The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope 161Tb, for targeted therapy in FGFR-overexpressing cancer cells. FGF1 was engineered (eFGF1) to incorporate a single cysteine at the C terminus for site-specific labeling with a DOTA chelator. eFGF1-DOTA was mixed with the radioisotope 161Tb under mild conditions, resulting in a labeling efficiency above 90%. The nonradioactive ligands were characterized by mass spectrometry, while radioligands were characterized by thin-layer chromatography. The targeting function of the radioligands was assessed through confocal microscopy, flow cytometry, and Western blot analysis, focusing on binding to cancer cells and the activation of downstream signaling pathways related to FGFR. When compared to MCF-7 and RD cell lines with low FGFR expression, eFGF1-DOTA-Tb[161Tb] radioligands demonstrated significantly higher accumulation in FGFR-overexpressing cell lines (MCF-7 FGFR1 and RMS559), leading to enhanced cytotoxicity. Besides radionuclides, eFGF1 can also deliver doxorubicin (DOX) into cancer cells. Considering these characteristics, eFGF1-DOTA-Tb[161Tb] and eFGF1-DOX emerge as promising candidates for FGFR-targeted cancer therapy, and further evaluation in vivo is warranted.
- Publikační typ
- časopisecké články MeSH
The use of new radiopharmaceuticals labeled with lutetium-177 represents a successful translation of experimental results into clinical practice. Recent experimental data suggests that terbium-161 might well follow the example of lutetium-177 regarding applicability in nuclear medicine. Similarly to lutetium-177, the terbium-161 emits beta particles and gamma-radiation, although terbium-161 emits short-ranged conversion and Auger electrons, creating an effect that may eliminate smaller tumor metastases more effectively than lutetium-177. Terbium-161 may exert a higher radiobiological effect in the target tissues in comparison with lutetium-177, a difference which makes possible a reduction in the doses of radioactivity administered. Further, due to the similar chemical properties of lutetium-177 and terbium-161, similar radiolabeling techniques can be used. The differences found in preclinical experiments on radiotoxicity of the counterparts seem to be minor. Despite intensive progress, the number of preclinical studies on 161Tb-labeled agents is still not comparable to studies on lutetium-177. Clinical trials with 161Tb-labeled radiopharmaceuticals focused on the treatment of prostate cancer and selected neuroendocrine tumors have already begun, although none of them have been completed yet.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay via the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier. Therefore, studying these daughter atoms is crucial in the search for new carriers. Nanoparticles have potential as carriers due to their structure, which can prevent the escape of daughter atoms and reduce radiation exposure to non-target tissues. This work focuses on determining the released activity of 221Fr and 213Bi resulting from the decay of 225Ac labelled TiO2 nanoparticles. RESULTS: Labelling of TiO2 nanoparticles has shown high sorption rates of 225Ac and its progeny, 221Fr and 213Bi, with over 92 % of activities sorbed on the nanoparticle surface for all measured radionuclides. However, in the quasi-dynamic in vitro system, the released activity of 221Fr and 213Bi is strongly dependent on the nanoparticles concentration, ranging from 15 % for a concentration of 1 mg/mL to approximately 50 % for a nanoparticle concentration of 10 μg/mL in saline solution. The released activities of 213Bi were lower, with a maximum value of around 20 % for concentrations of 0.05, 0.025, and 0.01 mg/mL. The leakage of 225Ac and its progeny was tested in various biological matrices. Minimal released activity was measured in saline at around 10 % after 48 h, while the maximum activity was measured in blood serum and plasma at 20 %. The amount of 225Ac released into the media was minimal (<3 %). The in vitro results were confirmed in a healthy mouse model. The difference in %ID/g was clearly visible immediately after dissection and again after 6 h when 213Bi reached equilibrium with 225Ac. CONCLUSION: The study verified the potential release of 225Ac progeny from the labelled TiO2 nanoparticles. Experiments were performed to determine the dependence of released activity on nanoparticle concentration and the biological environment. The results demonstrated the high stability of the prepared 225Ac@TiO2 NPs and the potential release of progeny over time. In vivo studies confirmed our hypothesis. The data obtained suggest that the daughter atoms can escape from the original carrier and follow their own biological pathways in the organism.
