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.

• Keywords
• Actinium-225, Bismuth-213, Nanoparticles, Targeted alpha therapy, TiO(2),
• MeSH
• Actinium * chemistry   MeSH
• Isotope Labeling MeSH
• Mice MeSH
• Nanoparticles * chemistry   MeSH
• Radioisotopes * chemistry   MeSH
• Titanium * chemistry   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Actinium-225 MeSH Browser
• Actinium * MeSH
• Radioisotopes * MeSH
• Titanium * MeSH
• titanium dioxide MeSH Browser

Inhaled cadmium oxide nanoparticles (CdONPs) represent an underrecognized environmental and occupational hazard because of their potential for systemic bioaccumulation and organ-specific toxicity. In this study, mice were exposed to subchronic inhalation of CdONPs, and cadmium distribution, clearance, and tissue responses were assessed over a 21-day recovery period using atomic absorption spectrometry, laser ablation inductively coupled plasma mass spectrometry, histopathology, and gene expression analysis. Cadmium accumulated predominantly in the lungs, where clearance was slow and accompanied by persistent inflammation and foam cell formation. The intestines exhibited efficient cadmium reduction, likely due to high epithelial turnover, while the liver showed minimal accumulation and no overt damage. By contrast, the kidneys retained cadmium primarily in the cortex, with partial clearance and ultrastructural changes, including mitochondrial disorganization and lipid accumulation. Bone tissues demonstrated differential retention: jaw bones effectively cleared cadmium, whereas femurs showed sustained or increased levels, suggesting redistribution from other organs. Gene expression analysis revealed moderate but consistent upregulation of Abca1, Apoe, and Ptch1 in the kidneys of clearance groups, indicating adaptations in lipid metabolism and membrane transport. These findings highlight organ-specific clearance kinetics and molecular responses to inhaled CdONPs, underscoring the need for tissue-targeted risk assessment frameworks in nanoparticle toxicology.

• Keywords
• Cadmium oxide nanoparticles, Clearance, Electron microscopy analysis, Inhalation, Kidney, Liver, Lung, Toxicity,
• MeSH
• Administration, Inhalation MeSH
• Inhalation Exposure MeSH
• Liver metabolism   drug effects   MeSH
• Cadmium * pharmacokinetics   MeSH
• Bone and Bones metabolism   MeSH
• Metal Nanoparticles * toxicity   MeSH
• Kidney metabolism   drug effects   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Nanoparticles * toxicity   MeSH
• Oxides * pharmacokinetics   toxicity   MeSH
• Lung metabolism   drug effects   MeSH
• Cadmium Compounds * pharmacokinetics   toxicity   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• cadmium oxide MeSH Browser
• Cadmium * MeSH
• Oxides * MeSH
• Cadmium Compounds * MeSH

Cannabidiol (CBD), a phytocannabinoid commonly isolated from chemotype III Cannabis sativa plants, is known for its therapeutic potential. However, comprehensive information on its bioavailability is still lacking. The key objective of this study was to investigate the impact of specific formulations on CBD delivery to the site of action and, in particular, the brain of experimental animals. As brain tissue is an extremely complex matrix, a highly sensitive method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) had to be implemented. To make it applicable for multiple analytes, the method was validated for 17 other phytocannabinoids and selected metabolites. Using this method, a pharmacokinetic study was conducted on 200 brain samples collected from rats that had been administered various CBD formulations (carriers) via oral gavage. The peak concentration in brain occurred within 1-2 h; notably, the highest was reached with carriers containing triacylglycerols with the shortest fatty acid chains (caprylic/capric). In addition to the parent compound, 7-hydroxy-cannabidiol and 7-carboxy-cannabidiol were detected, confirming rapid post-administration metabolism. Overall, this research enhances understanding of CBD distribution in the brain and underscores the impact of specific formulations on its bioavailability, offering insights into optimizing CBD-based therapies to be both effective and 'patient-friendly'.

• Keywords
• Cannabidiol, LC-MS/MS, bioavailability, brain tissue, metabolites,
• MeSH
• Administration, Oral MeSH
• Biological Availability MeSH
• Chromatography, Liquid MeSH
• Cannabidiol * pharmacokinetics   administration & dosage   chemistry   MeSH
• Rats MeSH
• Brain * metabolism   drug effects   MeSH
• Tandem Mass Spectrometry MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cannabidiol * MeSH

