Why bother with alpha particles?

King, Alan; Lin, Frank I.; Escorcia, Freddy E.

doi:10.1007/s00259-021-05431-y

Cited by 25 publications

(34 citation statements)

References 89 publications

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“…Fortunately, a number of other α-emitting radionuclides, such as 227 Th, 225 Ac, 213 Bi, 212 Bi, 212 Pb, and 211 At, have suitable properties for use in TAT . Among these radionuclides, 225 Ac has demonstrated particular promise due to advances in its large-scale production, its ideal 9.92-day physical half-life for conjugation to long-lived biomolecules, and its high cytotoxic potency, which arises from the four α particles emitted through its decay chain. , Clinical trials of 225 Ac small-molecule , and antibody conjugates are underway, and early results have been promising.…”

Section: Introductionmentioning

confidence: 99%

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

et al. 2022

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Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225 Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225 Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H 2 macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H 2 macropa, which contain either one (H 2 BZmacropa) or two (H 2 BZ 2 macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225 Ac TAT. The coordination chemistry of these ligands with La 3+ , used as a nonradioactive model for Ac 3+ , was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La 3+ complexes of these ligands revealed similar structural features to those found for the related complex of H 2 macropa. Thermodynamic stability constants of the La 3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H 2 macropa for H 2 BZmacropa and H 2 BZ 2 macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225 Ac radiolabeling and serum stability studies with H 2 BZmacropa showed that this chelator compares favorably with H 2 macropa. Based on these promising results, a bifunctional version of this chelator, H 2 BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225 Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [ 225 Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [ 225 Ac]Ac-GC33-macropa. Together, these results establish H 2 BZmacropa-NCS as a new bifunctional chelator for the preparation of 225 Ac radiopharmaceuticals.

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Section: Introductionmentioning

confidence: 99%

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

et al. 2022

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“…alpha (α)-particle emitters in targeted alpha therapy (TAT) presents an appealing alternative. Compared to β-particles, α-particles have higher energies, shorter path lengths, and much higher probabilities of DNA double-strand breaks when interacting with cell nuclei [1,2]. These are all properties desirable for targeting small tumours in metastasised cancer as they allow for high absorbed doses to cancerous tissue while avoiding toxicity in surrounding tissue.…”

mentioning

confidence: 99%

Quantitative SPECT/CT imaging of lead-212: a phantom study

2022

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Background Lead-212 (212Pb) is a promising radionuclide for targeted therapy, as it decays to α-particle emitter bismuth-212 (212Bi) via β-particle emission. This extends the problematic short half-life of 212Bi. In preparation for upcoming clinical trials with 212Pb, the feasibility of quantitative single photon-emission computed tomography/computed tomography (SPECT/CT) imaging of 212Pb was studied, with the purpose to explore the possibility of individualised patient dosimetric estimation. Results Both acquisition parameters (combining two different energy windows and two different collimators) and iterative reconstruction parameters (varying the iterations x subsets between 10 × 1, 15 × 1, 30 × 1, 30 × 2, 30 × 3, 30 × 4, and 30 × 30) were investigated to evaluate visual quality and quantitative uncertainties based on phantom images. Calibration factors were determined using a homogeneous phantom and were stable when the total activity imaged exceeded 1 MBq for all the imaging protocols studied, but they increased sharply as the activity decayed below 1 MBq. Both a 20% window centred on 239 keV and a 40% window on 79 keV, with dual scatter windows of 5% and 20%, respectively, could be used. Visual quality at the lowest activity concentrations was improved with the High Energy collimator and the 79 keV energy window. Fractional uncertainty in the activity quantitation, including uncertainties from calibration factors and small volume effects, in spheres of 2.6 ml in the NEMA phantom was 16–21% for all protocols with the 30 × 4 filtered reconstruction except the High Energy collimator with the 239 keV energy window. Quantitative analysis was possible both with and without filters, but the visual quality of the images improved with a filter. Conclusions Only minor differences were observed between the imaging protocols which were all determined suitable for quantitative imaging of 212Pb. As uncertainties generally decreased with increasing iterative updates in the reconstruction and recovery curves did not converge with few iterations, a high number of reconstruction updates are recommended for quantitative imaging.

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“…[ 68 Ga]Ga-PSMA-11 or [ 18 F]F-DCFPyL versus [ 177 Lu]Lu-PSMA-617), the use of same isotopic pairs (e.g., 203 Pb/ 212 Pb, 44 Sc/ 47 Sc, 86 Y/ 90 Y) is advantageous. Specifically, isotopic pairs ensure that the diagnostic and therapeutic conjugates behave identically in vitro and in vivo because they share identical charge, chelation geometry and radiochemical characteristics (20,21). When diagnostic and therapeutic radiopharmaceuticals are used in this manner, they can be referred to as theranostics.…”

Section: What Are the Properties Of Rpt That Impact Clinical Utility?mentioning

confidence: 99%

A Primer on Radiopharmaceutical Therapy

Salerno¹,

Roy²,

Ribaudo³

et al. 2023

International Journal of Radiation Oncology*Biology*Physics

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Why bother with alpha particles?

Cited by 25 publications

References 89 publications

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

Quantitative SPECT/CT imaging of lead-212: a phantom study

A Primer on Radiopharmaceutical Therapy

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Why bother with alpha particles?

Cited by 25 publications

References 89 publications

H2BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H2BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

Quantitative SPECT/CT imaging of lead-212: a phantom study

A Primer on Radiopharmaceutical Therapy

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H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy