The Radiochemical and Radiopharmaceutical Applications of Radium

Gott, Matthew; Steinbach, Jörg; Mamat, Constantin

doi:10.1515/chem-2016-0011

Cited by 41 publications

(34 citation statements)

References 34 publications

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“…[7][8][9][10][11][12][13][14] However, 223 Ra does not easily form stable complexes. 15 Therefore, it is possible that after the decay of 227 Th to 223 Ra, 223 Ra may dissociate from the antibody complex, resulting in free 223 Ra ions with a biodistribution independent of the 227 Th-labeled antibody. As these 227 Th compounds enter clinical trials, there is a need to assess these potentially independent biodistributions.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows

Murray

Rojas²,

Gear³

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Introduction: Thorium-227 is an alpha-emitting radioisotope with potential therapeutic applications in targeted alpha therapy. Thorium-227 decays to Radium-223, which may have an independent biodistribution to that of the parent Thorium-227 radiopharmaceutical. Quantitative in vivo imaging with sodium iodide (NaI) detectors is challenging due to cross-talk between neighboring c-photopeaks as well as scattered c-photons. The aim of this work was to validate the use of a spectral analysis technique to estimate the activity of each isotope within a region of interest applied to a pair of conjugate view planar acquisitions, acquired at multiple energy windows. Methods: Energy spectra per unit activity arising from unscattered Thorium-227 photons and Radium-223 photons as well as from scattered photons were modeled. These spectra were scaled until the combination of these component spectra resulted in the closest match to the measured data in four energy windows. Results: Measured estimates of activity followed the known decay curves in phantoms representative of a human torso. The mean errors in estimating Thorium-227 and Radium-223 were 5.1% (range-8.0% to 40.0%) and 3.4% (range-50.0% to 48.7%), respectively. The differences between the integrals of the theoretical and estimated time activity curve were <10% for both Thorium-227 and Radium-223. Conclusion: c-camera quantification of Thorium-227 and Radium-223 can be achieved by using multiple energy window acquisitions.

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Section: Introductionmentioning

confidence: 99%

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows

Murray

Rojas²,

Gear³

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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“…4 Nonetheless, Ra being a large divalent cation and an efficient bone-seeker, the inherent lack of strong chelators amenable to safely convey 223 Ra 2+ in vivo limits its use in tumor-targeting constructs (such as conjugated antibodies) and hinders its application for broader treatments in oncology. 5 Commercial production of 223 Ra, generated from its parent 227 Ac (t 1/2 = 21.8 y), has also created an opportunity for developing 227 Th-based therapy approaches since 227 Ac beta-decays to 227 Th, which then alphadecays to 223 Ra. In contrast to Ra, Th exhibits the oxidation state +IV in aqueous systems and complexing agents for such a hard metal ion can readily be developed, unleashing the potential for targeted alpha therapy (TAT) strategies based on 227 Th bioconjugates.…”

Section: Introductionmentioning

confidence: 99%

Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy

et al. 2018

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The solution chemistry of a chelator developed for 227 Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven pK a values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity towards tetravalent metal ions, with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL]-, and that of its Eu(III) analogue. Likewise, log β 110 values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25°C) were measured for [ThL]-and [Fe III L] 2-, respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single-crystal structural analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the P-1 space group. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. L III edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and Page 2 of 40 completed after1 hour at room temperature, reinforcing the high suitability of this chelator for 227 Th targeted alpha therapy.

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“…Current research using 227 Th conjugates centers on developing and testing new radiopharmaceuticals for the treatment of breast, lymphoma, renal, AML, ovarian, and prostate cancers ( Supplementary Table S3). 40,109 Therapy using the anti-CD20 mAb rituximab labeled with 227 Th was demonstrated to kill lymphoma cells in nude mice bearing human B-lymphoma xenografts, without any serous toxicity. 107 In addition, Dahle et al demonstrated that 227 Thrituximab has a better therapeutic effect per unit of absorbed dose than 99 Y-tiuxetan-ibritumomab (Zevalin) or external beam irradiation.…”

mentioning

confidence: 99%

“…The resulting free daughter nuclides can then diffuse from the target, leading to energy deposition in healthy tissue. 109 Palm et al demonstrated, using microdosimetric calculations, that the energy deposited in the target could be reduced by 50% if diffusion of daughters of 211 At was taken into account. 116 Furthermore, a study evaluating the anti-CD33 mAb lintuzumab 225 Ac labeled for the treatment of leukemia in mice found that most of the radiation dose in the kidneys was due to renal uptake of free 213 Bi released following a particle decay of 225 Ac.…”

mentioning

confidence: 99%

Targeted Alpha Therapy: Current Clinical Applications

Liberal

O’Sullivan

McMahon

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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a-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of a particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and a particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, a particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that a emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of a particles. The short range of a particles makes them a potent tool to irradiate singlecell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of 223 RaCl 2 in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition, 225 Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another gamechanging piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled 227 Th and 225 Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.

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The Radiochemical and Radiopharmaceutical Applications of Radium

Cited by 41 publications

References 34 publications

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows

Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy

Targeted Alpha Therapy: Current Clinical Applications

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