Magnetic nanoparticles have been at the center of biomedical research for decades, primarily for their applications in magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). Superparamagnetic particles, typically based on iron oxide crystals, are effective in both modalities, although each requires distinct magnetic properties for optimal performance. We investigated the performance of nanoparticles based on a nickel-substituted ferrite core and compared them to standard maghemite iron oxide nanoparticles. We synthesized γ-Fe2O3 and Ni x Fe2-x O3 nanoparticles and coated them with a statistical copolymer poly-(N,N-dimethylacrylamide-co-acrylic acid). In vitro testing included X-ray diffraction (XRD), Mössbauer spectroscopy, magnetometry, magnetic resonance relaxometry, magnetic particle spectroscopy, and imaging. In vivo testing involved monitoring of nanoparticle biodistribution using MPI and MRI after intracardial application in a murine model. Mössbauer spectra suggest that the Ni-substituted nanoparticles consist of a stoichiometric NiFe2O4 ferrite and a poorly crystalline antiferromagnetic iron-(III) oxide-hydroxide phase. Amorphous-like impurities in Ni x Fe2-x O3 nanoparticles were probably responsible for lower saturation magnetization than that of γ-Fe2O3 nanoparticles, as was proved by magnetometry, which led to lower r 2 relaxivity. However, MPI revealed a higher signal in the spectrum and superior imaging performance of Ni x Fe2-x O3 compared to γ-Fe2O3 particles, likely due to shorter Néél and Brownian relaxation times. Both types of nanoparticles showed similar performance in bimodal MRI/MPI imaging in vivo. They were detected in the liver immediately after application and appeared in the spleen within 24 h. Long-term localization in the lymph nodes was also observed. Substituting an iron with a nickel ion in the core altered the magnetic properties, leading to lower saturation magnetization and an increased signal in the magnetic particle spectra, which enhanced their performance in MPI. This study demonstrates that γ-Fe2O3 and Ni x Fe2-x O3 nanoparticles are both suitable for combined MRI/MPI imaging; magnetic particle imaging provides a highly specific signal for anatomical magnetic resonance images.

• Keywords
• magnetic particle imaging, magnetic resonance imaging, nickel ferrite nanoparticles, r2 relaxivity, saturation magnetization,
• Publication type
• Journal Article MeSH

In this work, we present the synthesis and evaluation of magnetic resonance (MR) properties of novel phosphorus/iron-containing probes for dual 31P and 1H MR imaging and spectroscopy (MRI and MRS). The presented probes are composed of biocompatible semitelechelic and multivalent phospho-polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) coordinated with small paramagnetic Fe3+ ions or superparamagnetic maghemite (γ-Fe2O3) nanoparticles via deferoxamine group linked to the end or along the polymer chains. All probes provided very short 1H T1 and T2 relaxation times even at low iron concentrations. The presence of iron had a significant impact on the shortening of 31P relaxation, with the effect being more pronounced for probes based on γ-Fe2O3 and multivalent polymer. While the water-soluble probe having one Fe3+ ion per polymer chain was satisfactorily visualized by both 31P-MRS and 31P-MRI, the probe with multiple Fe3+ ions could only be detected by 31P-MRS, and the probes consisting of γ-Fe2O3 nanoparticles could not be imaged by either technique due to their ultra-short 31P relaxations. In this proof-of-principle study performed on phantoms at a clinically relevant magnetic fields, we demonstrated how the different forms and concentrations of iron affect both the 1H MR signal of the surrounding water molecules and the 31P MR signal of the phospho-polymer probe. Thus, this double contrast can be exploited to simultaneously visualize body anatomy and monitor probe biodistribution.

• MeSH
• Magnetic Resonance Spectroscopy MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Polymers * MeSH
• Tissue Distribution MeSH
• Water MeSH
• Iron MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Polymers * MeSH
• Water MeSH
• Iron MeSH

