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Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: NMP.2013.1.4-2 | Award Amount: 11.56M | Year: 2013

The NanoMag project is to improve and redefine existing analyzing methods and in some cases, to develop new analyzing methods for magnetic nanostructures. Using improved manufacturing technologies we will synthesize magnetic nanoparticles with specific properties that will be analyzed with a multitude of characterization techniques (focusing on both structural as well as magnetic properties) and bring the experimental results together to obtain a self-consistent picture which describes how structural and magnetic properties are interrelated. This extensive survey will be used to define standard measurements and techniques which are necessary for defining a magnetic nanostructure and quality control. NanoMag brings together Europes and internationally leading experts in; manufacturing of magnetic single-core nanoparticles and magnetic multi-core particles, analyzing and characterization of magnetic nanostructures and national metrology institutes. In the consortium we have gathered partners within research institutes, universities and metrology institutes, all carrying out front end research and developing applications in the field of magnetic nanoparticles.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.1.4-2 | Award Amount: 7.65M | Year: 2012

Regenerative medicine focuses on repairing or replacing tissue or organ function lost due to damage or congenital defects using appropriate cells for therapy that have healing capacities like stem cells or progenitor cells. Although regenerative medicine has the potential for more effective therapeutic interventions major improvement in three areas are still needed for a wider establishment of such new concepts in clinical practise: identification of the appropriate cells with healing capacity for the use in therapy, homing of these cells to the damaged tissue, and monitoring of the therapeutic intervention and effect. Thus, a multidisciplinary consortium has set up IDEA, a 60 month collaborative project to develop and establish: Photonic methods that allow a contact and marker-free identification and selection of cells with healing capacity for vascular, musculoskeletal and neuronal tissue defects; Magnetic cell select devices that capture and transport cells with healing potential through the circulatory system to damaged tissue and organs improving homing; Tracer and imaging technologies to monitor the therapeutic effects of interventional regenerative medicine by showing anatomic structure AND demonstrating cellular function using magnetic resonance imaging (MRI) and a new imaging technology known as magnetic particle imaging (MPI). The IDEA project is intended to provide collaboration between scientists and clinicians from Karolinska Institute (Stockholm, Sweden), Kings College (London, UK), Paracelsus Medical University (Salzburg, Austria) and Julius-Maximilians-University (Wrzburg, Germany) together with experts from SMEs specialized in photonic technologies for tissue engineering, medical device manufacturing with extensive experience in regulatory approval, the design, synthesis and up-scaling of nanoparticles for molecular imaging, and regulatory affairs. This multidisciplinary consortium will address scale-up, regulatory work and exploratory clinical investigations using the developed tools, technologies and devices in the time frame of the project.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.1.4-3 | Award Amount: 7.73M | Year: 2012

DARTRIX, DARPin Targeted RX (therapy) is a multidisciplinary collaborative project that will develop high-affinity protein scaffolds to create a new generation of targeted therapeutics for the treatment of glioblastoma. There is great need; glioblastoma is virtually incurable and most patients die within 12 months of diagnosis. DARPins are small, non-immunoglobulin human protein scaffolds that bind specific targets with exceptionally high-affinity. DARPins are amenable to GMP production and to scale-up. They are remarkably stable, even at high temperatures and they can be engineered to incorporate additional favourable properties to target glioblastoma cells with exceptionally high affinity. The new DARPins will be coupled to dextran-coated iron oxide nanoparticles, such as ferucarbotran or nanomag-MIP, which has been used clinically as a contrast agent for Magnetic Resonance Imaging (MRI). These particles are safe to use in patients and are traceable within the body. When stimulated by an appropriate alternating magnetic current, the particles generate heat that can kill cancer cells very effectively. The conjugation of DARPins with ferucarbotran or nanomag-MIP (DARTRIX particle) leads to a potent therapeutic by delivering targeted hyperthermia to glioblastoma. In addition, DARTRIX particle will be created economically, exploiting the fact that DARPins can be produced to GMP in gram quantities using E. coli. The DARTRIX particles will target to glioblastoma cells by virtue of the high affinity and specificity of DARPins and the particles will remain in place when heated. By using DARPins to target the DARTRIX particle to tumour cells before application of the magnetic current, it should be possible to generate toxic heat specifically in the tumour. The consortium has all the skills and knowledge to develop DARPins from bench-to-bedside for glioblastoma treatment. This DARTRIX particle will pioneer targeted hyperthermic cancer treatment of glioblastoma in an innovative adaptive first-in-man trial, using direct injection or convection enhanced delivery to localise the particles to the tumour.

