Astatine, it weakens the Astatine electrophilicity at its σ-hole (reducing the charge transfer contribution to halogen bonding). These two antinomic characters, charge-shift bonding and halogen bonding, can result in weaker At-mediated interactions than their iodinated counterparts.
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towards a stronger halogen bond involving Astatine unexpected adduct with bu3po stabilized by hydrogen bonding
Chemistry: A European Journal, 2020Co-Authors: Lu Liu, Nicolas Galland, Ning Guo, Gilles Montavon, Julie Champion, Jerome Graton, Remi MauriceAbstract:The halogen bond is a powerful tool for the molecular design and pushing the limits of its strength is of major interest. Bearing the most potent halogen-bond donor atom, Astatine monoiodide (AtI) was recently successfully probed [Nat. Chem. 2018, 10, 428-434]. In this work, we continue the exploration of adducts between AtI and Lewis bases with the tributylphosphine oxide (Bu3 PO) ligand, revealing the unexpected experimental occurrence of two distinct chemical species with 1:1 and 2:1 stoichiometries. The 1:1 Bu3 PO⋅⋅⋅AtI complex is found to exhibit the strongest Astatine-mediated halogen bond so far (with a formation constant of 10(4.24±0.35) ). Quantum chemical calculations unveil the intriguing nature of the 2:1 2Bu3 PO⋅⋅⋅AtI adduct, involving a halogen bond between AtI and one Bu3 PO molecular unit plus CH⋅⋅⋅O hydrogen bonds chelating the second Bu3 PO unit.
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experimental and computational evidence of halogen bonds involving Astatine
Nature Chemistry, 2018Co-Authors: Ning Guo, David Teze, Remi Maurice, Gilles Montavon, Julie Champion, Jerome Graton, Nicolas GallandAbstract:The importance of halogen bonds-highly directional interactions between an electron-deficient σ-hole moiety in a halogenated compound and an acceptor such as a Lewis base-is being increasingly recognized in a wide variety of fields from biomedicinal chemistry to materials science. The heaviest halogens are known to form stronger halogen bonds, implying that if this trend continues down the periodic table, Astatine should exhibit the highest halogen-bond donating ability. This may be mitigated, however, by the relativistic effects undergone by heavy elements, as illustrated by the metallic character of Astatine. Here, the occurrence of halogen-bonding interactions involving Astatine is experimentally evidenced. The complexation constants of Astatine monoiodide with a series of organic ligands in cyclohexane solution were derived from distribution coefficient measurements and supported by relativistic quantum mechanical calculations. Taken together, the results show that Astatine indeed behaves as a halogen-bond donor-a stronger one than iodine-owing to its much more electrophilic σ-hole.
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Scrutinizing "invisible" Astatine: A challenge for modern density functionals
Journal of Computational Chemistry, 2016Co-Authors: Dumitru Claudiu Sergentu, Grégoire David, Remi Maurice, Ghislain Montavon, Nicolas GallandAbstract:The main-group 6p elements did not receive much attention in the development of recent density functionals. In many cases it is still difficult to choose among the modern ones a relevant functional for various applications. Here, we illustrate the case of Astatine species (At, Z = 85) and we report the first, and quite complete, benchmark study on several properties concerning such species. Insights on geometries, transition energies and thermodynamic properties of a set of 19 Astatine species, for which reference experimental or theoretical data has been reported, are obtained with relativistic (two-component) density functional theory calculations. An extensive set of widely used functionals is employed. The hybrid meta-generalized gradient approximation (meta-GGA) PW6B95 functional is overall the best choice. It is worth noting that the range-separated HSE06 functional as well as the old and very popular B3LYP and PBE0 hybrid-GGAs appear to perform quite well too. Moreover, we found that Astatine chemistry in solution can accurately be predicted using implicit solvent models, provided that specific parameters are used to build At cavities. © 2016 Wiley Periodicals, Inc.
François Guérard - One of the best experts on this subject based on the ideXlab platform.
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advances in the chemistry of Astatine and implications for the development of radiopharmaceuticals
Accounts of Chemical Research, 2021Co-Authors: François Guérard, Jean-françois Gestin, Gilles Montavon, Lu Liu, Clemence Maingueneau, Romain Eychenne, Nicolas GallandAbstract:ConspectusAstatine (At) is the rarest on Earth of all naturally occurring elements, situated below iodine in the periodic table. While only short-lived isotopes (t1/2 ≤ 8.1 h) are known, 211At is the object of growing attention due to its emission of high-energy alpha particles. Such radiation is highly efficient to eradicate disseminated tumors, provided that the radionuclide is attached to a cancer-targeting molecule. The interest in applications of 211At in nuclear medicine translates into the increasing number of cyclotrons able to produce it. Yet, many challenges related to the minute amounts of available Astatine are to be overcome in order to characterize its physical and chemical properties. This point is of paramount importance to develop synthetic strategies and solve the labeling instability in current approaches that limits the use of 211At-labeled radiopharmaceuticals. Despite its discovery in the 1940s, only the past decade has seen a significant rise in the understanding of Astatine's basic chemical and radiochemical properties, thanks to the development of new analytical and computational tools.In this Account, we give a concise summary of recent advances in the determination of the physicochemical properties of Astatine, putting in perspective the duality of this element which exhibits the characteristics both of a halogen and of a metal. Striking features were evidenced in the recent determination of its Pourbaix diagram such as the identification of stable cationic species, At+ and AtO+, contrasting with other halogens. Like metals, these species were shown to form complexes with anionic ligands and to exhibit a particular affinity for organic species bearing soft donor atoms. On the other hand, Astatine shares many characteristics with other halogen elements. For instance, the At- species exists in water, but with the least range of EH-pH stability in the halogen series. Astatine can form molecular interactions through halogen bonding, and it was only recently identified as the strongest halogen-bond donor. This ability is nonetheless affected by relativistic effects, which translate to other peculiarities for this heavy element. For instance, the spin-orbit coupling boosts Astatine's propensity to form charge-shift bonds, catching up with the behavior of the lightest halogens (fluorine, chlorine).All these new data have an impact on the development of radiolabeling strategies to turn 211At into radiopharmaceuticals. Inspired by the chemistry of iodine, the chemical approaches have sparsely evolved over the past decades and have long been limited to electrophilic halodemetalation reactions to form astatoaryl compounds. Conversely, recent developments have favored the use of the more stable At- species including the aromatic nucleophilic substitution with diaryliodonium salts or the copper-catalyzed halodeboronation of arylboron precursors. However, it is clear that new bonding modalities are necessary to improve the in vivo stability of 211At-labeled aryl compounds. The tools and data gathered over the past decade will contribute to instigate original strategies for overcoming the challenges offered by this enigmatic element. Alternatives to the C-At bond such as the B-At and the metal-At bonds are typical examples of exciting new axes of research.
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targeted alpha therapy combining Astatine 211 and anti cd138 antibody in a preclinical syngeneic mouse model of multiple myeloma minimal residual disease
Cancers, 2020Co-Authors: Sebastien Gouard, François Guérard, Cyrille Alliot, Nicolas Chouin, Ferid Haddad, Catherine Maurel, Severine Marionneaulambot, Delphine Dansette, Clement Bailly, Joelle GaschetAbstract:Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with Astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with Astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to Astatine-211.