- Klíčová slova
- Actinium-225, Bismuth-213, Nanoparticles, Targeted alpha therapy, TiO(2),
- Publikační typ
- časopisecké články MeSH
The utilization of nanomaterials in biomedical applications has surged in recent years; yet, the transition from research to practical implementation remains a great challenge. However, a promising area of research has emerged with the integration of nanomaterials with diagnostic and therapeutic radionuclides. In this Review, we elucidate the motivations behind selecting metal oxide- and phosphate-based nanomaterials in conjunction with these radionuclides, while addressing its issues and limitations. Various metal oxide- and phosphate-based nanoparticles, exhibiting low toxicity and high tolerability, have been proposed for diverse biomedical applications, ranging from bone substitutes to drug delivery systems and controlled release vectors for pharmaceuticals, including radionuclides for nuclear medicine imaging and therapy. Moreover, the potential synergistic effects of multimodal combinational therapies, integrating chemotherapeutics, immunomodulators, or hyperthermia, underscore the versatility of these nanoconstructs. Our comprehensive exploration includes the underlying principles of radiolabeling strategies, the pivotal attributes of nanomaterial platforms, and their applications. Through this perspective, we present the potential of nanotechnology-enabled nuclear medicine. Furthermore, we discuss the potential systemic and local applications of these nanoconstructs, considering their in vitro and in vivo characteristics, as well as their physicochemical properties.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Radioligand therapy using alpha emitters has gained more and more prominence in the last decade. Despite continued efforts to identify new appropriate radionuclides, the combination of 225Ac/213Bi remains among the most promising. Bismuth-213 has been employed in clinical trials in combination with appropriate vectors to treat patients with various forms of cancer, such as leukaemia, bladder cancer, neuroendocrine tumours, melanomas, gliomas, or lymphomas. However, the half-life of 213Bi (T½ = 46 min) implies that its availability for clinical use is limited to hospitals possessing a 225Ac/213Bi radionuclide generator, which is still predominantly scarce. We investigated a new Ac/Bi generator system based on using the composite sorbent α-ZrP-PAN (zirconium(IV) phosphate as active component and polyacrylonitrile as matrix). The developed 225Ac/213Bi generator was subjected to long-term testing after its development. The elution profile was determined and the elution yield, the contamination of the eluate with the parent 225Ac and the contamination of the eluate with the column material were monitored over time. RESULTS: The high activity (75 MBq of parent 225Ac) generator with a length of 75 mm and a diameter of 4 mm containing the composite sorbent α-ZrP-PAN with a particle size of 0.8 to 1.0 mm as the stationary phase, eluted with a mixture of 10 mM DTPA in 5 mM nitric acid, provided 213Bi with yields ranging from 77 % to 96 % in 2.8 mL of eluate, with parent 225Ac contamination in the order of 10-3 %, up to twenty days of use. CONCLUSION: All the results of the monitored parameters indicate that the composite sorbent α-ZrP-PAN based separation system for the elution of 213Bi is a very promising and functional solution.
- Klíčová slova
- Actinium-225, Bismuth-213, Diethylenetriaminepentaacetic acid, Ion exchange, Zirconium phosphate,
- MeSH
- aktinium * chemie MeSH
- alfa částice * terapeutické užití MeSH
- bismut * chemie MeSH
- radiochemie metody přístrojové vybavení MeSH
- radioisotopové generátory MeSH
- radionuklidy * chemie MeSH
- zirkonium chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- Actinium-225 MeSH Prohlížeč
- aktinium * MeSH
- bismut * MeSH
- Bismuth-213 MeSH Prohlížeč
- radionuklidy * MeSH
- zirkonium MeSH
BACKGROUND: Targeted alpha therapy is one of the most powerful therapeutical modalities available in nuclear medicine. It's therapeutic potency is based on the nuclides that emit one or several alpha particles providing strong and highly localized therapeutic effects. However, some of these radionuclides, like e.g.223Ra or 225Ac decay in cascades, where the radioactive progeny originating from the consecutive alpha-decays may leave the original vector and cause unwanted irradiation of non-target organs. This progeny, even if partially retained in target tissues by internalization processes, typically do not follow the fate of originally targeted radiopharmaceutical and potentially spread over body following their own biodistribution. In this study we aimed to estimate 211Pb/211Bi progeny fate from the 223Ra surface-labelled TiO2 nanoparticles in vitro and the fate of 211Pb in vivo in a mice model. RESULTS: In vitro stability studies have shown significant differences between the release of the mother 223Ra and its progeny (211Pb, 211Bi) in all the biological matrices that have been tested. The lowest released activities were measured in saline, resulting in less than 5 % of released activity for all nuclides. Contrary to that, the highest released activity of 223Ra of up to 10 % within 48 h was observed in 5 % solution of albumin. The released activity of its progeny; the 211Pb and 211Bi was in the range of 20-40 % in this test medium. Significantly higher released activities of 211Pb and 211Bi compared to 223Ra by at least 10 % was observed in each biological medium, except saline, where no significant differences were observed. The in vivo biodistribution studies results in a mice model, show similar pattern, where it was found that even after accumulation of nanoparticles in target tissues, approximately 10 % of 211Pb is continuously released into the blood stream within 24 h, followed by its natural accumulation in kidneys. CONCLUSION: This study confirms our assumption that the progeny formed in a chain alpha decay of a certain nuclide, in this case the 223Ra, can be released from its original vector, leave the target tissue, relocate and could be deposited in non-target organs. We did not observe complete progeny wash-out from its original target tissues in our model. This indicates strong dependence of the progeny hot atom fate after its release from the original radiopharmaceutical preparation on multiple factors, like their internalization and retention in cells, cell membranes, extracellular matrices, protein binding, etc. We hypothesize, that also the primary tumour or metastasis size, their metabolic activity may significantly influence progeny fate in vivo, directly impacting the dose delivered to non-target tissues and organs. Therefore a bottom-up approach should be followed and detailed pre-/clinical studies on the release and biodistribution of radioactive progeny originating from the chain alpha emitters should be preferably performed.
