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The field of medical application of organic or inorganic nanoparticles is extensive. Medical nanoparticles offer benefits but pose risks. For safe use in diagnostics and therapy, they should be inert, non-immunogenic, non-aggregating, and avoid long-term accumulation in sensitive tissues like bone marrow or the brain. We have developed in-house very small superparamagnetic iron oxide nanoparticles (VSOP), 7 nm in size, which have been successfully used in preclinical magnetic resonance imaging (MRI) to detect intestinal inflammation, neuroinflammation and atherosclerosis. This study examines nanoparticle effects on human blood cells focusing on monocytes in vitro as a first step toward clinical application. Whole blood and monocytes from healthy donors and patients with inflammatory bowel disease were treated with VSOP in vitro and analyzed for changes in their transcriptome, phenotype and function. RNA sequencing of monocytes identified the transferrin receptor as one of the most significantly downregulated genes after VSOP treatment, likely to limit iron uptake. Whereas whole blood RNA sequencing showed significant changes only in three non-coding genes. CyTOF analysis confirmed that VSOP-treated monocytes remain inactive, with no increased proliferation or altered migration. Metabolically, VSOP uptake enhanced the oxygen consumption rate. This effect was likely due to phagocytosis rather than effects mediated by the VSOP itself, as phagocytosis of latex beads showed comparable results. In summary, the analysis of peripheral blood mononuclear cells and monocytes suggests that VSOP treatment has no major impact on immune cell phenotype or function indicating VSOP as a promising diagnostic tool in MRI for inflammatory bowel disease.
Magnetic nanoparticles are gaining increasing attention as a promising alternative to gadolinium-based contrast agents in magnetic resonance imaging, primarily due to their low toxicity. In this study, we investigated the use of magnetic iron oxide nanoparticles in mouse models of intestinal inflammation to assess their potential for detecting changes in the extracellular matrix. For magnetic quantification, we employed magnetic particle spectroscopy, which offers high sensitivity and minimal interference from biological tissue. However, we observed significant variations in magnetic signals within the intestine, as well as measurable signals in control animals, indicating possible magnetic contamination. By doping the nanoparticles with europium, we were able to confirm this suspicion through quantitative elemental analysis. Examination of mouse feed and feces allowed us to identify the source of contamination. Based on these findings, we developed a method to reliably distinguish genuine signals of magnetic nanoparticles from those caused by external magnetic contaminations. This approach is essential to ensure reliable results in future diagnostic and preclinical research.
Iron isotope ratios of haematite (Fe2O3) and magnetite (Fe3O4) provide insights into geochemical, environmental and planetary processes. In most studies, Fe isotope measurements are commonly performed using solution nebulisation multi-collector inductively coupled plasma-mass spectrometry (SN-MC-ICP-MS). Nanosecond laser ablation multi-collector inductively coupled plasma-mass spectrometry (ns-LA-MC-ICP-MS) requires minimal sample preparation, and provides spatially resolved variation of iron isotopes at micro-scale. However, homogeneous and matrix-matched haematite/magnetite reference materials are lacking for precise in situ isotopic measurement. The iron isotope ratios of two potential reference materials resembling natural haematite (HMIE-NP-B01) and natural magnetite (MAKP-NP-B01) were characterised. Size fractions between 5–63 μm of the powdered Fe oxides were milled to nanoparticles, freeze-dried, homogenised, and pressed into pellets. The materials were then evaluated using SN-MC-ICP-MS and LA-MC-ICP-MS. Sample powders of the two materials were measured by SN-MC-ICPMS after sample digestion and column separation and pressed pellets were analysed directly via ns-LA-MC-ICP-MS. In both cases iron isotope delta values are reported relative to the certified reference material IRMM-014, used as the bracketing standard (calibrator). The solution measurements yielded δ56Fe values of -0.25 ± 0.08‰ (N = 13, 2s) for HMIE-NP-B01, and -0.05 ± 0.09‰ (N = 12, 2s) for MAKP-NP-B01, considered as the preferred Fe isotope delta values. In situ isotopic analysis via ns-LA-MC-ICP-MS yielded δ56Fe values of -0.28 ± 0.28‰ (N = 19, 2s) for HMIE-NP-B01 and -0.12 ± 0.24‰ (N = 22, 2s) for MAKP-NP-B01, consistent with the solution Fe isotope data. The homogeneity of Fe isotopes of the pellets was evaluated by ns-LA-MC-ICP-MS analyses of three different positions to further confirm that both materials are isotopically homogeneous. Both materials can be considered as potential quality control and bracketing reference materials for Fe isotopic measurements by in situ ns-LA-MC-ICP-MS analysis.
