Hydroxypyridinones as a Very Promising Platform for Targeted Diagnostic and Therapeutic Radiopharmaceuticals.

Hydroxypyridinones (HOPOs) have been used in the chelation therapy of iron and actinide metals. Their application in metal-based radiopharmaceuticals has also been increasing in recent years. This review article focuses on how multidentate HOPOs can be used in targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. The general structure of radiometal-based targeted radiopharmaceuticals, a brief description of siderophores, the basic structure and properties of bidentate HOPO, some representative HOPO multidentate chelating agents, radiopharmaceuticals based on HOPO multidentate bifunctional chelators for gallium-68, thorium-227 and zirconium-89, as well as the future prospects of HOPO multidentate bifunctional chelators in other metal-based radiopharmaceuticals are described and discussed in turn. The HOPO metal-based radiopharmaceuticals that have shown good prospects in clinical and preclinical studies are gallium-68, thorium-227 and zirconium-89 radiopharmaceuticals. We expect HOPO multidentate bifunctional chelators to be a very promising platform for building novel targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals.

A reverse 230U/226Th radionuclide generator for targeted alpha therapy applications.

PURPOSE: Thorium-226 (half-life 30.6 m) is a radionuclide of interest for use in targeted alpha therapy applications. Due to its short half-life, 226Th must be provided through a radionuclide generator system from its parent 230U (20.8 d). Furthermore, as the half-life of 226Th is very short, it should be provided in a form that is directly amenable to use in biomedical applications. METHODS: A reverse radionuclide generator system was developed employing a DGA extraction chromatography column. A 230U/226Th parent/daughter solution in equilibrium is added to a DGA column in >6 M HCl. The parent 230U is eluted first in 0.1 M HNO3 followed by elution of 226Th in 0.1 M citrate buffer pH 5. RESULTS: Thorium-226 was recovered from the radionuclide generator column with >96% yield. Greater than 99.5% of the 230U parent was isolated for reuse in the generator. Long term evaluation over six weeks demonstrated consistent supply of 226Th with greater than 99.5% radionuclidic purity. The only contaminant found in the final product was 230U (<0.5%). CONCLUSIONS: The reverse radionuclide generator described herein was shown to be a feasible method for providing 226Th in high yield, purity and in a chemical form that is amenable for direct use in biomedical applications.

Preclinical Combination Studies of an FGFR2 Targeted Thorium-227 Conjugate and the ATR Inhibitor BAY 1895344.

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344. METHODS AND MATERIALS: The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice. RESULTS: In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect. CONCLUSIONS: The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.

Production of 230U/226Th for targeted alpha therapy via proton irradiation of 231Pa.

(230)U and its daughter nuclide (226)Th are novel therapeutic nuclides for application in targeted alpha-therapy of cancer. We have investigated the feasibility of producing (230)U/(226)Th via proton irradiation of (231)Pa according to the reaction (231)Pa(p,2n)(230)U. The experimental excitation function for this reaction is reported for the first time. Cross sections were measured using thin targets of (231)Pa prepared by electrodeposition and (230)U yields were analyzed using alpha-spectrometry. Beam parameters (energy and intensity) were determined both by calculation using a mathematical model based on measured beam orbits and beam current integrator and by parallel monitor reactions on copper foils using high-resolution gamma-spectrometry and IAEA recommended cross-section data. The measured cross sections are in good agreement with model calculations using the EMPIRE-II code and are sufficiently high for the production of (230)U/(226)Th in clinically relevant amounts. A highly effective separation process was developed to isolate clinical grade (230)U from irradiated protactinium oxide targets. Product purity was assessed using alpha- and gamma-spectrometry as well as ICPMS.

Observation of changes in urinary excretion of thorium in humans following ingestion of a therapeutic soil.

The study investigated the changes in urinary thorium excretion by humans following ingestion of a therapeutic soil, which contains about 10 ppm of thorium. This well-known healing earth in Germany has been considered as an alternative medicine for diarrhoea and gastric hyper-acidity. Six adult volunteers ingested this therapeutic soil in varying quantities for 1-15 days at levels approximating those described in the package insert of the medicine (10-60 g of soil per day). The subjects ingested about 0.1-0.6 mg of thorium daily, which is 100-600 times higher than the normal daily intake of about 1 microg thorium in Germany. All 24-h urine samples collected from the subjects during pre-ingestion, ingestion and post-ingestion periods of the soil were analyzed for (232)Th using inductively coupled plasma mass spectrometry (ICP-MS). The measured excretion values varied in a wide range. Apparently, the high thorium amounts administered did not increase the (232)Th excretion in urine as expected, suggesting that this soil ingestion will not result in a considerably higher and harmful uptake of thorium into the human body.