Recent progress of astatine-211 in endoradiotherapy: Great advances from fundamental properties to targeted radiopharmaceuticals

Li, Feize; Yang, Yuanyou; Liao, Jiali; Liu, Ning

doi:10.1016/j.cclet.2022.03.025

Cited by 28 publications

(16 citation statements)

References 267 publications

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“…Apart from superheavy elements, the rarest naturally occurring element and the heaviest halogen astatine 85 At remains one of the most “enigmatic” in the periodic table. , The 211 At isotope’s unique properties have been attracting much attention in the nuclear medicine community for several decades. As a pure α-emitter, 211 At is ideally suited for targeted therapy of malignant tumors due to its half-life, linear energy transfer, and the absence of harmful radioactive or toxic decay products or harmful deceleration γ-rays. − However, 211 At’s scarcity due to production complexity and cost keeps its experimental chemistry elusive, thus creating a major obstacle in translating accelerator-generated elemental 211 At to radiopharmaceuticals …”

Section: Introductionmentioning

confidence: 99%

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

et al. 2022

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We present a systematic study of electron-correlation and relativistic effects in diatomic molecular species of the heaviest halogen astatine (At) within relativistic single-and multireference coupled-cluster approaches and relativistic density functional theory. We establish revised reference ab initio data for the ground states of At 2 , HAt, AtAu, and AtO + using a highly accurate relativistic effective core potential model and in-house basis sets developed for accurate modeling of molecules with large spin−orbit effects. Spin-dependent relativistic effects on chemical bonding in the ground state are comparable to the binding energy or even exceed it in At 2 . Electron-correlation effects near the equilibrium internuclear separation are mostly dynamical and can be adequately captured using single-reference CCSD(T). However, bond elongation in At 2 and, especially, AtO + results in rapid manifestation of its multireference character. While useful for evaluating the spin−orbit effects on the ground-state bonding and properties, the two-component density functional theory lacks predictive power, especially in combination with popular empirically adjusted exchange-correlation functionals. This drawback supports the necessity to develop new functionals for reliable quantum-chemical models of heavy-element compounds with strong relativistic effects.

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Section: Introductionmentioning

confidence: 99%

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

et al. 2022

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“…TRT is an emerging approach for the treatment of cancer, , especially in clinical settings where tumor burden is low or malignant cell populations are located near essentially normal tissue structures. Alpha-emitting radionuclides can offer significant advantages for targeted radiotherapy due to their innate nuclear properties. , As one of the α-emitters for targeted therapy, 211 At is probably the most promising radionuclide for TAT . Currently, there are several clinical trials involving 211 At-labeled pharmaceuticals.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 As one of the α-emitters for targeted therapy, 211 At is probably the most promising radionuclide for TAT. 8 Currently, there are several clinical trials involving 211 At-labeled pharmaceuticals. For example, Zalutsky et al employed 211 At-labeled ch81C6 mAb to treat 18 patients with recurrent brain tumors by administering the radiopharmaceuticals into a surgically created resection cavity.…”

Section: Discussionmentioning

confidence: 99%

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Targeted Alpha Therapy of Glioma Using ²¹¹At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Liu

Liang

et al. 2022

Mol. Pharmaceutics

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Targeted radionuclide therapy based on α-emitters plays an increasingly important role in cancer treatment. In this study, we proposed to apply a heterodimeric peptide (iRGD-C6-lys-C6-DA7R) targeting both VEGFR and integrins as a new vector for 211At radiolabeling to obtain high-performance radiopharmaceuticals with potential in targeted alpha therapy (TAT). An astatinated peptide, iRGD-C6-lys(211At-ATE)-C6-DA7R, was prepared with a radiochemical yield of ∼45% and high radiochemical purity of >95% via an electrophilic radioastatodestannylation reaction. iRGD-C6-lys(211At-ATE)-C6-DA7R showed good stability in vitro and high binding ability to U87MG (glioma) cells. Systematic in vitro antitumor investigations involving cytotoxicity, apoptosis, distribution of the cell cycle, and reactive oxygen species (ROS) clearly demonstrated that 211At-labeled heterodimeric peptides could significantly inhibit cell viability, induce cell apoptosis, arrest the cell cycle in G2/M phase, and increase intracellular ROS levels in a dose-dependent manner. Biodistribution revealed that iRGD-C6-lys(211At-ATE)-C6-DA7R had rapid tumor accumulation and fast normal tissue/organ clearance, which was mainly excreted through the kidneys. Moreover, in vivo therapeutic evaluation indicated that iRGD-C6-lys(211At-ATE)-C6-DA7R was able to obviously inhibit tumor growth and prolong the survival of mice bearing glioma xenografts without notable toxicity to normal organs. All these results suggest that TAT mediated by iRGD-C6-lys(211At-ATE)-C6-DA7R can provide an effective and promising strategy for the treatment of glioma and some other tumors.

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“…As a pure α-emitter, 211 At is ideally suited for targeted therapy of malignant tumors due to its half-life, linear energy transfer, and the absence of harmful radioactive or toxic decay products or harmful deceleration γ-rays. [3][4][5][6] However, 211 At's scarcity due to production complexity and cost keeps its experimental chemistry elusive, thus creating a major obstacle in translating accelerator-generated elemental 211 At to radiopharmaceuticals. 7 The absence of spectroscopic data even for diatomic species, such as At 2 , HAt, or AtO + , leaves state-of-the-art ab initio quantum-chemical calculations the sole source of basic reference data on the equilibrium internuclear distance R e , dissociation energy D e , and vibrational frequency ω e .…”

Section: Introductionmentioning

confidence: 99%

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine's Small Molecules

Rusakov

Casetti

MacLean

et al. 2022

Preprint

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We present a systematic study of electron-correlation and relativistic effects in diatomic molecular species of the heaviest halogen astatine (At) within relativistic single- and multi-reference coupled-cluster approaches and relativistic density functional theory. We establish revised reference \textit{ab initio} data for the ground states of \ce{At2}, \ce{HAt}, \ce{AtAu}, and \ce{AtO+} using a highly accurate relativistic effective core potential model and in-house basis sets developed for accurate modeling of molecules with large spin-orbit effects. Spin-dependent relativistic effects on chemical bonding in the ground state are comparable to the binding energy or even exceed it in \ce{At2}. Electron-correlation effects near the equilibrium internuclear separation are mostly dynamical and can be adequately captured using single-reference CCSD(T). However, bond elongation in \ce{At2} and, especially, \ce{AtO+} results in rapid manifestation of its multi-reference character. While useful for evaluating the spin-orbit effects on the ground-state bonding and properties, the two-component density functional theory lacks predictive power, especially in combination with popular empirically adjusted exchange-correlation functionals. This drawback supports the necessity to develop new functionals for reliable quantum-chemical models of heavy-element compounds with strong relativistic effects.

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Recent progress of astatine-211 in endoradiotherapy: Great advances from fundamental properties to targeted radiopharmaceuticals

Cited by 28 publications

References 267 publications

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

Targeted Alpha Therapy of Glioma Using ²¹¹At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine's Small Molecules

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Recent progress of astatine-211 in endoradiotherapy: Great advances from fundamental properties to targeted radiopharmaceuticals

Cited by 28 publications

References 267 publications

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine’s Small Molecules

Targeted Alpha Therapy of Glioma Using 211At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Investigating the Heaviest Halogen: Lessons Learned from Modeling the Electronic Structure of Astatine's Small Molecules

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Targeted Alpha Therapy of Glioma Using ²¹¹At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins