Ac-225 Production using TRIUMF’s 500 MeV Cyclotron

Robertson, Andrew K. H.; Hoehr, Cornelia; Lobbezoo, Andrew; Moskven, Louis; Radchenko, Valery; Yang, Hua; Zeisler, Stefan; Schaffer, Paul

doi:10.1016/j.jmir.2019.03.057

Cited by 5 publications

(6 citation statements)

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“…For labeling of the chelators, actinium-225 in 0.05 M nitric acid was produced by TRIUMF via Th-232 spallation. 48 For antibody labeling for either in vitro or in vivo experiments, 225 AcCl 3 was purchased from Isotope Technologies Garching (ITG, Germany) as a solution in dilute HCl. For antibody purification, PD-10 desalting columns (Sephadex G-25M, 50 kDa, GE Healthcare) and/or centrifugal filter devices (Amicon Ultra 4 Centrifugal Filtration Units, 50 kDa cutoff, Millipore Corp.) were used.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Radiochemical purities and specific activities of the final 225 Ac-labeled antibodies were determined by using gamma-spectrometry performed with a GR1520 (Canberra Industries, Meriden, CT, USA) high-purity germanium detector (HPGe) in addition to size-exclusion column (Phenomenex, BioSep-SEC-s-3000) on an Agilent HPLC system equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 280 nm), and a Bioscan (Washington, DC) NaI scintillation detector (the radiodetector was connected to a Bioscan B-FC-1000 flow-count system, and the output from the Bioscan flow-count system was fed into an Agilent 35900E interface, which converted the analogue signal to a digital signal). For labeling of the chelators, actinium-225 in 0.05 M nitric acid was produced by TRIUMF via Th-232 spallation . For antibody labeling for either in vitro or in vivo experiments, 225 AcCl 3 was purchased from Isotope Technologies Garching (ITG, Germany) as a solution in dilute HCl.…”

Section: Methodsmentioning

confidence: 99%

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²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

Rousseau²,

Jaraquemada-Peláez

et al. 2020

Bioconjugate Chem.

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Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t 1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10–6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]− anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]− complex also demonstrated a superb thermodynamic stability (log K [La(py4pa)] – ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K [La(DOTA)] – ∼ 24.25, pLa = 19.2) or H2macropa (log K [La(macropa)] – = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

Rousseau²,

Jaraquemada-Peláez

et al. 2020

Bioconjugate Chem.

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“…TRIUMF has developed a novel technique where, by processing the target with a radium separation procedure a few hours after bombardment, the short-lived 227 Ra will have decayed, while the 15-day 225 Ra isotope then becomes a generator for very pure 225 Ac. This enables therapeutic doses free of 227 Ac [146]. This isotope remains in the waste stream, but is treated as radioactive waste and never reaches the sanitary sewer.…”

Section: Isotope Facilities For Research and Productionmentioning

confidence: 99%

High-power Fixed-Field Accelerators

et al. 2023

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We report the state of the field of High-Power Fixed-Field Accelerators (with an emphasis on cyclotrons) as discussed by international experts during a three-day workshop of the same name in 2021. The workshop was part of the Snowmass'21 Community Planning Exercise. Here, we take stock of the world inventory of high-power fixed-field accelerators, assess available beam currents and beam powers, and investigate limitations. Furthermore, we evaluate the role of these machines in particle physics, directly used or as injectors to other machines, and in industry, as drivers for (medical) isotope production and, potentially, for accelerator-driven systems and sub-critical reactors. Finally, we discuss novel concepts and cutting-edge developments to push the available current higher at several energy scales, thereby increasing relative power. Highlights include new spiral inflector types, direct RFQ injection, H2 + acceleration, utilizing vortex motion, and self-extraction schemes. We also discuss modern computational frameworks to optimize accelerators more efficiently, and better describe the relevant physical processes in simulations.

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“…The DOE is in the process of preparing a drug master file as part of the Food and Drug Administration (FDA) approval process. TRIUMF is conducting a similar program at the Isotope Production Facility (IPF) at its 500 MeV proton cyclotron . About 500 MBq of 225 Ac and 65 MBq of 225 Ra were produced after 30 to 40 hours of irradiation.…”

Section: Production Of 225acmentioning

confidence: 99%

“…TRIUMF is conducting a similar program at the Isotope Production Facility (IPF) at its 500 MeV proton cyclotron. 46 About 500 MBq of 225 Ac and 65 MBq of 225 Ra were produced after 30 to 40 hours of irradiation.…”

Section: Medium-energy Proton Irradiation Of 226 Ramentioning

confidence: 99%

Targeted alpha therapy with bismuth‐213 and actinium‐225: Meeting future demand

Bruchertseifer

Kellerbauer

Malmbeck

et al. 2019

Labelled Comp Radiopharmac

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Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over conventional therapies. The short range of alpha radiation in human tissue (less than 0.1 mm), corresponding to only a few cell diameters, allows selective killing of targeted cancer cells while sparing surrounding healthy tissue. At the same time, the high energy (several MeV) of alpha radiation and its associated high linear energy transfer leads to highly effective cell kill. Consequently, alpha radiation can destroy cells which otherwise exhibit resistance to treatment with beta or gamma irradiation or chemotherapeutic drugs, and can thus offer a therapeutic option for tumors resistant to conventional therapies. Recent results demonstrating the remarkable therapeutic efficacy of alpha emitters to treat various cancers have underlined the clinical potential of TAT. This paper describes the recent clinical experience with 213Bi and 225Ac. In view of the enormous benefit of targeted cancer treatment with alpha emitters, their production will have to be considerably increased beyond current supply capabilities. Alternative production methods based on the irradiation of uranium, thorium, or radium targets at reactors or accelerator facilities have the potential to meet future demand.

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Ac-225 Production using TRIUMF’s 500 MeV Cyclotron

Abstract: tumor xenograft types. The mechanism of action involves induction of DNA double-stranded breaks and progression into apoptosis. These results strongly support the use of FPI-1434 in IGF-1R overexpressing cancers.

Cited by 5 publications

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²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

High-power Fixed-Field Accelerators

Targeted alpha therapy with bismuth‐213 and actinium‐225: Meeting future demand

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Ac-225 Production using TRIUMF’s 500 MeV Cyclotron

Abstract: tumor xenograft types. The mechanism of action involves induction of DNA double-stranded breaks and progression into apoptosis. These results strongly support the use of FPI-1434 in IGF-1R overexpressing cancers.

Cited by 5 publications

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225Ac-H4py4pa for Targeted Alpha Therapy

225Ac-H4py4pa for Targeted Alpha Therapy

High-power Fixed-Field Accelerators

Targeted alpha therapy with bismuth‐213 and actinium‐225: Meeting future demand

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²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

²²⁵Ac-H₄py4pa for Targeted Alpha Therapy