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efficacy of Astatine 211 radioimmunotherapy of multiple myeloma using an anti mcd138 monoclonal antibody in a syngeneic murine model
European Journal of Nuclear Medicine and Molecular Imaging, 2018Co-Authors: Sebastien Gouard, François Guérard, Jean-françois Gestin, Cyrille Alliot, Benjamin Chalopin, Catherine Saimaurel, Laurent Navarro, Nicolas Chouin, Ferid Haddad, Francoise KraeberbodereAbstract:Aim: Multiple myeloma is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. In spite of a very active search for new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) is a new cancer treatment modality with tumour specific antibodies coupled to alpha particle-emitting radionuclides. CD138 (Syndecan-1) is found mainly in epithelial cells, but was shown to be expressed by most myeloma cells, both in human and in the mouse. The aim of the study was to evaluate the biodistribution, toxicity and efficacy of a rat Astatin-211-labelled anti-mouse CD138 antibody (211At-9E7.4) in a syngeneic mouse myeloma model. Materials and methods: C57BL/KaLwRij mice were grafted with 106 5T33 cells (murine myeloma cell line). Biodistribution was studied 15 min, 1h, 4h, 7h, 14h and 21h post-administration of 211At- 9E7.4 mAb. Toxicity (animal weight, blood cell counts and transaminase) and RIT efficacy were studied after a dose escalation using 370, 555, 740 and 1110 kBq of 211At-9E7.4 and two control groups 211At-IgG2a isotype control at 555 kBq or no treatment, 10 days after tumour engraftment. Results: Studies demonstrated a highly statistical survival benefit for the mice treated with 211At-9E7.4 at 555 kBq (p=0,0006) and 740 kBq (p<0,0001). At 555 kBq, the survival median was increase by 34 days and at 740 kBq 65% of the mice survived 160 days after engraftment. For treatments with 370 kBq with 211At-9E7.4 or 211At-isotype control at 555 kBq no significant benefit was observed. The higher activity with 1110 kBq of 211At-9E7.4 was clearly radiotoxic since mice were euthanized after a lost more than 30% of baseline weight 14 days after radiopharmaceutical injection. For the other groups, except transient decreases of leukocytes and red cells, no other toxicity could be demonstrated, especially on liver function, which does not seem to be affected. Concerning red blood cells, the effect is much weaker than that observed with the use of Bismuth-213 at an injected activity of 3.7 MBq. Conclusions: RIT of MM using Astatine-211 coupled to monoclonal antibody directed against murine CD138 is effective. The activity in astate-211 which allows 60% survival corresponds to an activity injected in Bismuth-213 located between 3.7 and 7.4 MBq, which seems to reflect the influence of the half life of the two radionuclides. In addition, the upper half-life of Astatine appears to be a benefit, particularly because of the lower toxicity observed in this syngeneic model of MM.
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radiolabelling of proteins with stabilised hypervalent Astatine 211 feasability and stability
The Journal of Nuclear Medicine, 2011Co-Authors: François Guérard, Holisoa Rajerison, Jacques Barbet, Alain Faivrechauvet, G J Meyer, Isidro Da Silva, Jean-françois GestinAbstract:1486 Objectives Astatine-211 has become of major interest for alpha immunoradiotherapy thanks to its good radiophysic properties. But the standard procedures for the radiolabelling of proteins with Astatine-211 are known to be lacking of in vivo stability, particularly in the case of small proteins or antibody fragments. We recently developed an original radiolabelling procedure providing aromatic rings radiolabelled with hypervalent Astatine. The aim of this study was to develop a bifunctional tin precursor allowing the radiolabelling of proteins for stability evaluations. Methods The relatively hard conditions necessary to introduce Astatine on the precursor (100°C in methanol/acetic acid) led us to develop a bifunctional compound able to resist to the radiolabelling steps and then to be coupled to a protein. That is why a maleimide was chosen as coupling function. The radiolabelled compound was prepared in two steps. In the first step, the tin precursor and N-chlorosuccinimide were incubated at 100°C for 30 min with Astatine-211 in methanol to give the monovalent compound. In the second step N-bromosuccinimide in chloroform and hydrochloric acid