Applications of 211At and 223Ra in Targeted Alpha-Particle Radiotherapy

Vaidyanathan, Ganesan; Zalutsky, Michael R.

doi:10.2174/1874471011104040283

Cited by 63 publications

(40 citation statements)

References 60 publications

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“…It is a high linear energy transfer (LET) α-emitter that deposits enough energy (>80 keV/μm) to break double-stranded DNA [1]. It has a short emission range (<50 μm) inside cells, and has a 7.2-hr treatment half-life [2]. Moreover, the decay sequence of 211 At (α-decay to 207 Bi, or electron capture leading to 211 Po alpha-decay to 207 Pb) has reduced side effects from daughter nuclei because of the short 211 Po half-life (0.5 sec); this more favourable that the 210 At decay sequence, which is another candidate for targeted radionuclide therapy.…”

Section: Introductionmentioning

confidence: 99%

Validating α-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors

Kodaira

Konishi

et al. 2017

PLoS ONE

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Recently, 211At has received increasing attention as a potential radionuclide for cancer radioimmunotherapy. It is a α-particle emitter, which is extremely effective against malignant cells. We demonstrate a method to verify the efficiency of 211At-labeled trastuzumab antibodies (211At-trastuzumab) against HER2 antigens, which has not been determined for radioimmunotherapy. A CR-39 plastic nuclear detector is used for measuring the position and the linear energy transfer (LET) of individual 211At α- particle tracks. The tracks and 211At-trastuzumab-binding cells were co-visualized by using the geometric information recorded on the CR-39. HER2-positive human gastric cancer cells (NCI-N87), labelled with 211At-trastuzumab, were dropped on the centre of the CR-39 plate. Microscope images of the cells and the corresponding α-tracks acquired by position matching were obtained. In addition, 3.5 cm × 3.5 cm macroscopic images of the whole plate were acquired. The distribution of number of α-particles emitted from single cells suggests that 80% of the 211At-trastuzumab-binding cells emitted α-particles. It also indicates that the α-particles may strike the cells several times along their path. The track-averaged LET of the α-particles is evaluated to be 131 keV/μm. These results will enable quantitative evaluation of delivered doses to target cells, and will be useful for the in vitro assessment of 211At-based radioimmunotherapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Validating α-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors

Kodaira

Konishi

et al. 2017

PLoS ONE

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“…The optimum conditions for performing halodestannylation reactions generally is includes a pH of about 5–5.5, which is usually accomplished by adding acetic acid to the reaction mixture [3–5]. However, our previous results [8,9] suggest that addition of acetic acid may not be necessary and might even be counterproductive at radiation doses greater than about 3,000 Gy due to radiolysis-induced generation of reducing species in methanol under these conditions [16].…”

Section: Resultsmentioning

confidence: 99%

“…One of the most attractive α-emitters for this purpose, 211 At, has a half-life of 7.2 h, and has two features distinguishing it from other α-emitters of potential clinical interest: absence of potentially confounding long-lived α-emitting daughters and halogenic rather than metallic character [2]. As a consequence of the later, labeling methods for 211 At are different than those for α-emitting radiometals, with electrophilic demetallation of stannyl or silyl precursors being the most widely used approach for labeling biomolecules with 211 At [3,4]. This labeling strategy has been successfully utilized at 211 At activity levels of the order of 37 MBq with a variety of compounds.…”

Section: Introductionmentioning

confidence: 99%

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At α-particles

Pozzi

Zalutsky

2017

Nuclear Medicine and Biology

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Introduction Alpha particles are radiation of high energy and short range, properties that can lead to radiolysis-mediated complications in labeling chemistry at the high radioactivity levels required for clinical application. In previous papers in this series, we have shown that radiation dose has a profound effect on the astatine species that are present in the labeling reaction and their suitability for the synthesis of N-succinimidyl 3-[211At]astatobenzoate. The purpose of this study was to evaluate the effects of adding N-chlorosuccinimide (NCS) to the methanol solution used for initial isolation of 211At after distillation, a process referred to as 211At stabilization, on 211At chemistry after exposure to high radiation doses. Methods High performance liquid chromatography was used to evaluate the distribution of 211At species present in methanol in the 500–65,000 Gy radiation dose range and the synthesis of SAB from N-succinimidyl 3-(tri-n-butylstanny)benzoate in the 500–120,000 Gy radiation dose range using different 211At time activity combinations under conditions with/without 211At stabilization. Results In the absence of NCS stabilization, a reduced form of astatine, At(2), increased with increasing radiation dose, accounting for about half the total activity by about 15,000 Gy, while with stabilization, At(2) accounted for <10% of 211At activity even at doses >60,000 Gy. SAB yields without stabilization rapidly declined with increasing dose, falling to ~20% at about 5,000 Gy while with stabilization, yields >80% were obtained with 211At solutions stored for more than 23 h and receiving radiation doses >100,000 Gy. Conclusions Adding NCS to the methanol solution used for initial isolation of 211At is a promising strategy for countering the deleterious effects of radiolysis on 211At chemistry. Advances in Knowledge and Implications for Patient Care This strategy could facilitate the ability to perform 211At labeling at sites remote from its production and at the high activity levels required for clinical applications.

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“…This affects the potential application of 211 At to medicine. Nevertheless, 211 At is considered as one of the most promising radionuclides for targeted alpha therapy, due to its favourable physical properties (notably its half-life time of 7.2 h and its α-particle emission yield of 100%) 2, 3 .…”

Section: Introductionmentioning

confidence: 99%

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

Tezé

Sergentu

Kalichuk

et al. 2017

Sci Rep

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211At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C−At “organometalloid” bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 106 faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the “internal” deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.

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Applications of 211At and 223Ra in Targeted Alpha-Particle Radiotherapy

Cited by 63 publications

References 60 publications

Validating α-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors

Validating α-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At α-particles

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

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