Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates

Tezé, David; Sergentu, Dumitru‐Claudiu; Kalichuk, Valentina; Barbet, Jacques; Deniaud, David; Galland, Nicolas; Maurice, Rémi; Montavon, Gilles

doi:10.1038/s41598-017-02614-2

Cited by 54 publications

(62 citation statements)

References 67 publications

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“…56,89 The reabsorption of free 211 At after sequestering of 211 At molecules by the kidneys is believed to be related to intracellular oxidative decomposition after exocytosis and subsequent systemic recycling. 56,90 There are intense efforts made to improve the in vivo stability of 211 At compounds to enable general nuclear medicine applications. 66,91,92 Many of the hampering features of 211 At relate to its halogen characteristics.…”

Section: Discussionmentioning

confidence: 99%

Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Lindegren

Albertsson

Bäck

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Despite the consensus around the clinical potential of the a-emitting radionuclide astatine-211 (211 At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing 211 At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of 211 At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with 211 At depend on custom systems for recovering 211 At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of 211 At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between 211 At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing 211 At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with 211 At.

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Section: Discussionmentioning

confidence: 99%

Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Lindegren

Albertsson

Bäck

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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“…211 At was used for labeling anti-CXCR4 mAb by a standard two-step procedure; however, 211 At has been found to be unstable after binding by this method 22 . In vivo deastatination has been reported to be attributable to the weaker carbon-halogen bond and oxidative dehalogenation for astatine than for iodine 23 .…”

Section: Discussionmentioning

confidence: 99%

Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody

Oriuchi

Aoki

Ukon

et al. 2020

Sci Rep

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to explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the 211 At-labeled anti-C-X-C chemokine receptor type 4 monoclonal antibody ( 211 At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of 211 At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using 211 At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.Targeted α-particle therapy (TAT) has great potential for the treatment of cancer based on the specific delivery of a high radiation dose from α-particles emitting radionuclides to tumors while minimizing systemic toxic effects, and it may lead to additional treatment options for many types of advanced or refractory cancer 1 . The high level of radiobiological effectiveness of α-particles, in comparison with β-particles emissions, requires fewer radiation tracks to induce cell death. The short path length of α-particles radiation confines its cytotoxic effect to the target tissue and the surrounding tumor microenvironment while limiting toxic effects to non-neoplastic tissues.Following the successful clinical TAT with 223 Ra dichloride for the treatment of metastatic castration-resistant prostate cancer with bone metastases and the clinical experience with 213 Bi-and 225 Ac-labeled compounds 2-4 , there has been an increased interest in new applications of TAT for many tumor types. Among the α-particles-emitting radionuclides for TAT, 211 At can be produced using a cyclotron with an α-particle beam, and its separation and purification from the target has been established after decades of continuous research. After a branch decay with a half-life of 7.21 h, 211 At completely emits α-particles with 100% probability. A few clinical applications of 211 At for the treatment of malignant neoplasms have been reported 5,6 .The failure of medical and radiological anti-cancer therapies is partially attributable to the heterogeneity of cancer. One of the mechanisms explaining cancer heterogeneity is the existence of cancer stem cells (CSCs) 7 . CSCs exhibit self-renewal activity and long-term proliferating capability 8 . The concept of neoplastic stem cells may explain the failure of various therapies to achieve long-lasting responses in patients 9 , because CSCs are suggested as a potential source of resistance to different types of anti-neoplastic drug. Anti-neoplastic drugs are considered to act on mature neoplastic cells rather than on CSCs in many neoplastic tissues. This is partially owing to th...

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“…As there is no existing stable isotope, non‐radioactive astatine‐labeled compounds cannot be prepared and used as reference material, e. g. to enable identification of 211 At‐labeled compounds by HPLC after radiosynthesis. Therefore, iodine‐labeled analogs are often used as reference compounds, not only for analytics, but also to study in vivo deastatination by comparison with structurally equivalent 211 At‐labeled compounds, although significant differences of 211 At and iodine have been reported . Another drawback of 211 At‐radiopharmaceuticals is that several manual steps are often required in the production process .…”

Section: Figurementioning

confidence: 99%

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

et al. 2019

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In the past decade, several developments have expanded the chemical toolbox for astatination and the preparation of 211At‐labeled radiopharmaceuticals. However, there is still a need for advanced methods for the synthesis of astatinated (bio)molecules to address challenges such as limited in vivo stability. Herein, we report the development of multifunctional 211At‐labeled reagents that can be prepared by applying a modular and versatile click approach for rapid assembly. The introduction of tetrazines as bioorthogonal tags enables rapid radiolabeling and radio‐crosslinking, which is demonstrated by steric shielding of 211At to significantly increase label stability in human blood plasma.

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Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates

Cited by 54 publications

References 67 publications

Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure

Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

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