Shanehsazzadeh S.,Nuclear Science and Technology Research Institute, Iran | Gruettner C.,Micromod Partikeltechnologie GmbH | Lahooti A.,Tehran University of Medical Sciences | Mahmoudi M.,Tehran University of Medical Sciences | And 4 more authors.
Contrast Media and Molecular Imaging | Year: 2015

MUC1 antigen is recognized as a high-molecular-weight glycoprotein that is unexpectedly over-expressed in human breast and other carcinomas. In contrast, C595 a monoclonal antibody (mAb) against the protein core of the human urinary epithelial machine, is commonly expressed in breast carcinomas. The aim of this study was to conjugate ultra-small super paramagnetic iron oxide nanoparticles (USPIO) with C595 mAb, in order to detect in vivo MUC1 expression. A dual contrast agent (the C595 antibody-conjugated USPIO labeled with 99mTc) was prepared for targeted imaging and therapy of anti-MUC1-expressing cancers. The C595 antibody-conjugated USPIO had good stability and reactivity in the presence of blood plasma at 37°C. No significant differences were observed in immunoreactivity results between conjugated and nonconjugated nanoparticles. The T1 and T2 measurements show >79 and 29% increments (for 0.02mg/ml iron concentrations) in T1 and T2 values for USPIO-C595 in comparison with USPIO, respectively. The nanoprobes showed the interesting targeting capability of finding the MUC1-positive cell line in vitro. However, we found disappointing in vivo results (i.e. very low accumulation of nanoprobes in the targeted site while >80% of the injected dose per gram was taken up by the liver and spleen), not only due to the coverage of targeting site by protein corona but also because of absorption of opsonin-based proteins at the surface of nanoprobes. © 2014 John Wiley & Sons, Ltd.

Kasten A.,University of Rostock | Gruttner C.,Micromod Partikeltechnologie GmbH | Kuhn J.-P.,University of Greifswald | Bader R.,University of Rostock | And 2 more authors.
PLoS ONE | Year: 2014

Magnetic resonance imaging (MRI) using measurement of the transverse relaxation time (R2∗) is to be considered as a promising approach for cell tracking experiments to evaluate the fate of transplanted progenitor cells and develop successful cell therapies for tissue engineering. While the relationship between core composition of nanoparticles and their MRI properties is well studied, little is known about possible effects on progenitor cells. This in vitro study aims at comparing two magnetic iron oxide nanoparticle types, single vs. multi-core nanoparticles, regarding their physico-chemical characteristics, effects on cellular behavior of adipose tissue-derived stem cells (ASC) like differentiation and proliferation as well as their detection and quantification by means of MRI. Quantification of both nanoparticle types revealed a linear correlation between labeling concentration and R2∗values. However, according to core composition, different levels of labeling concentrations were needed to achieve comparable R2∗values. Cell viability was not altered for all labeling concentrations, whereas the proliferation rate increased with increasing labeling concentrations. Likewise, deposition of lipid droplets as well as matrix calcification revealed to be highly dose-dependent particularly regarding multi-core nanoparticle-labeled cells. Synthesis of cartilage matrix proteins and mRNA expression of collagen type II was also highly dependent on nanoparticle labeling. In general, the differentiation potential was decreased with increasing labeling concentrations. This in vitro study provides the proof of principle for further in vivo tracking experiments of progenitor cells using nanoparticles with different core compositions but also provides striking evidence that combined testing of biological and MRI properties is advisable as improved MRI properties of multi-core nanoparticles may result in altered cell functions. © 2014 Kasten et al.