were added to give the hypervalent species. The monovalent and hypervalent astatinated compounds were then conjugated to bovine serum albumin.The stability in human serum was evaluated from 4°C to 37°C. Results The two-steps radiolabelling procedure gave excellent yields (85-90%). The monovalent and hypervalent astatinated compounds were coupled to BSA with good yields (respectively 96% and 81%). The radiolabelling was stable with 90% of the activity remaining on the BSA for both compounds at the temperatures studied. Conclusions This study demonstrates the possibility to radiolabel a protein with hypervalent Astatine. The excellent in vitro stability of BSA labelled with this method encourages us to continue this study with the evaluation of the in vivo stability
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Feasibility of the radioastatination of a monoclonal antibody with Astatine-211 purified by wet extraction
Journal of Labelled Compounds and Radiopharmaceuticals, 2008Co-Authors: M. Bourgeois, Holisoa Rajerison, François Davodeau, François Guérard, Patricia Remaud-le Saëc, Jean-françois Gestin, Michel Cherel, Marie Mougin-degraef, Cyrille Alliot, Jacques BarbetAbstract:Astatine-211, a most promising alpha-particle emitter for targeted radiotherapy, is generally obtained by high-temperature distillation. However, a liquid-liquid extraction procedure (wet extraction) has also been described. The purpose of this study was to develop and optimize the labelling of the stannylated-activated ester N-hydroxysuccinimidyl-meta-trimethylstannylbenzoate ester (MeSTB) with Astatine-211 extracted in di-isopropylether (DIPE) in the presence of the oxidant N-chlorosuccinimide (NCS). The effect of final volume, incubation duration and NCS amounts on radiolabelling yield was studied. The best yields (85-90%) of N-hydroxysuccinimidyl-meta-[211At]astatobenzoate ester (SAB) were obtained with 20 nmol of MeSTB, 100 nmol of NCS in 120 µL of DIPE after 15 min. The Astatine-211-labelled-activated ester was then used to radiolabel a monoclonal antibody (mAb). The labelling yield was 20-25% and the radiochemical purity was 97-99%. These results show that mAbs may be efficiently labelled with Astatine-211 obtained by wet extraction, a fully automatable technique that may prove to be a useful alternative to dry distillation for high activity labelling of radiopharmaceuticals. Copyright © 2008 John Wiley & Sons, Ltd.
Cyrille Alliot - One of the best experts on this subject based on the ideXlab platform.
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targeted alpha therapy combining Astatine 211 and anti cd138 antibody in a preclinical syngeneic mouse model of multiple myeloma minimal residual disease
Cancers, 2020Co-Authors: Sebastien Gouard, François Guérard, Cyrille Alliot, Nicolas Chouin, Ferid Haddad, Catherine Maurel, Severine Marionneaulambot, Delphine Dansette, Clement Bailly, Joelle GaschetAbstract:Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with Astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with Astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to Astatine-211.
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evidence for the heaviest expected halide species in aqueous solution at by electromobility measurements
Inorganic Chemistry, 2018Co-Authors: Fabien Pottier, Cyrille Alliot, Jean Aupiais, Gilles Montavon, Julie ChampionAbstract:At– (astatide) is commonly expected to be the heaviest halide in the halogen group. However, there is no proof for the existence of this −1 charged species. Furthermore, investigations with Astatine are restricted by its specific radioactive properties, which entail working at ultratrace concentrations (typically less than 10–10 M). In this work, an especially built electromigration device is applied to obtain information about the charge/size ratio characterizing an ion in aqueous solution. An anionic At species is observed in reducing conditions. Moreover, we propose the first absolute mobility value for the Astatine species in acidic reducing condition: (−8.26 ± 0.59) × 10–4 cm2·V–1·s–1. This value appears close to that of I– ((−8.30 ± 0.33) × 10–4 cm2·V–1·s–1), which is obtained by the same method. The similar absolute mobilities obtained for both ions are coherent with theoretical calculations indicating similar diffusion behaviors for At– and I–. This good agreement confirms the existence of the At–...