TiO2 nanoparticles (NPs) are extensively used in various applications, highlighting the importance of ongoing research into their effects. This work belongs among rare whole-body inhalation studies investigating the effects of TiO2 NPs on mice. Unlike previous studies, the concentration of TiO2 NPs in the inhalation chamber (130.8 μg/m3) was significantly lower. This 11-week study on mice confirmed in vivo the presence of TiO2 NPs in lung macrophages and type II pneumocytes including their intracellular localization by using the electron microscopy and the state-of-the-art methods detecting NPs' chemical identity/crystal structure, such as the energy-dispersed X-ray spectroscopy (EDX), cathodoluminescence (CL), and detailed diffraction pattern analysis using powder nanobeam diffraction (PNBD). For the first time in inhalation study in vivo, the alterations in erythrocyte morphology with evidence of echinocytes and stomatocytes, accompanied by iron accumulation in spleen, liver, and kidney, are reported following NP's exposure. Together with the histopathological evidence of hyperaemia in the spleen and kidney, and haemosiderin presence in the spleen, the finding of NPs containing iron might suggest the increased decomposition of damaged erythrocytes. The detection of TiO2 NPs on erythrocytes through CL analysis confirmed their potential systemic availability. On the contrary, TiO2 NPs were not confirmed in other organs (spleen, liver, and kidney); Ti was detected only in the kidney near the detection limit.

• Keywords
• cathodoluminescence, electron microscopy, lung, powder nanobeam diffraction, titanium dioxide nanoparticles,
• MeSH
• Administration, Inhalation MeSH
• Erythrocytes * drug effects   pathology   MeSH
• Inhalation Exposure * adverse effects   MeSH
• Metal Nanoparticles * toxicity   MeSH
• Mice MeSH
• Nanoparticles * toxicity   MeSH
• Lung * drug effects   metabolism   pathology   MeSH
• Toxicity Tests, Subchronic MeSH
• Titanium * toxicity   pharmacokinetics   administration & dosage   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Titanium * MeSH
• titanium dioxide MeSH Browser

PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.

• Keywords
• Kidneys, PSMA, Prostate cancer, Radioligand therapy, Salivary glands,
• MeSH
• Antigens, Surface * metabolism   MeSH
• Glutamate Carboxypeptidase II * metabolism   MeSH
• Rats MeSH
• Kidney * drug effects   diagnostic imaging   metabolism   radiation effects   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Radiation-Protective Agents * pharmacology   pharmacokinetics   MeSH
• Salivary Glands * drug effects   diagnostic imaging   metabolism   radiation effects   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Surface * MeSH
• FOLH1 protein, human MeSH Browser
• Glutamate Carboxypeptidase II * MeSH
• Radiation-Protective Agents * MeSH

The cellular adhesion receptor αvβ6-integrin is highly expressed in many cancers, e.g., pancreatic, lung, head-and-neck, cervical, bladder, and esophageal carcinoma. Multimerization of αvβ6-integrin-specific RGD peptides increases the target affinity and retention but affects biodistribution and pharmacokinetics. Amide formation of the terminal carboxylic acid moieties of the square-symmetrical bifunctional chelator DOTPI with 3-azidopropylamine yields derivatives with 4, 3, and 2 terminal azides and zero, 1, and 2 remaining carboxylic acids, respectively, whereby formation of the 2-cis-isomer is preferred according to NMR investigation of the Eu(III)-complexes. Cu(II)-catalyzed alkyne-azide cycloaddition (CuAAC) of the alkyne-functionalized αvβ6-integrin binding peptide cyclo[YRGDLAYp(NMe)K(pent-4-ynoic amide)] (Tyr2) yields the respective di-, tri-, and tetrameric conjugates for Lu-177-labeling. In mice bearing αvβ6-integrin-expressing xenografts of H2009 (human lung adenocarcinoma) cells, the Lu-177-labeled trimer's tumor-to-blood ratio of 112 exceeds that of the tetramer (10.4) and the dimer (54). Co-infusion of gelofusine (succinylated gelatin) reduces the renal uptake of the trimer by 89%, resulting in a 10-fold better tumor-to-kidney ratio, while no improvement of that ratio is observed with arginine/lysine, para-aminohippuric acid (PAH), and hydroxyethyl starch (HES) coinfusions. Since the Lu-177-labeled Tyr2-trimer outperforms the dimer and the tetramer, such trimers are considered the best lead structures for the ongoing development of αvβ6-integrin targeted anticancer theranostics.

• MeSH
• Antigens, Neoplasm * metabolism   MeSH
• Chelating Agents * chemistry   MeSH
• Click Chemistry MeSH
• Integrins * metabolism   MeSH
• Humans MeSH
• Lutetium * chemistry   MeSH
• Mice, Nude MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms drug therapy   MeSH
• Oligopeptides * chemistry   pharmacokinetics   MeSH
• Radiopharmaceuticals pharmacokinetics   chemistry   therapeutic use   MeSH
• Radioisotopes * chemistry   MeSH
• Theranostic Nanomedicine methods   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, Neoplasm * MeSH
• arginyl-glycyl-aspartic acid MeSH Browser
• Chelating Agents * MeSH
• integrin alphavbeta6 MeSH Browser
• Integrins * MeSH
• Lutetium * MeSH
• Lutetium-177 MeSH Browser
• Oligopeptides * MeSH
• Radiopharmaceuticals MeSH
• Radioisotopes * MeSH