Stable metal isotopes receive increasing attention as medical biomarkers due to their potential to detect changes of the metal metabolism related to disease. Potential mechanisms causing isotope fractionation include biological processes that involve redox- or bond-forming reactions and interaction of metals during transmembrane import and export. In order to advance our understanding of the underlying processes responsible for isotope fractionation between normal and diseased cells, we need in situ, spatially resolved methods. Despite its frequent use, laser ablation - multi-collector - inductively coupled plasma mass spectrometry (LA-MC-ICPMS) analysis of biological material is severely limited by the scarcity of matrix-matched standards. Such matrix-matched standards are necessary to correct for instrumental sources of isotope fractionation such as particle size distribution, ablation physics and differential ionization.
Copper stable isotopes have proven to be a particularly powerful tool to identify differences in isotope composition between tumors and healthy tissue suggesting application in cancer diagnosis [1, 2]. To further our knowledge of Cu isotope fractionation processes induced by diseases we have developed gelatin-based bracketing standards allowing to correct instrumentally induced isotope fractionation during LA-MC-ICPMS analysis. Since gelatin properties resemble properties of protein-rich cellular material, they mimic biological matrices and their ablation behaviour. Hence, gelatin standards are spiked with known amounts of Cu stable isotopes of a known Cu isotope composition and used as matrix-matched bracketing standard. The method achieved reproducibilities of better than 0.15‰ (2SD) for inorganic reference materials and reproducibilities of better than 0.17‰ (2SD) for biological reference materials. The developed routine was tested on a liver tumor model and in situ Cu isotope compositions between healthy (δ65/63Cu = -1.5 to 0.2 ‰) and tumorous (δ65/63Cu = 0.0 to 1.3 ‰) liver tissue could be distinguished (Figure 1) [3].
Stable metal isotopes receive increasing attention as medical biomarkers due to their potential to detect changes of the metal metabolism related to disease. Potential mechanisms causing isotope fractionation include biological processes that involve redox- or bond-forming reactions and interaction of metals during transmembrane import and export. In order to advance our understanding of the underlying processes responsible for isotope fractionation between normal and diseased cells, we need in situ, spatially resolved methods. Despite its frequent use, laser ablation - multi-collector - inductively coupled plasma mass spectrometry (LA-MC-ICPMS) analysis of biological material is severely limited by the scarcity of matrix-matched standards. Such matrix-matched standards are necessary to correct for instrumental sources of isotope fractionation such as particle size distribution, ablation physics and differential ionization.
Copper stable isotopes have proven to be a particularly powerful tool to identify differences in isotope composition between tumors and healthy tissue suggesting application in cancer diagnosis [1, 2]. To further our knowledge of Cu isotope fractionation processes induced by diseases we have developed gelatin-based bracketing standards allowing to correct instrumentally induced isotope fractionation during LA-MC-ICPMS analysis. Since gelatin properties resemble properties of protein-rich cellular material, they mimic biological matrices and their ablation behaviour. Hence, gelatin standards are spiked with known amounts of Cu stable isotopes of a known Cu isotope composition and used as matrix-matched bracketing standard. A Ni reference solution was aspirated to the plasma to allow for mass bias correction and laser energy densities were below the glass ablation threshold. The method achieved reproducibilities of better than 0.10‰ (2SD) for inorganic reference materials and reproducibilities of better than 0.17‰ (2SD) for biological reference materials. The developed routine is tested on biomedical samples and the in situ Cu isotope data will be presented.