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Evidence for the Heaviest Expected Halide Species in Aqueous Solution, At–, by Electromobility Measurements
2018Co-Authors: Ning Guo, Cyrille Alliot, Fabien Pottier, Jean Aupiais, Gilles Montavon, Julie ChampionAbstract:At– (astatide) is commonly expected to be the heaviest halide in the halogen group. However, there is no proof for the existence of this −1 charged species. Furthermore, investigations with Astatine are restricted by its specific radioactive properties, which entail working at ultratrace concentrations (typically less than 10–10 M). In this work, an especially built electromigration device is applied to obtain information about the charge/size ratio characterizing an ion in aqueous solution. An anionic At species is observed in reducing conditions. Moreover, we propose the first absolute mobility value for the Astatine species in acidic reducing condition: (−8.26 ± 0.59) × 10–4 cm2·V–1·s–1. This value appears close to that of I– ((−8.30 ± 0.33) × 10–4 cm2·V–1·s–1), which is obtained by the same method. The similar absolute mobilities obtained for both ions are coherent with theoretical calculations indicating similar diffusion behaviors for At– and I–. This good agreement confirms the existence of the At– species
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efficacy of Astatine 211 radioimmunotherapy of multiple myeloma using an anti mcd138 monoclonal antibody in a syngeneic murine model
European Journal of Nuclear Medicine and Molecular Imaging, 2018Co-Authors: Sebastien Gouard, François Guérard, Jean-françois Gestin, Cyrille Alliot, Benjamin Chalopin, Catherine Saimaurel, Laurent Navarro, Nicolas Chouin, Ferid Haddad, Francoise KraeberbodereAbstract:Aim: Multiple myeloma is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. In spite of a very active search for new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) is a new cancer treatment modality with tumour specific antibodies coupled to alpha particle-emitting radionuclides. CD138 (Syndecan-1) is found mainly in epithelial cells, but was shown to be expressed by most myeloma cells, both in human and in the mouse. The aim of the study was to evaluate the biodistribution, toxicity and efficacy of a rat Astatin-211-labelled anti-mouse CD138 antibody (211At-9E7.4) in a syngeneic mouse myeloma model. Materials and methods: C57BL/KaLwRij mice were grafted with 106 5T33 cells (murine myeloma cell line). Biodistribution was studied 15 min, 1h, 4h, 7h, 14h and 21h post-administration of 211At- 9E7.4 mAb. Toxicity (animal weight, blood cell counts and transaminase) and RIT efficacy were studied after a dose escalation using 370, 555, 740 and 1110 kBq of 211At-9E7.4 and two control groups 211At-IgG2a isotype control at 555 kBq or no treatment, 10 days after tumour engraftment. Results: Studies demonstrated a highly statistical survival benefit for the mice treated with 211At-9E7.4 at 555 kBq (p=0,0006) and 740 kBq (p<0,0001). At 555 kBq, the survival median was increase by 34 days and at 740 kBq 65% of the mice survived 160 days after engraftment. For treatments with 370 kBq with 211At-9E7.4 or 211At-isotype control at 555 kBq no significant benefit was observed. The higher activity with 1110 kBq of 211At-9E7.4 was clearly radiotoxic since mice were euthanized after a lost more than 30% of baseline weight 14 days after radiopharmaceutical injection. For the other groups, except transient decreases of leukocytes and red cells, no other toxicity could be demonstrated, especially on liver function, which does not seem to be affected. Concerning red blood cells, the effect is much weaker than that observed with the use of Bismuth-213 at an injected activity of 3.7 MBq. Conclusions: RIT of MM using Astatine-211 coupled to monoclonal antibody directed against murine CD138 is effective. The activity in astate-211 which allows 60% survival corresponds to an activity injected in Bismuth-213 located between 3.7 and 7.4 MBq, which seems to reflect the influence of the half life of the two radionuclides. In addition, the upper half-life of Astatine appears to be a benefit, particularly because of the lower toxicity observed in this syngeneic model of MM.
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Advances on the Determination of the Astatine Pourbaix Diagram: Predomination of AtO(OH)2-over At-in Basic Conditions
Chemistry - A European Journal, 2016Co-Authors: Dumitru Claudiu Sergentu, Andréa Sabatié-gogova, Fadel Bassal, Isidro Da Silva, David Deniaud, David Teze, Remi Maurice, Cyrille Alliot, Ning Guo, Justin ChampionAbstract:It is generally assumed that astatide (At(-) ) is the predominant Astatine species in basic aqueous media. This assumption is questioned in non-complexing and non-reductive aqueous solutions by means of high-pressure anion-exchange chromatography. Contrary to what is usually believed, astatide is found to be a minor species at pH=11. A different species, which also bears a single negative charge, becomes predominant when the pH is increased beyond 7. Using competition experiments, an equilibrium constant value of 10(-6.9) has been determined for the formation of this species from AtO(OH) with the exchange of one proton. The identification of this species, AtO(OH)2 (-) , is achieved through relativistic quantum mechanical calculations, which rule out the significant formation of the AtO2 (-) species, while leading to a hydrolysis constant of AtO(OH) in excellent agreement with experiment when the AtO(OH)2 (-) species is considered. Beyond the completion of the Pourbaix diagram of Astatine, this new information is of interest for the development of (211) At radiolabeling protocols.
Scott D Wilbur - One of the best experts on this subject based on the ideXlab platform.
