Feasibility of a novel photoproduction of 225Ac and 227Th with natural thorium target.
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SUBMITTER: Ju K
PROVIDER: S-EPMC8748787 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer.
| S-EPMC9688344 | biostudies-literature
Project description:PurposeWe demonstrate cyclotron production of high-quality 225Ac using an electroplated 226Ra target.Methods226Ra 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.ResultsWe 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.ConclusionThis 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.
| S-EPMC8712309 | biostudies-literature
Project description:We report the first synthesis of 225Ac (t 1/2 = 10 days) endohedral fullerenes,225Ac@C60. The 225Ac@C60 was produced with a 12 ± 2% efficiency by applying an electrical arc discharge between a source of α-particle emitter 225Ac (∼1 mCi, electroplated on a Pt disk) and a thin coat of "preformed" C60 on an Al disk (C60 thickness of ∼0.25 mg/cm2). After formation by electrical arc discharge, the resulting radiofullerenes on the Al disk were dissolved in toluene under anaerobic conditions and converted to a malonate derivative using the Bingel reaction. Subsequent to repeated washings of the organic phase with dilute acidic solutions to remove exohedral 225Ac, ∼45% of 225Ac activity was retained in the organic phase, which resisted extraction into the aqueous phase. Failure to extract the 225Ac from the organic phase provided definitive evidence that the 225Ac is located inside of the fullerene. The formation of 225Ac@C60 was further confirmed using a classical hot-atom chemistry technique in which the organic phase containing purified endohedral 225Ac@C60 malonate was contacted with fresh dilute acid to repeatedly extract the ionic 4.8 m 221Fr and 45.6 m 213Bi activities (decay daughters of 225Ac), which were released by molecular disruption due to nuclear recoil. The result from the extraction experiments was further supported by a series of thin-layer chromatography and high-pressure liquid chromatography analysis of the organic phase containing 225Ac@C60 or 225Ac@C60 malonate. Taken together, studies show that, like polydentate chelators, single-wall fullerenes are not capable of retaining the 225Ac decay daughters.
| S-EPMC7594009 | biostudies-literature
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.
| S-EPMC10495309 | biostudies-literature
Project description:[Formula: see text]Ac is a radio-isotope that can be linked to biological vector molecules to treat certain distributed cancers using targeted alpha therapy. However, developing [Formula: see text]Ac-labelled radiopharmaceuticals remains a challenge due to the supply shortage of pure [Formula: see text]Ac itself. Several techniques to obtain pure [Formula: see text]Ac are being investigated, amongst which is the high-energy proton spallation of thorium or uranium combined with resonant laser ionization and mass separation. As a proof-of-principle, we perform off-line resonant ionization mass spectrometry on two samples of [Formula: see text]Ac, each with a known activity, in different chemical environments. We report overall operational collection efficiencies of 10.1(2)% and 9.9(8)% for the cases in which the [Formula: see text]Ac was deposited on a rhenium surface and a ThO[Formula: see text] mimic target matrix respectively. The bottleneck of the technique was the laser ionization efficiency, which was deduced to be 15.1(6)%.
| S-EPMC9873802 | biostudies-literature
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.
| S-EPMC10241010 | biostudies-literature
Project description:Actinium-225 (225Ac) can be produced from a Thorium-229/Radium-225 (229Th/225Ra) generator, from high/low energy proton irradiated natural Thorium or Radium-226 target. Titanium based ion exchanger were evaluated for purification of 225Ac. Poorly crystalline silicotitanate (PCST) ion exchanger had high selectivity for Ba, Ag and Th. 225Ac was received with trace amounts of 227Ac, 227Th and 223Ra, and the solution was used to evaluate the retention of the isotopes on PCST ion exchanger. Over 90% of the 225Ac was recovered from PCST, and the radiopurity was >99% (calculated based on 225Ac, 227Th, and 223Ra). The capacity of the PCST inorganic ion exchange for Barium and 232Th was determined to be 24.19 mg/mL for Barium and 5.05 mg/mL for Thorium. PCST ion exchanger could separate 225Ac from isotopes of Ra and Th, and the process represents an interesting one step separation that could be used in an 225Ac generator from 225Ra and/or 229Th. Capacity studies indicated PCST could be used to separate 225Ac produced on small 226Ra targets (0.3-1 g), but PCST did not have a high enough capacity for production scale Th targets (50-100 g).
| S-EPMC6694158 | biostudies-literature
Project description:PurposeInterest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene-bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT).Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.ResultsA comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but-importantly-further allowed for the ex vivo monitoring of 225Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.ConclusionsThe ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.
| S-EPMC6343144 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [177Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [225Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.ResultsCell binding and internalisation of [225Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [225Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [225Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [225Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [225Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.Conclusion[225Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.
| S-EPMC10484829 | biostudies-literature
Project description:BackgroundAs 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and QC testing. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately quantified.ResultsSix ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP for any pre-equilibrium measurement taken at an early time point. The 585 TLC measurements span RCP values of 1.8-99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. A measurement of RCP > 90% at 2 h predicts a true RCP > 97% and guarantees that RCP will exceed 90% after secular equilibrium is reached. These findings were independently validated using NaI(Tl) scintillation counting and high resolution gamma spectroscopy on a smaller set of samples with 10% ≤ RCP ≤ 100%.ConclusionsRCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC using various methods of quantifying particle emissions. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.
| S-EPMC8688611 | biostudies-literature