Superparamagnetic iron oxide nanoparticles (SPION) with a "non-fouling" surface represent a versatile group of biocompatible nanomaterials valuable for medical diagnostics, including oncology. In our study we present a synthesis of novel maghemite (γ-Fe2O3) nanoparticles with positive and negative overall surface charge and their coating by copolymer P(HPMA-co-HAO) prepared by RAFT (reversible addition-fragmentation chain-transfer) copolymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with N-[2-(hydroxyamino)-2-oxo-ethyl]-2-methyl-prop-2-enamide (HAO). Coating was realized via hydroxamic acid groups of the HAO comonomer units with a strong affinity to maghemite. Dynamic light scattering (DLS) demonstrated high colloidal stability of the coated particles in a wide pH range, high ionic strength, and the presence of phosphate buffer (PBS) and serum albumin (BSE). Transmission electron microscopy (TEM) images show a narrow size distribution and spheroid shape. Alternative coatings were prepared by copolymerization of HPMA with methyl 2-(2-methylprop-2-enoylamino)acetate (MMA) and further post-polymerization modification with hydroxamic acid groups, carboxylic acid and primary-amino functionalities. Nevertheless, their colloidal stability was worse in comparison with P(HPMA-co-HAO). Additionally, P(HPMA-co-HAO)-coated nanoparticles were subjected to a bio-distribution study in mice. They were cleared from the blood stream by the liver relatively slowly, and their half-life in the liver depended on their charge; nevertheless, both cationic and anionic particles revealed a much shorter metabolic clearance rate than that of commercially available ferucarbotran.

• Keywords
• MRI, contrast agents, hydroxamic acid, maghemite, non-fouling surface, polymer coating, superparamagnetic iron oxide nanoparticles,
• Publication type
• Journal Article MeSH

Photoacoustic imaging, an emerging modality, provides supplemental information to ultrasound imaging. We investigated the properties of polypyrrole nanoparticles, which considerably enhance contrast in photoacoustic images, in relation to the synthesis procedure and to their size. We prepared polypyrrole nanoparticles by water-based redox precipitation polymerization in the presence of ammonium persulphate (ratio nPy:nOxi 1:0.5, 1:1, 1:2, 1:3, 1:5) or iron(III) chloride (nPy:nOxi 1:2.3) acting as an oxidant. To stabilize growing nanoparticles, non-ionic polyvinylpyrrolidone was used. The nanoparticles were characterized and tested as a photoacoustic contrast agent in vitro on an imaging platform combining ultrasound and photoacoustic imaging. High photoacoustic signals were obtained with lower ratios of the oxidant (nPy:nAPS ≥ 1:2), which corresponded to higher number of conjugated bonds in the polymer. The increasing portion of oxidized structures probably shifted the absorption spectra towards shorter wavelengths. A strong photoacoustic signal dependence on the nanoparticle size was revealed; the signal linearly increased with particle surface. Coated nanoparticles were also tested in vivo on a mouse model. To conclude, polypyrrole nanoparticles represent a promising contrast agent for photoacoustic imaging. Variations in the preparation result in varying photoacoustic properties related to their structure and allow to optimize the nanoparticles for in vivo imaging.

• Keywords
• contrast agents, nanoparticles, photoacoustic imaging, polypyrrole,
• Publication type
• Journal Article MeSH

Dextran-coated magnetic nanoparticles are promising biocompatible agents in various biomedical applications, including hyperthermia and magnetic resonance imaging (MRI). However, the influence of dextran molecular weight on the physical properties of dextran-coated magnetic nanoparticles has not been described sufficiently. We synthesise magnetite nanoparticles with a dextran coating using a co-precipitation method and study their physical properties as a function of dextran molecular weight. Several different methods are used to determine the size distribution of the particles, including microscopy, dynamic light scattering, differential centrifugal sedimentation and magnetic measurements. The size of the dextran-coated particles increases with increasing dextran molecular weight. We find that the molecular weight of dextran has a significant effect on the particle size, efficiency, magnetic properties and specific absorption rate. Magnetic hyperthermia measurements show that heating is faster for dextran-coated particles with higher molecular weight. The different molecular weights of the coating also significantly affected its MRI relaxation properties, especially the transversal relaxivity r2. Linear regression analysis reveals a statistically significant dependence of r2 on the differential centrifugal sedimentation diameter. This allows the targeted preparation of dextran-coated magnetic nanoparticles with the desired MRI properties. These results will aid the development of functionalised magnetic nanoparticles for hyperthermia and MRI applications.

