Dataset Information

Cyclotron production of ²²⁵Ac from an electroplated ²²⁶Ra target.

ABSTRACT:

Purpose

We demonstrate cyclotron production of high-quality ²²⁵Ac using an electroplated ²²⁶Ra target.

Methods

²²⁶Ra was extracted from legacy Ra sources using a chelating resin. Subsequent ion-exchange purification gave pure ²²⁶Ra with a certain amount of carrier Ba. The radium target was prepared by electroplating. We successfully deposited about 37 MBq of ²²⁶Ra on a target box. Maximum activation was achieved using 15.6 MeV protons on the target at 20 µA for 5 h. Two functional resins with various concentrations of nitric acid purified ²²⁵Ac and recovered ²²⁶Ra. Cooling the intermediate ²²⁵Ac for 2-3 weeks decayed the major byproduct of ²²⁶Ac and increased the radionuclidic purity of ²²⁵Ac. Repeating the same separation protocol provided high-quality ²²⁵Ac.

Results

We obtained ²²⁵Ac at a yield of about 2.4 MBq at the end of bombardment (EOB), and the subsequent initial purification gave 1.7 MBq of ²²⁵Ac with ²²⁶Ac/²²⁵Ac ratio of < 3% at 4 days from EOB. Additional cooling time coupled with the separation procedure (secondary purification) effectively increased the ²²⁵Ac (4n + 1 series) radionuclidic purity up to 99 + %. The recovered ²²⁵Ac had a similar identification to commercially available ²²⁵Ac originating from a ²²⁹Th/²²⁵Ac generator.

Conclusion

This procedure, which involves the ²²⁶Ra(p,2n)²²⁵Ac reaction and the appropriate purification, has the potential to be a major alternative pathway for ²²⁵Ac production because it can be performed in any facility with a compact cyclotron to address the increasing demand for ²²⁵Ac.

SUBMITTER: Nagatsu K

PROVIDER: S-EPMC8712309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimOver recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered.MethodsThis study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies.ResultsBased on the simulated dose-effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively.ConclusionIn this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

Project description:α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Methods: Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N (DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor-bearing nude mice. Results: TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to 225Ac-PP-F11N. As compared with the control and monotherapies, the combination of 225Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Conclusion: Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to 225Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.

Dataset Information

Cyclotron production of ²²⁵Ac from an electroplated ²²⁶Ra target.

Purpose

Methods

Results

Conclusion

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Cyclotron production of ²²⁵Ac from an electroplated ²²⁶Ra target.