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development of an autonomous solvent extraction system to isolate Astatine 211 from dissolved cyclotron bombarded bismuth targets
Scientific Reports, 2019Co-Authors: Matthew J Ohara, Donald K Hamlin, Eric F Dorman, Anthony J Krzysko, Scott D WilburAbstract:Cyclotron-produced Astatine-211 (211At) shows tremendous promise in targeted alpha therapy (TAT) applications due to its attractive half-life and its 100% α-emission from nearly simultaneous branched alpha decay. Astatine-211 is produced by alpha beam bombardment of naturally monoisotopic bismuth metal (209Bi) via the (α, 2n) reaction. In order to isolate the small mass of 211At (specific activity = 76 GBq·µg−1) from several grams of acid-dissolved Bi metal, a manual milliliter-scale solvent extraction process using diisopropyl ether (DIPE) is routinely performed at the University of Washington. As this process is complex and time consuming, we have developed a fluidic workstation that can perform the method autonomously. The workstation employs two pumps to concurrently deliver the aqueous and organic phases to a mixing tee and in-line phase mixer. The mixed phases are routed to a phase settling reservoir, where they gravity settle. Finally, each respective phase is withdrawn into its respective pump. However, development of a phase boundary sensor, placed in tandem with the phase settling reservoir, was necessary to communicate to the system when withdrawal of the denser aqueous phase was complete (i.e., the intersection of the two phases was located). The development and optimization of the autonomous solvent extraction system is described, and the 211At yields from several ~1.1 GBq-level 211At processing runs are reported.
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an automated process for Astatine 211 isolation from irradiated bismuth targets using a tellurium packed column
The Journal of Nuclear Medicine, 2018Co-Authors: Mingkuan Chyan, Donald K Hamlin, Scott D WilburAbstract:666 Objectives: The objective of this research effort was to evaluate automation of a facile method for isolation of 211At from irradiated bismuth targets using tellurium-packed columns (Te-column). 211At is an attractive radionuclide for targeted alpha therapy (TAT) due to its physical properties; 7.21 h half-life, minimal high energy gamma-ray emission and 100% alpha emission. Highly efficient and robust automated 211At isolation systems are required for improving its availability and to facilitate clinical studies of 211At-labeled TAT agents. Methods: Chromatographic conditions for manually separating 211At using Te-columns were optimized using small amounts, i.e. ≤37 MBq (≤1 mCi), of 211At based on the early studies of Bochvarova and co-workers1. In evaluations of the automated system, targets containing ~0.96 GBq (~26 mCi) of 211At were dissolved in 10 M HNO3 using an in-line dissolution chamber2 and the resultant solution was routed into a 250-mL reaction vessel. Then an NH2OH·HCl solution was added dropwise into the reaction vessel to destroy the nitrate ions, followed by a HCl solution to reconstitute the 211At/Bi mixture to 1.5 M HCl solution. Subsequently, the Te-column was loaded with the 211At/Bi mixture, washed with 1.5 M HCl and H2O. Finally, 211At was eluted using 5 mL of 2 M NaOH. In the automated system, Hamilton Microlab 500 Series Diluter/Dispenser dual-syringe pump and Modular Valve Positioners controlled by the Microlab 500 Control Software were used for routing and delivering all the liquids. The radiochemical purity of the 211At was assessed using radio-HPLC and radio-iTLC. The 211At obtained was used to radiolabel isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS)-conjugated antibodies after adjusting the pH to ~7.0. The concentrations of Bi and Te in 211At solutions and astatinated antibodies were determined using ICP-MS. Results: The automated isolation process took less than 2 h, and 211At isolated yields (after attenuation and decay correction) of 88-95% were achieved. Radio-HPLC analyses showed that ≥ 99% of the 211At in the final product was astatide. Astatination yields of B10-conjugated antibody were high (77-95%) and the concentration of Bi and Te in the size-exclusion column purified final product was less than 0.031 and 0.19 ppm, respectively. Conclusions: An efficient automated process that uses Te-columns for separating 211At from irradiated Bi targets has been developed. The purified 211At is of high radiochemical purity and suitable for B10-conjugated antibody astatination reactions. Acknowledgments: The authors gratefully acknowledge the staff of the U.W. Medical Cyclotron Facility, especially E.F. Dorman and R.C. Emery, for assistance in obtaining irradiated bismuth targets. We thank the Isotope Research & Development program, Office of Science, United States Department of Energy for funding this research (DE-SC0013618 & DE-SC0018013). References: 1. M. Bochvarova, D. K. T., I. Dudova, Yu. V. Norseev, and V. A. Khalkin, Investigation of Columns Filled with Crystalline Tellurium for the Production of Radiochemically Pure Preparations of Astatine. Translated from Radiokhimiya 1972,14 (6), 858-865. 2. O’Hara, M. J., Krzysko, A. J., Niver, C. M., Morrison, S. S., Owsley, S. L., Hamlin, D. K., Dorman, E. F., and Wilbur, D.S, An automated flow system incorporating in-line acid dissolution of bismuth metal from a cyclotron irradiated target assembly for use in the isolation of Astatine-211. Applied Radiation and Isotopes 2017,122 (Supplement C), 202-210.