Eberbeck D.,Physikalisch - Technische Bundesanstalt | Dennis C.L.,U.S. National Institute of Standards and Technology | Huls N.F.,U.S. National Institute of Standards and Technology | Krycka K.L.,U.S. National Institute of Standards and Technology | And 2 more authors.
IEEE Transactions on Magnetics | Year: 2013

Biocompatible magnetic nanoparticles are interesting tracers for diagnostic imaging techniques, including magnetic resonance imaging and magnetic particle imaging (MPI). Here, we will present our studies of the physical and especially magnetic properties of dextran coated multicore magnetic iron oxide nanoparticles, with promising high MPI signals revealed by magnetic particle spectroscopy (MPS) measurements. The Nanomag-MIP particles with a hydrodynamic diameter of 106 nm show an increase of the MPS amplitude by a factor of about two at the 3rd harmonic, as compared to Resovist. In particular, the signal improves progressively with the order of the harmonic, a prerequisite for better spatial resolution. To understand this behavior, we investigated the samples using quasistatic magnetization measurements yielding bimodal size distributions for both systems, and magnetorelaxometry providing the mean effective anisotropy constant. The mean effective magnetic diameter of the dominant larger size mode is 19 nm with a dispersion parameter of σ=0.3 for Nanomag-MIP, and 22 nm with σ=0.25 for Resovist. However, about 80% of the magnetic nanoparticles of Nanomag-MIP belong to this larger size mode whereas in Resovist only 30% do. The remaining Resovist particles are in the range of 5 nm, and, in practice, do not contribute to the MPI signal. © 1965-2012 IEEE.

Rimkus G.,University Hospital Jena | Bremer-Streck S.,University Hospital Jena | Gruttner C.,Micromod Partikeltechnologie GmbH | Kaiser W.A.,University Hospital Jena | Hilger I.,University Hospital Jena
Contrast Media and Molecular Imaging | Year: 2011

Targeted magnetic resonance contrast agents (e.g. iron oxide nanoparticles) have the potential to become highly selective imaging tools. In this context, quantification of the coupled amount of protein is essential for the design of antibody- or antibody fragment-conjugated nanoparticles. Nevertheless, the presence of magnetic iron oxide nanoparticles is still an unsolved problem for this task. The aim of the present work was to clarify whether proteins can be reliably quantified directly in the presence of magnetic iron oxide nanoparticles without the use of fluorescence or radioactivity. Protein quantification via Bradford was not influenced by the presence of magnetic iron oxide nanoparticles (0-17.2mmol Fe l-1). Instead, bicinchoninic acid based assay was, indeed, distinctly affected by the presence of nanoparticle-iron in suspension (0.1-17.2mmol Fe l-1), although the influence was linear. This observation allowed for adequate mathematical corrections with known iron content of a given nanoparticle. The applicability of our approach was demonstrated by the determination of bovine serum albumin (BSA) content coupled to dextrane-coated magnetic nanoparticles, which was found with the QuantiPro Bicinchoninic acid assay to be of 1.5±0.2μg BSA per 1mg nanoparticle. Both Bradford and bicinchoninic acid assay protein assays allow for direct quantification of proteins in the presence of iron oxide containing magnetic nanoparticles, without the need for the introduction of radioactivity or fluorescence modules. Thus in future it should be possible to make more precise estimations about the coupled protein amount in high-affinity targeted MRI probes for the identification of specific molecules in living organisms, an aspect which is lacking in corresponding works published so far. Additionally, the present protein coupling procedures can be drastically improved by our proposed protein quantification method. © 2011 John Wiley & Sons, Ltd.

Gruttner C.,Micromod Partikeltechnologie GmbH | Muller K.,Micromod Partikeltechnologie GmbH | Teller J.,Micromod Partikeltechnologie GmbH
IEEE Transactions on Magnetics | Year: 2013

The preservation of the bioreactivity of antibodies and proteins by immobilization on the surface of magnetic nanoparticles is essential for particle targeting applications in diagnosis and therapy. Here we compare the conjugation of a model antibody and of streptavidin to the surface of biocompatible 100 nm magnetic starch nanoparticles by strain-promoted alkyne-azide cycloaddition (SPAAC) with the established carbodiimide and maleimide chemistry. Under our reaction conditions the bioreactivity of the immobilized antibody was about 28% for the random amide bond formation using carbodiimide chemistry, the bioreactivity increased to about 61% for bioorthogonal SPAAC and to about 90% for maleimide conjugation. The same order was found for the biotin binding capacity of streptavidin, that was conjugated to the magnetic nanoparticles with the same methods. The described analytical methods are a platform for further studies with improved bioorthogonal conjugation reactions, e.g. the strain-promoted alkyne-nitrone cycloaddition (SPANC). © 1965-2012 IEEE.

Gruttner C.,Micromod Partikeltechnologie GmbH | Muller K.,Micromod Partikeltechnologie GmbH | Teller J.,Micromod Partikeltechnologie GmbH
IEEE Transactions on Magnetics | Year: 2013

The conjugation of magnetic nano-and microparticles with biomolecules and its analysis very often require a dense coating of the iron oxide to prevent any reaction with redox-sensitive molecules or ions. The shielding of the iron oxide cores in different types of magnetic particles was compared by rapid assays that are based on the analysis of redox reactions. The oxidation of cysteine to the corresponding cysteine disulfide in the presence of incompletely covered iron oxide was analyzed with Ellman's reagent. Similar results were obtained by analysis of the reduction of copper (II) to copper(I) by the magnetite containing particles under the conditions of the Bicinchoninic Acid (BCA) assay. We show the assay results for different commercially available magnetic particles in the size range of 20 nm to 30 μ and conclude that an incomplete coverage of the iron oxide cores requires the comparison with reference particles in redox-sensitive assays, e.g., for the characterization of the protein coating or of the density of functional groups on the particle surface. © 1965-2012 IEEE.

Gruttner C.,Micromod Partikeltechnologie GmbH | Muller K.,Micromod Partikeltechnologie GmbH | Teller J.,Micromod Partikeltechnologie GmbH | Westphal F.,Micromod Partikeltechnologie GmbH
International Journal of Hyperthermia | Year: 2013

A summary of recent developments in the synthesis, stabilisation and coating of magnetic iron oxide nanoparticles for hyperthermia applications is presented. Methods for synthesis in aqueous, organic and microemulsion systems are reviewed together with the resulting heating rates of the nanoparticles. Different stabilisation mechanisms for iron oxide nanoparticles from aqueous and organic media are discussed as intermediates for further coating and functionalisation. Coating with silica and/or polysaccharides is mainly used for design of nanoparticles especially for targeted hyperthermia application. These coatings permit versatile functionalisation as a basis for conjugating biomolecules, e.g. antibodies or peptides. Various strategies to conjugate biomolecules on the particle surface are discussed, with emphasis on methods that preserve biofunctionality after immobilisation. The efficiency of established methods such as carbodiimide coupling and oriented conjugation strategies is compared with new developments such as the bioorthogonal approaches that are based on the cycloaddition of strain-promoted alkynes with azides or nitrones. For targeted hyperthermia applications the study of the formation of a protein corona around nanoparticles with site-specific biomolecules on the surface is essential to achieve improved circulation times in the blood and reduced non-specific uptake by non-targeted organs for a high specific accumulation in the target tissue. © 2013 Informa UK Ltd.

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