BACKGROUND: Targeted alpha therapy represents an advanced and rapidly evolving form of precision cancer treatment with increasing importance in recent years. The alpha-emitter 225Ac plays a key role in this clinical development due to its attractive physical and chemical properties. In this context, the macropa chelator has favorable characteristics in terms of labeling conditions and complex stability, making its derivatives exceptionally appealing for 225Ac-labeling of heat-sensitive biomolecules. However, preclinical evaluation of such 225Ac-containing molecules and comprehensive assessment of their pharmacokinetics, dosimetry and radiobiology necessitate a suitable diagnostic counterpart. Due to its attractive radiation properties, 133La represents an adequate positron-emitting radionuclide to form a matched pair with 225Ac for macropa-based radiopharmaceuticals. Herein, we describe the preparation and radiopharmacological characterization of macropa-functionalized, 133La/225Ac-labeled single-domain antibodies (sdAbs) targeting the epidermal growth factor receptor (EGFR) to demonstrate the general suitability of this theranostic pair of radionuclides. RESULTS: The synthesis of a clickable, bicyclononyne-modified macropa chelator and its site-specific conjugation to azide-modified, monovalent and biparatopic sdAbs is presented. Subsequent labeling at room temperature (rt) for 15 min resulted in molar activities of 30 MBq/nmol for 133La and 0.5 MBq/nmol for 225Ac, respectively. In vitro studies using the 133La-labeled sdAbs revealed comparable binding characteristics, but an enhanced cellular internalization of the biparatopic variant compared to its monovalent counterparts. This increased uptake consequently resulted in higher cytotoxicity of the 225Ac-labeled biparatopic conjugate. In vivo PET imaging of the 133La-labeled conjugates indicated comparable uptake and retention of the mono- and biparatopic variants in liver and kidneys, with the former showing slightly higher tumor accumulation. Ex vivo biodistribution studies conducted with 225Ac-labeled conjugates largely confirmed the findings obtained by PET imaging, albeit with a marginally higher tumor accumulation of the biparatopic 225Ac-radioimmunoconjugate. Final histological examinations of tumor and kidney tissues showed DNA damage in the renal cortex of the 225Ac-radioimmunoconjugate-treated mice, but no differences in the number of γ-H2AX-positive cells in the corresponding tumor tissues could be detected. CONCLUSIONS: We present a comprehensive study on the theranostic application of 133La and 225Ac for antibody-based biomolecules and lay the foundation for the future application of this matched pair of radionuclides towards labeling of heat-sensitive, macropa-functionalized radiopharmaceuticals in general. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41181-025-00354-7.

• Klíčová slova
• 133La, 225Ac, Biodistribution, Macropa, Pharmacokinetics, Positron emission tomography, Single-domain antibody, Targeted alpha therapy TAT, Theranostics,
• 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

BACKGROUND: Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. Nanomedicine, a term for the application of nanotechnology in medical and health fields, uses nanoparticles for several applications such as imaging, diagnostic, targeted cancer therapy, drug and gene delivery, tissue engineering, and theranostics. RESULTS: Here, we overview the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and radionuclide therapy. Nanostructured radiopharmaceuticals of technetium-99m, copper-64, lutetium-177, and radium-223 are discussed within the scope of this review article. CONCLUSION: Nanoradiopharmaceuticals may lead to better development of theranostics inspired by ingenious delivery and imaging systems. Cancer nano-theranostics have the potential to lead the way to more specific and individualized cancer treatment.

• Klíčová slova
• Copper-64, Lutetium-177, Molecular imaging, Radiolabeled nanoparticles, Radionuclide therapy, Radiopharmacy, Radium-223, Technetium-99m, Theranostics, Toxicity,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal 225Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding 225Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target.

• Klíčová slova
• PSMA, actinium-225, click chemistry, targeted alpha therapy, theranostics,
• Publikační typ
• časopisecké články MeSH

We provide characterization data of hydroxyapatite (nHAp) and titanium dioxide (nTiO2) nanoparticles as potential materials for ion sorption, e.g. in targeted therapy, barrier materials for waste repositories or photovoltaics. The study is focused on the determination of the values of protonation and ion exchange constants and site densities (∑SOH, ∑X; [mol kg-1]) of nTiO2 and nHAp for further Ra kinetics and sorption experiments. These data are very important for further investigation of the materials, which can be used e.g. as drug delivery systems or in engineered barriers of deep geological repositories. The characterization was based on the evaluation of the dependence of titrating agent consumption on pH. Titration results were evaluated on the basis of several model combinations, however the combination of the Chemical Equilibrium Model (CEM) and Ion Exchange Model (IExM) fits best to the experimental titration curves. However, the differences between the two sorbents were relatively large. Due to stability in a broad pH range and available surface sites, nTiO2 seems to have a wide application range. The applicability of nHAp is not so wide because of its dissolution under pH 5. Both sorbents are virtually able to sorb cationic species on deprotonated edge and layer sites with different capacities, which can be important for sorption and decontaminating applications.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: The recently growing interest in targeted alpha-therapy (TAT) calls for improvement of the labelling chemistry of the corresponding radionuclides. 213BiIII is a short-lived alpha emitter which emits only one alpha particle in its decay chain. Hence, it might be safer in application than other respective nuclides, such as 223Ra or 225Ac, because no alpha-emitting daughters are released upon recoil. We investigated cyclen derivatives with phosphorus-containing pendant arms regarding their suitability for 213Bi labelling. RESULTS: The concentration dependency of 213Bi labelling at 25 °C and 95 °C was determined for DOTP, DOTPH, DOTPEt, and DOTPI, as well as for DOTA and CHX-A"-DTPA for comparison. The labelling efficiency of the phosphorus-containing ligands was at least comparable to CHX-A"-DTPA and exceeded that of DOTA. DOTP was most efficient, requiring chelator concentrations for labelling which were approx. two orders of magnitude lower than those required for CHX-A"-DTPA, both at 25 °C and 95 °C. The 213Bi complexes of phosphorus ligands furthermore showed a higher stability against demetallation (> 96% of intact complex after 120-min incubation in plasma were found for DOTP, DOTPH, and DOTPEt, compared to 85% for DOTA and 76% for CHX-A"-DTPA). CONCLUSION: Cyclen derivatives bearing four N-methylenephosphonic or -phosphinic acid substituents, e.g., DOTP, are capable of complexing the alpha-emitting radionuclide 213BiIII with higher efficiency and in-vitro stability than the current gold standards DOTA and CHX-A"-DTPA.

• Klíčová slova
• Bismuth, Phosphinic acid, Phosphonic acid, Radiopharmaceuticals, Targeted alpha therapy,
• Publikační typ
• časopisecké články MeSH