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Astatine 211 labeling of an antimelanoma antibody and its fab fragment using n succinimidyl p 211at astatobenzoate comparisons in vivo with the p 125i iodobenzoyl conjugate
Bioconjugate Chemistry, 1991Co-Authors: Stephen W Hadley, Scott D Wilbur, Mary Ann Gray, Robert W AtcherAbstract:Astatine-211 labeling of an antimelanoma antibody, NR-ML-05, and its Fab fragment with N-succinimidyl p-[211At]astatobenzoate (2a) has been described. Preparation of the astatinated intermediate 2a was accomplished by distilling Astatine-211 from an irradiated bismuth target directly into a reaction mixture containing an organometallic compound, N-succinimidyl p-(tri-n-butylstannyl)benzoate (1), and an oxidant, N-chlorosuccinimide, in 5% HOAc/MeOH. Trapping of distilled Astatine as 2a was found to be efficient, resulting in 70-90% yields based on the amount of Astatine-211 in the reaction mixture. The dry distillation technique employed gave recoveries of Astatine-211 which ranged from 20% to 75%. Conjugation of 2a to NR-ML-05 and its Fab fragment was accomplished in 40-60% yields. The [211At]astatobenzoyl-conjugated antibodies were found to be stable in vitro when challenged by strong denaturants and nucleophilic reagents. Coinjected dual-labeled studies of the 2a astatinated antibodies and the same antibodies labeled with N-succinimidyl p-[125I]iodobenzoate (2b) in athymic mice bearing the human tumor xenograft A375 Met/Mix demonstrated that both radiolabeled antibodies had equivalent tumor localization. Data from the dual-labeled biodistribution of the intact antibody suggests that the Astatine is stably attached. Data from the dual-labeled Fab fragment suggests that a portion of the Astatine label is released as astatide, either from the astatinated Fab or from a catabolite.
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Astatine 211 labeling of an antimelanoma antibody and its fab fragment using n succinimidyl p 211at astatobenzoate comparisons in vivo with the p 125i iodobenzoyl conjugate
Bioconjugate Chemistry, 1991Co-Authors: Stephen W Hadley, Scott D Wilbur, Mary Ann Gray, Robert W AtcherAbstract:Astatine-211 labeling of an anti-melanoma antibody, NR-ML-05, and its Fab fragment using N-succinimidyl para[{sup 211} At]astatobenzoate has been described. Preparation of the astatinated intermediate 2a was accomplished by distilling Astatine-211 from an irradiated bismuth target directly into a reaction mixture containing an organometallic compound, N-succinimidyl p-(tri-n-butylstannyl)benzoate (1), and an oxidant, N-chlorosuccinimide, in 5% HOAc/MeOH. Trapping of distilled Astatine as 2a was found to be efficient, resulting in 70-90% yields based on the amount of Astatine-211 which ranged from 20% to 75%. Conjugation of 2a to NR-ML-05 and its Fab fragment was accomplished in 40-60% yields. The [{sup 211}At]astatobenzoyl-conjugated antibodies were found to be stable in vitro when challenged by strong denaturants and nucleophilic reagents. Coinjected dual-labeled studies of the 2a astatinated antibodies and the same antibodies labeled with N-succinimidyl p-[{sup 125}I]iodobenzoate (2b) in athymic mice bearing the human tumor xenograft A375 Met/Mix demonstrated that both radiolabeled antibodies had equivalent tumor localization. Data from the dual-labeled biodistribution of the intact antibody suggests that the Astatine is stably attached. Data from the dual-labeled Fab fragment suggests that a portion of the Astatine label is released as astatide, either from the astatinated Fab or from a catabolite.