Stable metal isotopes receive increasing attention as medical biomarkers due to their potential to detect changes of the metal metabolism related to disease. Potential mechanisms causing isotope fractionation include biological processes that involve redox- or bond-forming reactions and interaction of metals during transmembrane import and export. In order to advance our understanding of the underlying processes responsible for isotope fractionation between normal and diseased cells, we need in situ, spatially resolved methods. Despite its frequent use, laser ablation - multi-collector - inductively coupled plasma mass spectrometry (LA-MC-ICPMS) analysis of biological material is severely limited by the scarcity of matrix-matched standards. Such matrix-matched standards are necessary to correct for instrumental sources of isotope fractionation such as particle size distribution, ablation physics and differential ionization, which currently restrict the application of LA-MC-ICPMS in isotope metallomics. Copper stable isotopes have proven to be a particularly powerful tool to identify differences in isotope composition between tumors and healthy tissue suggesting application in cancer diagnosis [1, 2]. To further our knowledge of Cu isotope fractionation processes induced by diseases we have developed gelatin-based bracketing standards allowing to correct instrumentally induced isotope fractionation during LA-MC-ICPMS analysis. Since gelatin properties resemble properties of protein-rich cellular material, they mimic biological matrices and their ablation behaviour. Hence, gelatin standards are spiked with known amounts of Cu stable isotopes of a known Cu isotope composition and used as matrix-matched bracketing standard. A Ni reference solution was aspirated to the plasma to allow for mass bias correction and laser energy densities were below the glass ablation threshold. The method achieved reproducibilities of better than 0.10‰ (2SD) for inorganic reference materials and reproducibilities of better than 0.17‰ (2SD) for biological reference materials. We will present in situ Cu isotope data of an hepatocellular carcinoma animal model comparing healthy and tumorous liver tissue.
Stable metal isotopes receive increasing attention as medical biomarkers due to their potential to detect changes of the metal metabolism related to disease. Potential mechanisms causing isotope fractionation include biological processes that involve redox- or bond-forming reactions and interaction of metals during transmembrane import and export. In order to advance our understanding of the underlying processes responsible for isotope fractionation between normal and diseased cells, we need in situ, spatially resolved methods. Despite its frequent use, laser ablation - multi-collector - inductively coupled plasma mass spectrometry (LA-MC-ICPMS) analysis of biological material is severely limited by the scarcity of matrix-matched standards. Such matrix-matched standards are necessary to correct for instrumental sources of isotope fractionation such as particle size distribution, ablation physics and differential ionization.
Copper stable isotopes have proven to be a particularly powerful tool to identify differences in isotope composition between tumors and healthy tissue suggesting application in cancer diagnosis [1, 2]. To further our knowledge of Cu isotope fractionation processes induced by diseases we have developed gelatin-based bracketing standards allowing to correct instrumentally induced isotope fractionation during LA-MC-ICPMS analysis. Since gelatin properties resemble properties of protein-rich cellular material, they mimic biological matrices and their ablation behaviour. Hence, gelatin standards are spiked with known amounts of Cu stable isotopes of a known Cu isotope composition and used as matrix-matched bracketing standard. The method achieved reproducibilities of better than 0.15‰ (2SD) for inorganic reference materials and reproducibilities of better than 0.17‰ (2SD) for biological reference materials. The developed routine was tested on a liver tumor model and in situ Cu isotope compositions between healthy (δ65/63Cu = -1.5 to 0.2 ‰) and tumorous (δ65/63Cu = 0.0 to 1.3 ‰) liver tissue could be distinguished [3].
Stable metal isotopes have received increasing attention as medical biomarkers due to their potential to detect changes in metal metabolism related to diseases. In particular, copper stable isotopes are a powerful tool to identify isotopic variation between tumors and healthy tissue, suggesting application in cancer diagnosis. However, potential mechanisms causing isotope fractionation, such as redox- or bond-forming reactions and interactions of metals during transmembrane import and export, are less well understood. Here, we established an in situ method using laser ablation-multicollector-inductively coupled plasma-mass spectrometry (LA-MC-ICP-MS) to advance our understanding of the underlying processes responsible for isotope fractionation between normal and diseased tissues. Gelatin-based bracketing standards and quality control reference materials, crucial for laser ablation analysis, were developed to allow correction for instrumentally induced isotope fractionation during LA-MC-ICP-MS analysis. Using such matrix-matched standards, the method achieved intermediate precisions for delta values of better than 0.15 ‰ (2 s) for inorganic reference materials and of better than 0.17 ‰ (2 s) for biological reference materials. The developed routine was tested on rabbit VX2 liver tumor samples, a model system resembling human hepatocellular carcinoma (HCC) used to study liver cancer. In situ Cu isotope compositions between healthy (𝛿65/63NIST976(Cu) = −1.5 ‰ to 0.2 ‰) and tumorous (𝛿65/63NIST976(Cu) = 0.0 ‰ to 1.3 ‰) liver tissue show distinct differences in their isotope ratios. The observed isotopic dichotomy is consistent with previous solution-based MC-ICP-MS work, showing enrichment of heavy 65Cu in cancer biopsies relative to healthy tissue.
