Search Results (9)

Recent years have seen a swift rise in the use of α-emitting radionuclides such as ²²⁵Ac and ²²³Ra as various radiopharmaceuticals to treat (micro)metastasized tumors. They have shown remarkable effectiveness in clinical practice owing to the highly cytotoxic α-particles that are emitted, which have a very short range in tissue, causing mainly double-stranded DNA breaks. However, it is essential that both chelation and targeting strategies are optimized for their successful translation to clinical application, as α-emitting radionuclides have distinctly different features compared to β⁻-emitters, including their much larger atomic radius. Furthermore, upon α-decay, any daughter nuclide irrevocably breaks free from the targeting molecule, known as the recoil effect, dictating the need for faster targeting to prevent healthy tissue toxicity. In this review we provide a brief overview of the current status of targeted α-therapy and highlight innovations in α-emitter-based chelator design, focusing on the role of click chemistry to allow for fast complexation to biomolecules at mild labeling conditions. Finally, an outlook is provided on different targeting strategies and the role that pre-targeting can play in targeted alpha therapy. Full article

We investigated nuclear medicine therapeutics targeting the L-type amino acid transporter 1 (LAT1). We previously reported that a nuclear medicine therapeutic drug using astatine 211 (²¹¹At), an alpha-emitting nuclide that can be produced in an accelerator and targets LAT1 as a molecular target, is effective. The seed compound was 3-[²¹¹At] Astato-α-methyl-L-tyrosine (²¹¹At-AAMT-OH-L). We used a unique labeling method. By changing the OH group of phenol to a methyl group, retention was successfully increased. It was also found that the amount of the L-isomer taken up by the D-isomer and L-isomer was clearly higher, and the L-isomer was superior as a therapeutic drug. Compounds in which the methyl group was replaced with an ethyl or propyl group were also examined, but their retention did not increase significantly. In fact, we observed increased non-specific accumulation and dynamics, suggesting that labeling may be off. In addition, ²¹¹At-AAMT-O-Me-L, which has a simple structure, was clearly superior in terms of uptake speed for several candidate compounds. As a result, we were able to develop a compound that can be easily labeled, has high specific radioactivity, is stable, and has a strong therapeutic effect. Full article

Triple-negative breast cancer (TNBC) presents limited therapeutic options and is associated with poor prognosis. Early detection and the development of novel therapeutic agents are therefore imperative. Fibroblast activation protein (FAP) is a membrane protein expressed on cancer-associated fibroblasts (CAFs) that plays an essential role in TNBC proliferation, migration, and invasion. Consequently, it is hypothesized that the Astatine (²¹¹At)-labeled FAP inhibitor (FAPI) selectively exerts anti-tumor effects through alpha-particle emission. In this study, we aimed to assess its theranostic capabilities by integrating [¹⁸F]FAPI-74 PET imaging with targeted alpha therapy using [²¹¹At]FAPI1 in TNBC models. Mice xenografts were established by transplanting MDA-MB-231 and HT1080 cells (control). As a parallel diagnostic method, [¹⁸F]FAPI-74 was administered for PET imaging to validate FAP expression. A single dose of [²¹¹At]FAPI1 (1.04 ± 0.10 MBq) was administered to evaluate the therapeutic efficacy. [¹⁸F]FAPI-74 exhibited high accumulation in MDA-MB-231 xenografts, and FAP expression was pathologically confirmed via immunostaining. The group that received [²¹¹At]FAPI1 (n = 11) demonstrated a significantly enhanced anti-tumor effect compared with the control group (n = 7) (p = 0.002). In conclusion, [¹⁸F]FAPI-74 PET imaging was successfully used to diagnose FAP expression, and as [²¹¹At]FAPI1 showed promising therapeutic efficacy in TNBC models, it is expected to be a viable therapeutic option. Full article

Currently, targeted alpha therapy (TAT) is a new therapy involving the administration of a therapeutic drug that combines a substance of α-emitting nuclides that kill cancer cells and a drug that selectively accumulates in cancer cells. It is known to be effective against cancers that are difficult to treat with existing methods, such as cancer cells that are widely spread throughout the whole body, and there are high expectations for its early clinical implementation. The nuclides for TAT, including ¹⁴⁹Tb, ²¹¹At, ^212/213Bi, ²¹²Pb (for ²¹²Bi), ²²³Ra, ²²⁵Ac, ^226/227Th, and ²³⁰U, are known. However, some nuclides encounter problems with labeling methods and lack sufficient preclinical and clinical data. We labeled the compounds targeting prostate specific membrane antigen (PSMA) with ²¹¹At and ²²⁵Ac. PSMA is a molecule that has attracted attention as a theranostic target for prostate cancer, and several targeted radioligands have already shown therapeutic effects in patients. The results showed that ²¹¹At, which has a much shorter half-life, is no less cytotoxic than ²²⁵Ac. In ²¹¹At labeling, our group has also developed an original method (Shirakami Reaction). We have succeeded in obtaining a highly purified labeled product in a short timeframe using this method. Full article