- Klíčová slova
- (211)Bi, (211)Pb, (223)Ra, Radioactive progeny, Recoil effect, Targeted alpha therapy,
- MeSH
- myši MeSH
- nanočástice * MeSH
- olovo MeSH
- radiofarmaka * terapeutické užití MeSH
- radionuklidy terapeutické užití MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- olovo MeSH
- radiofarmaka * MeSH
- radionuklidy MeSH
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 Dw (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 Dw 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.
- Klíčová slova
- actinium-225, bismuth-213, kinetics, phosphate, sorption, zirconium,
- Publikační typ
- časopisecké články MeSH
The overall need for the preparation of new medicinal radionuclides has led to the fast development of new sorption materials, extraction agents, and separation methods. Inorganic ion exchangers, mainly hydrous oxides, are the most widely used materials for the separation of medicinal radionuclides. One of the materials that has been studied for a long time is cerium dioxide, a competitive sorption material for the broadly used titanium dioxide. In this study, cerium dioxide was prepared through calcination of ceric nitrate and fully characterized using X-ray powder diffraction (XRPD), infrared spectrometry (FT-IR), scanning and transmission electron microscopy (SEM and TEM), thermogravimetric and differential thermal analysis (TG and DTA), dynamic light scattering (DLS), and analysis of surface area. In order to estimate the sorption mechanism and capacity of the prepared material, characterization of surface functional groups was carried out using acid-base titration and mathematical modeling. Subsequently, the sorption capacity of the prepared material for germanium was measured. It can be stated that the prepared material is prone to exchange anionic species in a wider range of pH than titanium dioxide. This characteristic makes the material superior as a matrix in 68Ge/68Ga radionuclide generators, and its suitability should be further studied in batch, kinetic, and column experiments.
- Klíčová slova
- FT-IR, SEM, TEM, XRPD, acid-base titration, cerium dioxide, mechanism, sorption, thermal analysis,
- Publikační typ
- časopisecké články MeSH
Nanoparticles of various materials were proposed as carriers of nuclides in targeted alpha particle therapy to at least partially eliminate the nuclear recoil effect causing the unwanted release of radioactive progeny originating in nuclear decay series of so-called in vivo generators. Here, we report on the study of 211Pb and 211Bi recoils release from the 223Ra surface-labelled TiO2 nanoparticles in the concentration range of 0.01-1 mg/mL using two phase separation methods different in their kinetics in order to test the ability of progeny resorption. We have found significant differences between the centrifugation and the dialysis used for labelled NPs separation as well as that the release of 211Pb and 211Bi from the nanoparticles also depends on the NPs dispersion concentration. These findings support our previously proposed recoils-retaining mechanism of the progeny by their resorption on the NPs surface. At the 24 h time-point, the highest overall released progeny fractions were observed using centrifugation (4.0% and 13.5% for 211Pb and 211Bi, respectively) at 0.01 mg/mL TiO2 concentration. The lowest overall released fractions at the 24 h time-point (1.5% and 2.5% for 211Pb and 211Bi respectively) were observed using dialysis at 1 mg/mL TiO2 concentration. Our findings also indicate that the in vitro stability tests of such radionuclide systems designed to retain recoil-progeny may end up with biased results and particular care needs to be given to in vitro stability test experimental setup to mimic in vivo dynamic conditions. On the other hand, controlled and well-defined progeny release may enhance the alpha-emitter radiation therapy of some tumours.
- Klíčová slova
- Bi-213, Bismuth, Pb-211, Ra-223, Radium, TiO2, lead, nanoparticles, nuclear recoil,
- Publikační typ
- časopisecké články MeSH
Targeted alpha therapy with radionuclides undergoing multiple alpha-particle decays is a promising method of nuclear medicine. To study the effectiveness of alpha versus beta emitters, survival of DU145 prostate cancer cells exposed to 223Ra or 177Lu was assessed. Per decay, the cells were much more sensitive to the alpha than beta emitter. However, per unit dose the sensitivities would be comparable, contrary to the well-known evidence, if the decay energy were deposited within the sample completely and homogeneously. Measurements by Timepix detectors showed about three times higher counts of alpha particles above than below the sample. After the first alpha decay of 223Ra to 219Rn, this gas likely moves upwards and its subsequent three alpha decays occur in the upper part of the sample. Correct estimation of absorbed dose is a critical issue when analysing in vitro data and when translating their results to clinical applications.
- MeSH
- alfa částice terapeutické užití MeSH
- lidé MeSH
- radiometrie metody MeSH
- radionuklidy terapeutické užití MeSH
- radium * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- radionuklidy MeSH
- Radium-223 MeSH Prohlížeč
- radium * MeSH