• Keywords
• MRI, dextran, diameter, magnetic fluid, magnetic hyperthermia, magnetic nanoparticles, physical properties, relaxivity,
• Publication type
• Journal Article MeSH

Maghemite (γ-Fe2O3) nanoparticles obtained through co-precipitation and oxidation were coated with heparin (Hep) to yield γ-Fe2O3@Hep, and subsequently with chitosan that was modified with different phenolic compounds, including gallic acid (CS-G), hydroquinone (CS-H), and phloroglucinol (CS-P), to yield γ-Fe2O3@Hep-CS-G, γ-Fe2O3@Hep-CS-H, and γ-Fe2O3@Hep-CS-P particles, respectively. Surface modification of the particles was analyzed by transmission electron microscopy, dynamic light scattering, attenuated total reflection Fourier transform infrared spectroscopy, and thermogravimetric analysis. Magnetic measurements indicated that the polymer coating does not affect the superparamagnetic character of the iron oxide core. However, magnetic saturation decreased with increasing thickness of the polymer coating. The antioxidant properties of the nanoparticles were analyzed using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Cellular uptake and intracellular antioxidant activity of the particles were evaluated by an iron assay and flow cytometry, respectively, using L-929 and LN-229 cells. Compared to the control, the phenolic modification significantly reduced intracellular reactive oxygen species (ROS) levels to 35-56%, which was associated with a 6-8-times higher cellular uptake in L-929 cells and a 21-31-times higher cellular uptake in LN-229 cells. In contrast, γ-Fe2O3@Hep particles induced a 3.8-times and 14.9-times higher cellular uptake without inducing antioxidant activity. In conclusion, the high cellular uptake and the antioxidant properties associated with the phenolic moieties in the modified particles allow for a potential application in biomedical areas.

• Keywords
• antioxidants, chitosan, maghemite nanoparticles, oxidative stress, phenolic compound,
• Publication type
• Journal Article MeSH

Manganese-zinc ferrite nanoparticles were synthesized by using a hydrothermal treatment, coated with silica, and then tested as efficient cellular labels for cell tracking, using magnetic resonance imaging (MRI) in vivo. A toxicity study was performed on rat mesenchymal stem cells and C6 glioblastoma cells. Adverse effects on viability and cell proliferation were observed at the highest concentration (0.55 mM) only; cell viability was not compromised at lower concentrations. Nanoparticle internalization was confirmed by transmission electron microscopy. The particles were found in membranous vesicles inside the cytoplasm. Although the metal content (0.42 pg Fe/cell) was lower compared to commercially available iron oxide nanoparticles, labeled cells reached a comparable relaxation rate R 2, owing to higher nanoparticle relaxivity. Cells from transgenic luciferase-positive rats were used for in vivo experiments. Labeled cells were transplanted into the muscles of non-bioluminescent rats and visualized by MRI. The cells produced a distinct hypointense signal in T2- or T2*-weighted MR images in vivo. Cell viability in vivo was verified by bioluminescence.

• Keywords
• cell labeling, cell transplantation, doping, magnetic resonance imaging, nanoparticles,
• Publication type
• Journal Article MeSH

Doxorubicin-conjugated magnetic nanoparticles containing hydrolyzable hydrazone bonds were developed using a non-toxic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) coating, which ensured good colloidal stability in aqueous media and limited internalization by the cells, however, enabled adhesion to the cell surface. While the neat PHPMA-coated particles proved to be non-toxic, doxorubicin-conjugated particles exhibited enhanced cytotoxicity in both drug-sensitive and drug-resistant tumor cells compared to free doxorubicin. The newly developed doxorubicin-conjugated PHPMA-coated magnetic particles seem to be a promising magnetically targeted vehicle for anticancer drug delivery.

• Keywords
• cytotoxicity, doxorubicin, magnetic, nanoparticles, poly[N-(2-hydroxypropyl)methacrylamide],
• Publication type
• Journal Article MeSH

BACKGROUND: Poly-l-lysine (PLL) enhances nanoparticle (NP) uptake, but the molecular mechanism remains unresolved. We asked whether PLL may interact with negatively charged glycoconjugates on the cell surface and facilitate uptake of magnetic NPs (MNPs) by tumor cells. METHODS: PLL-coated MNPs (PLL-MNPs) with positive and negative ζ-potential were prepared and characterized. Confocal and transmission electron microscopy was used to analyze cellular internalization of MNPs. A colorimetric iron assay was used to quantitate cell-associated MNPs (MNPcell). RESULTS: Coadministration of PLL and dextran-coated MNPs in culture enhanced cellular internalization of MNPs, with increased vesicle size and numbers/cell. MNPcell was increased by eight- to 12-fold in response to PLL in a concentration-dependent manner in human glioma and HeLa cells. However, the application of a magnetic field attenuated PLL-induced increase in MNPcell. PLL-coating increased MNPcell regardless of ζ-potential of PLL-MNPs, whereas magnetic force did not enhance MNPcell. In contrast, epigallocatechin gallate and magnetic force synergistically enhanced PLL-MNP uptake. In addition, heparin, but not sialic acid, greatly reduced the enhancement effects of PLL; however, removal of heparan sulfate from heparan sulfate proteoglycans of the cell surface by heparinase III significantly reduced MNPcell. CONCLUSION: Our results suggest that PLL-heparan sulfate proteoglycan interaction may be the first step mediating PLL-MNP internalization by tumor cells. Given these results, PLL may facilitate NP interaction with tumor cells via a molecular mechanism shared by infection machinery of certain viruses.