Alpha particle-emitting radiopharmaceuticals are in high demand for use in targeted alpha therapy. Ac-225 is currently produced using Th-229, but its annual production remains low, approximately 63 GBq. Previously, we produced a large amount of Ac-225 via the (n,2n) reaction in fast reactors; however, it required repetitive irradiation. In this work, we investigated a method to produce Th-229 via the (3n,x) reaction through long-term irradiation using neutrons from Pressurized Water Reactors. As target nuclides, Ra-226, which is commonly used for Ac-225 production, and Th-230, which is not widely used but is abundant, were selected. The evaluation was conducted under mixed conditions of Th-230 and Th-232. Ra-226 and Th-230 produce Th-229 (T1/2 = 7920 years) after long-term neutron irradiation. Th-229, which has a long half-life, the α-decays to produce Ra-225, and the β-decays of Ra-225 to produce Ac-225. These processes are semi-permanent owing to the long half-life of Th-229. Further, an irradiation method that does not require major changes in the upper part of the PWR fuel assembly geometry was employed by replacing the plugging device attached to the control rod guide tube with a target pin. The PWR loaded with abundant natural thorium target and irradiated with thermal neutrons for as long as approximately 5 years can produce more than twice the current world supply of Ac-225 annually and permanently. Full article

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to β− or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves ²²⁵Ac and its daughter nuclide ²¹³Bi. Additionally, the ²²⁵Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying ²²⁵Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of ²²⁵Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods. Full article

Zirconium phosphate (ZrP), especially its alpha allotropic modification, appears to be a very promising sorbent material for the sorption and separation of various radionuclides due to its properties such as an extremely high ion exchange capacity and good radiation stability. Actinium-225 and its daughter nuclide ²¹³Bi are alpha emitting radioisotopes of high interest for application in targeted alpha therapy of cancer. Thus, the main aim of this paper is to study the sorption of ²²⁵Ac on the α-ZrP surface and its kinetics, while the kinetics of the sorption is studied using ^natEu as a non-radioactive homologue of ²²⁵Ac. The sorption properties of α-ZrP were tested in an acidic environment (hydrochloric and nitric acid) using batch sorption experiments and characterized using equilibrium weight distribution coefficients D_w (mL/g). The modeling of the experimental data shows that the kinetics of ²²⁵Ac sorption on the surface of α-ZrP can be described using a film diffusion model (FD). The equilibrium weight distribution coefficient D_w for ²²⁵Ac in both hydrochloric and nitric acid reached the highest values in the concentration range 5.0–7.5 mM (14,303 ± 153 and 65,272 ± 612 mL/g, respectively). Considering the results obtained in radioactive static sorption experiments with ²²⁵Ac and in non-radioactive kinetic experiments with ^natEu, α-ZrP seems to be a very promising material for further construction of a ²²⁵Ac/²¹³Bi generator. Full article

The actinium-225 (²²⁵Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the ²²⁵Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the ²²⁵Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on ²²⁵Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on ²²⁵Ac is discussed. Quality control measures in the preparation of ²²⁵Ac-conjugates are also highlighted. Full article

Recently, new high-resolution cadmium–zinc–telluride (CZT) drift strip detectors for room temperature gamma-ray spectroscopic imaging were developed by our group. The CZT detectors equipped with orthogonal anode/cathode collecting strips, drift strips and dedicated pulse processing allow a detection area of 6 × 20 mm² and excellent room temperature spectroscopic performance (0.82% FWHM at 661.7 keV). In this work, we investigated the potentialities of these detectors for prompt gamma-ray spectroscopy (PGS) in boron neutron capture therapy (BNCT). The detectors, exploiting the measurement of the 478 keV prompt gamma rays emitted by 94% ⁷Li nuclides from the ¹⁰B(n, α)⁷Li reaction, are very appealing for the development of single-photon emission computed tomography (SPECT) systems and Compton cameras in BNCT. High-resolution gamma-ray spectra from ¹⁰B samples under thermal neutrons were measured at the T.R.I.G.A. Mark II research nuclear reactor of the University of Pavia (Italy). Full article