Objective: Iron-based contrast agents (IBCAs) have potential as alternatives to Gd-based contrast agents (GBCAs), intending to address the long-term safety concerns associated with gadolinium. We investigated [Fe-EOB-tCDTA] as a potential alternative to [Gd-EOB-DTPA]2- for liver magnetic resonance imaging (MRI).
Materials and methods: [Fe-EOB-tCDTA] was synthesized by reacting the monoanhydride of tCDTA with 4-ethoxybenzylamine followed by iron chelation. Its kinetic stability was spectrophotometrically evaluated using a zinc stress test. The T1 relaxivity was measured in water and serum at 1.41 T, 37 °C and 3 T, 23 °C. Cellular cytotoxicity against liver-derived BRL-3A cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The uptake of [Fe-EOB-tCDTA] by liver cells was investigated using LA-ICP-MS, in competition with [Gd-EOB-DTPA]2-. T1 contrast effects in BALB/c mice were evaluated by DCE-MRI.
Results: [Fe-EOB-tCDTA] exhibited higher kinetic stability than [Fe-(tCDTA)]-and demonstrated a r1 of 1.94 and 2.45 mM-1s-1at 1.4 and 3 T in serum. No significant differences in the short-term cytotoxicity were observed between [Gd-EOB-DTPA]2-and [Fe-EOB-tCDTA]. [Fe-EOB-tCDTA] inhibited [Gd-EOB-DTPA]2- uptake in BRL-3A liver cells. [Fe-EOB-tCDTA] (0.2 mmol/kg) demonstrated a comparable blood peak RE% compared to [Gd-DO3A-butrol] (0.1 mmol/kg). However, RE of [Gd-EOB-DTPA]2- in liver at a clinical dose was significantly higher than that of [Fe-EOB-tCDTA] at both injection doses.
Conclusion: [Fe-EOB-tCDTA] provides comparable blood enhancement to [Gd-DO3A-butrol] and exhibits hepatobiliary excretion like [Gd-EOB-DTPA]2- but without a comparable liver contrast. [Fe-EOB-tCDTA] may serve as an alternative to nonspecific GBCAs, particularly for patients with renal insufficiency and a contraindication to GBCAs.
The porcine in-stent stenosis model has been essential for developing drug-coated devices but does not replicate the hyperlipidemic, pro-atherogenic conditions driving neoatherosclerosis. We aimed to establish a practical porcine model for testing endovascular therapies targeting neoatherosclerosis. Juvenile pigs were fed a high-fat, nicotine-supplemented diet (HFDN). After two weeks, bare-metal stents were implanted in coronary and peripheral arteries; controls received a standard diet. Four weeks later, stented, and non-stented artery segments were analyzed. HFDN feeding induced elevated serum LDL and cotinine. At follow-up, in-stent late lumen loss was significantly greater in peripheral arteries (A. iliaca: 2.3 ± 0.6 vs. 1.1 ± 0.5 mm; A. femoralis: 3.4 ± 1.2 vs. 2.0 ± 0.4 mm), but not coronary arteries. HFDN-fed pigs showed distinct signs of early neoatherosclerosis, including peri-strut foam cell accumulations and atheroma formation. Elemental imaging and chemical analysis confirmed increased calcium phosphate deposition in arteries of HFDN-fed pigs. This straightforward protocol enables testing of devices aimed at preventing or treating neoatherosclerosis.