• Keywords
• glycoconjugate, heparan sulfate proteoglycan, magnetic nanoparticles, poly-l-lysine, tea catechin,
• MeSH
• Cell Membrane metabolism   MeSH
• Dextrans chemistry   metabolism   MeSH
• Human Umbilical Vein Endothelial Cells MeSH
• Glioma drug therapy   pathology   MeSH
• HeLa Cells MeSH
• Heparan Sulfate Proteoglycans chemistry   metabolism   MeSH
• Humans MeSH
• Magnetite Nanoparticles administration & dosage   chemistry   MeSH
• Magnetic Fields MeSH
• Cell Line, Tumor MeSH
• Polylysine chemistry   metabolism   pharmacokinetics   MeSH
• Polysaccharide-Lyases metabolism   MeSH
• Microscopy, Electron, Transmission MeSH
• Iron metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Dextrans MeSH
• Heparan Sulfate Proteoglycans MeSH
• heparitinsulfate lyase MeSH Browser
• Magnetite Nanoparticles MeSH
• Polylysine MeSH
• Polysaccharide-Lyases MeSH
• Iron MeSH

INTRODUCTION: Rat mesenchymal stem cells (rMSCs) labeled with 1) poly-l-lysine-coated superparamagnetic iron oxide nanoparticles or 2) silica-coated cobalt-zinc-iron nanoparticles were implanted into the left brain hemisphere of rats, to assess their effects on the levels of oxidative damage to biological macromolecules in brain tissue. METHODS: Controls were implanted with unlabeled rMSCs. Animals were sacrificed 24 hours or 4 weeks after the treatment, and the implantation site along with the surrounding tissue was isolated from the brain. At the same intervals, parallel groups of animals were scanned in vivo by magnetic resonance imaging (MRI). The comet assay with enzymes of excision DNA repair (endonuclease III and formamidopyrimidine-DNA glycosylase) was used to analyze breaks and oxidative damage to DNA in the brain tissue. Oxidative damage to proteins and lipids was determined by measuring the levels of carbonyl groups and 15-F2t-isoprostane (enzyme-linked immunosorbent assay). MRI displayed implants of labeled cells as extensive hypointense areas in the brain tissue. In histological sections, the expression of glial fibrillary acidic protein and CD68 was analyzed to detect astrogliosis and inflammatory response. RESULTS: Both contrast labels caused a similar response in the T2-weighted magnetic resonance (MR) image and the signal was clearly visible within 4 weeks after implantation of rMSCs. No increase of oxidative damage to DNA, lipids, or proteins over the control values was detected in any sample of brain tissue from the treated animals. Also, immunohistochemistry did not indicate any serious tissue impairment around the graft. CONCLUSION: Both tested types of nanoparticles appear to be prospective and safe labels for tracking the transplanted cells by MR.

• Keywords
• MRI, cell transplantation, comet assay, genotoxicity, lipid peroxidation, protein oxidative damage,
• MeSH
• Dinoprost analogs & derivatives   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Isoprostanes analysis   metabolism   MeSH
• Cobalt chemistry   MeSH
• Metal Nanoparticles administration & dosage   chemistry   toxicity   MeSH
• Magnetic Resonance Imaging methods   MeSH
• Mesenchymal Stem Cells chemistry   MeSH
• Brain diagnostic imaging   drug effects   metabolism   MeSH
• Silicon Dioxide chemistry   MeSH
• Rats, Inbred Lew MeSH
• Prospective Studies MeSH
• Tissue Extracts MeSH
• Mesenchymal Stem Cell Transplantation * MeSH
• Ferric Compounds chemistry   MeSH
• Iron chemistry   MeSH
• Zinc chemistry   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 8-epi-prostaglandin F2alpha MeSH Browser
• Dinoprost MeSH
• ferric oxide MeSH Browser
• Isoprostanes MeSH
• Cobalt MeSH
• Silicon Dioxide MeSH
• Tissue Extracts MeSH
• Ferric Compounds MeSH
• Iron MeSH
• Zinc MeSH