To date, the presence of pharmaceuticals has been extensively documented across a wide range of aquatic systems and biota. Further, substantial progress has been made in transitioning from laboratory assessments of pharmaceutical fate and effects in fish to in situ assessments of exposure and effects; however, certain research areas remain understudied. Among these is investigation of differential accumulation across multiple internal tissues in wild marine fish beyond the species commonly sampled in laboratory and freshwater field settings. This study examined the presence of pharmaceuticals across four tissues (plasma, muscle, brain, and liver) in a wild marine fish, bonefish (Albula vulpes), throughout coastal South Florida, USA. Differential accumulation across tissues was assessed for the number and concentration, identity, and composition of accumulated pharmaceuticals by sampling 25 bonefish and analyzing them for 91 pharmaceuticals. The concentration of pharmaceuticals was highest in plasma > liver > brain > muscle, while the number of pharmaceuticals was highest in liver > brain > plasma > muscle. The identity of detected pharmaceuticals was tissue specific, and there was an inverse relationship between the number of detections for each pharmaceutical and its log Kow. The composition of pharmaceuticals was tissue specific for both pharmaceutical presence/absence and concentration. Across all tissues, the greatest similarity was between brain and liver, which were more similar to plasma than to muscle, and muscle was the most distinct tissue. For tissue compositional variability, muscle was the most diverse in accumulated pharmaceuticals, while plasma, brain, and liver were similarly variable. With the highest concentrations in plasma and highest number in liver, and documented variability in accumulated pharmaceuticals across tissues, our results highlight the importance of tissue selection when surveying exposure in wild fish, suggesting that multi-tissue analysis would allow for a more comprehensive assessment of exposure diversity and risk of adverse effects.

• Keywords
• Coastal environments, Emerging contaminants, Marine environments, Pharmaceutical accumulation, Tissue distribution,
• MeSH
• Water Pollutants, Chemical * analysis   MeSH
• Liver * chemistry   metabolism   MeSH
• Pharmaceutical Preparations analysis   metabolism   MeSH
• Environmental Monitoring MeSH
• Brain metabolism   MeSH
• Fishes * metabolism   MeSH
• Muscles chemistry   metabolism   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Florida MeSH
• Names of Substances
• Water Pollutants, Chemical * MeSH
• Pharmaceutical Preparations MeSH

Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding β-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.

• MeSH
• Pulmonary Artery drug effects   metabolism   MeSH
• Biomarkers MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Galectin 3 * antagonists & inhibitors   metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Hypertension, Pulmonary * drug therapy   metabolism   MeSH
• Polymers chemistry   pharmacology   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Galectin 3 * MeSH
• Polymers MeSH

INTRODUCTION: Gold nanoparticles are promising candidates as vehicles for drug delivery systems and could be developed into effective anticancer treatments. However, concerns about their safety need to be identified, addressed, and satisfactorily answered. Although gold nanoparticles are considered biocompatible and nontoxic, most of the toxicology evidence originates from in vitro studies, which may not reflect the responses in complex living organisms. METHODS: We used an animal model to study the long-term effects of 20 nm spherical AuNPs coated with bovine serum albumin. Mice received a 1 mg/kg single intravenous dose of nanoparticles, and the biodistribution and accumulation, as well as the organ changes caused by the nanoparticles, were characterized in the liver, spleen, and kidneys during 120 days. RESULTS: The amount of nanoparticles in the organs remained high at 120 days compared with day 1, showing a 39% reduction in the liver, a 53% increase in the spleen, and a 150% increase in the kidneys. The biological effects of chronic nanoparticle exposure were associated with early inflammatory and fibrotic responses in the organs and were more pronounced in the kidneys, despite a negligible amount of nanoparticles found in renal tissues. CONCLUSION: Our data suggest, that although AuNPs belong to the safest nanomaterial platforms nowadays, due to their slow tissue elimination leading to long-term accumulation in the biological systems, they may induce toxic responses in the vital organs, and so understanding of their long-term biological impact is important to consider their potential therapeutic applications.

• Keywords
• AuNPs, biodistribution, fibrosis, in vivo, inflammation, long-term accumulation,
• MeSH
• Liver * drug effects   metabolism   MeSH
• Metal Nanoparticles * chemistry   toxicity   administration & dosage   MeSH
• Kidney * drug effects   metabolism   MeSH
• Mice MeSH
• Serum Albumin, Bovine * chemistry   pharmacokinetics   MeSH
• Spleen * drug effects   MeSH
• Tissue Distribution MeSH
• Particle Size MeSH
• Gold * chemistry   pharmacokinetics   toxicity   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Serum Albumin, Bovine * MeSH
• Gold * 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.

• Keywords
• (211)Bi, (211)Pb, (223)Ra, Radioactive progeny, Recoil effect, Targeted alpha therapy,
• MeSH
• Mice MeSH
• Nanoparticles * MeSH
• Lead MeSH
• Radiopharmaceuticals * therapeutic use   MeSH
• Radioisotopes therapeutic use   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Lead MeSH
• Radiopharmaceuticals * MeSH
• Radioisotopes MeSH