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a cytokine like factor astakine accelerates the hemocyte production in pacific oyster crassostrea gigas
Developmental and Comparative Immunology, 2016Co-Authors: Shuai Jiang, Lusheng Xin, Lingling Wang, Hao Wang, Limei Qiu, Linsheng SongAbstract:Astakine has been reported to be a hematopoietic growth factor of prokineticin homolog firstly found in arthropods freshwater crayfish Pacifastacus leniusculus. In the present study, an astakine homologous gene was identified from Pacific oyster Crassostrea gigas (designated CgAstakine). The full length cDNA of CgAstakine encoded a polypeptide of 103 amino acids containing a prokineticin (PK) domain homologous to that in astakine from freshwater crayfish P. leniusculus. The deduced amino acid sequence of CgAstakine shared higher similarity with those of other invertebrate astakines than prokineticins from vertebrates. The mRNA of CgAstakine was highly expressed in hepatopancreas and adductor muscle of oyster, while the CgAstakine protein was mainly distributed in hepatopancreas, gill and hemocytes. The mRNA expression of CgAstakine in hemocytes was significantly increased (p < 0.01) and maintained at a high level from 3 h to 9 h after Vibrio anguillarum challenge. After the oyster hemocytes were incubated with 5 μg/mL recombinant CgAstakine protein (rCgAstakine) for 24 h in vitro, the proliferation of hemocytes was significantly increased to 1.89 fold of that in control group (p < 0.05). Moreover, the total count of oyster hemocytes was significantly upregulated (2.45 fold of that in control group, p < 0.05) at 12 h after the oysters were received an injection of rCgAstakine (0.5 μg/g). These results collectively indicated that CgAstakine could modulate the hemocytes proliferation both in vitro and in vivo, and probably involved in the hematopoietic process fighting against the invasion of foreign pathogens.
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a cytokine like factor astakine accelerates the hemocyte production in pacific oyster crassostrea gigas
Developmental and Comparative Immunology, 2016Co-Authors: Yiqun Li, Shuai Jiang, Lingling Wang, Hao Wang, Meijia Li, Linsheng SongAbstract:Astakine has been reported to be a hematopoietic growth factor of prokineticin homolog firstly found in arthropods freshwater crayfish Pacifastacus leniusculus. In the present study, an astakine homologous gene was identified from Pacific oyster Crassostrea gigas (designated CgAstakine). The full length cDNA of CgAstakine encoded a polypeptide of 103 amino acids containing a prokineticin (PK) domain homologous to that in astakine from freshwater crayfish P. leniusculus. The deduced amino acid sequence of CgAstakine shared higher similarity with those of other invertebrate astakines than prokineticins from vertebrates. The mRNA of CgAstakine was highly expressed in hepatopancreas and adductor muscle of oyster, while the CgAstakine protein was mainly distributed in hepatopancreas, gill and hemocytes. The mRNA expression of CgAstaldne in hemocytes was significantly increased (p < 0.01) and maintained at a high level from 3 h to 9 h after Vibrio anguillarum challenge. After the oyster hemocytes were incubated with 5 mu g/mL recombinant CgAstakine protein (rCgAstakine) for 24 h in vitro, the proliferation of hemocytes was significantly increased to 1.89 fold of that in control group (p < 0.05). Moreover, the total count of oyster hemocytes was significantly upregulated (2.45 fold of that in control group, p < 0.05) at 12 h after the oysters were received an injection of rCgAstakine (0.5 mu g/g). These results collectively indicated that CgAstakine could modulate the hemocytes proliferation both in vitro and in vivo, and probably involved in the hematopoietic process fighting against the invasion of foreign pathogens. (C) 2015 Elsevier Ltd. All rights reserved.
