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Alexander Sekita,1 Harald Unterweger,1 Sonja Berg,1 Sabine Ohlmeyer,2 Tobias Bäuerle,3 Kang H Zheng,4 Bram F Coolen,5 Aart J Nederveen,6 Claudia Cabella,7 Silvia Rossi,7 Erik SG Stroes,4 Christoph Alexiou,1 Stefan Lyer,1,* Iwona Cicha1,* 1ENT-Department, Section of Experimental Oncology Und Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, Universitätsklinikum Erlangen, Erlangen, Germany; 2Institute of Radiology, Universitätsklinikum Erlangen, Erlangen, Germany; 3Preclinical Imaging Platform Erlangen (PIPE), Universitätsklinikum Erlangen, Erlangen, Germany; 4Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 5Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 6Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 7Bracco Imaging SpA, Centro Ricerche Bracco, Colleretto Giacosa, Turin, Italy*These authors contributed equally to this workCorrespondence: Iwona Cicha, Universitätsklinikum Erlangen, Glückstr, 10a, Erlangen, 91054, Germany, Tel +49 9131 85 43953, Fax +49 9131 85 34828, Email Iwona.Cicha@uk-erlangen.dePurpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI).Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats.Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg.Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.Keywords: atherosclerosis, plaque vulnerability, rabbit model, macrophages, histology, tissue iron, SPION-enhanced MRI

Bernhard Friedrich,1 Rainer Tietze,1 Michaela Dümig,2 Alexandru Sover,3 Marius-Andrei Boca,3 Eveline Schreiber,1 Julia Band,1 Christina Janko,1 Sven Krappmann,2 Christoph Alexiou,1,* Stefan Lyer1,4,* 1Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, Universitätsklinikum Erlangen, Erlangen, Germany; 2Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; 3Faculty of Engineering, Ansbach University of Applied Sciences, Ansbach, Germany; 4Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Professorship for AI-Controlled Nanomaterials, Universitätsklinikum Erlangen, Erlangen, Germany*These authors contributed equally to this workCorrespondence: Stefan Lyer, Section of Experimental Oncology & Nanomedicine (SEON), Glückstraße 10a, Erlangen, 91054, Germany, Tel +49-9131-85-33142, Fax +49-9131-85-34828, Email stefan.lyer@uk-erlangen.dePurpose: Magnetic separation of microbes can be an effective tool for pathogen identification and diagnostic applications to reduce the time needed for sample preparation. After peptide functionalization of superparamagnetic iron oxide nanoparticles (SPIONs) with an appropriate interface, they can be used for the separation of sepsis-associated yeasts like Candida albicans. Due to their magnetic properties, the magnetic extraction of the particles in the presence of an external magnetic field ensures the accumulation of the targeted yeast.Materials and Methods: In this study, we used SPIONs coated with 3-aminopropyltriethoxysilane (APTES) and functionalized with a peptide originating from GP340 (SPION-APTES-Pep). For the first time, we investigate whether this system is suitable for the separation and enrichment of Candida albicans, we investigated its physicochemical properties and by thermogravimetric analysis we determined the amount of peptide on the SPIONs. Further, the toxicological profile was evaluated by recording cell cycle and DNA degradation. The separation efficiency was investigated using Candida albicans in different experimental settings, and regrowth experiments were carried out to show the use of SPION-APTES-Pep as a sample preparation method for the identification of fungal infections.Conclusion: SPION-APTES-Pep can magnetically remove more than 80% of the microorganism and with a high selective host-pathogen distinction Candida albicans from water-based media and about 55% in blood after 8 minutes processing without compromising effects on the cell cycle of human blood cells. Moreover, the separated fungal cells could be regrown without any restrictions.Keywords: Candida albicans, SPIONs, fungal sepsis, GP340, microbiological identification

Harald Unterweger,1,* Christina Janko,1,* Tamara Folk,1 Iwona Cicha,1 Noémi Kovács,2 Gyula Gyebnár,3 Ildikó Horváth,4 Domokos Máthé,2,3 Kang H Zheng,5 Bram F Coolen,6 Erik Stroes,5 János Szebeni,7,8 Christoph Alexiou,1 László Dézsi,7,8,* Stefan Lyer1,* 1ENT-Department, Section of Experimental Oncology und Nanomedicine (SEON), Universitätsklinikum Erlangen, Erlangen, Germany; 2Hungarian Centre of Excellence for Molecular Medicine, Semmelweis University, Budapest, Hungary; 3Medical Imaging Centre, Semmelweis University, Budapest, Hungary; 4Department Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary; 5Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, the Netherlands; 6Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, the Netherlands; 7Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; 8SeroScience Ltd, Budapest, Hungary*These authors contributed equally to this workCorrespondence: Harald Unterweger, Universitätsklinikum Erlangen, Glueckstr. 10a, Erlangen, 91054, Germany, Tel +49 9131 85-33142, Fax +49 9131 85-34828, Email harald.unterweger@uk-erlangen.deIntroduction: One of the major challenges in the clinical translation of nanoparticles is the development of formulations combining favorable efficacy and optimal safety. In the past, iron oxide nanoparticles have been introduced as an alternative for gadolinium-containing contrast agents; however, candidates available at the time were not free from adverse effects.Methods: Following the development of a potent iron oxide-based contrast agent SPIONDex, we now performed a systematic comparison of this formulation with the conventional contrast agent ferucarbotran and with ferumoxytol, taking into consideration their physicochemical characteristics, bio- and hemocompatibility in vitro and in vivo, as well as their liver imaging properties in rats.Results: The results demonstrated superior in vitro cyto-, hemo- and immunocompatibility of SPIONDex in comparison to the other two formulations. Intravenous administration of ferucarbotran or ferumoxytol induced strong complement activation-related pseudoallergy in pigs. In contrast, SPIONDex did not elicit any hypersensitivity reactions in the experimental animals. In a rat model, comparable liver imaging properties, but a faster clearance was demonstrated for SPIONDex.Conclusion: The results indicate that SPIONDex possess an exceptional safety compared to the other two formulations, making them a promising candidate for further clinical translation.Keywords: magnetic resonance imaging, MRI, nanomedicine, nanoparticles, complement activation, CARPA

Jasmin Matuszak, Barbara Lutz, Aleksander Sekita, Jan Zaloga, Christoph Alexiou, Stefan Lyer,* Iwona Cicha* Cardiovascular Nanomedicine Unit, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-endowed Professorship for Nanomedicine, ENT Department, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany *These authors contributed equally to this work Introduction: Magnetic drug targeting utilizes superparamagnetic iron oxide nanoparticles (SPIONs) to accumulate drugs in specified vasculature regions.Methods: We produced SPIONs conjugated with dexamethasone phosphate (SPION-DEXA). The efficacy of magnetic drug targeting was investigated in a rabbit model of atherosclerosis induced by balloon injury and high cholesterol diet.Results: In vitro, SPION-DEXA were well-tolerated by endothelial cells. SPION-DEXA were internalized by human peripheral blood mononuclear cells and induced CD163 expression comparable with the free drug. In vivo, magnetic targeting of SPIONs to abdominal aorta was confirmed by histology. Upon vascular injury followed by high-cholesterol diet, early administration of SPION-DEXA enhanced the inflammatory burden in the plaques. Increased macrophage content and larger intima–media thickness were observed in animals treated with SPION-DEXA compared with controls. In advanced atherosclerosis, no beneficial effect of local glucocorticoid therapy was detectable.Conclusion: Magnetic drug targeting represents an efficient platform to deliver drugs to diseased arteries in vivo. However, targeting of vascular injury in the lipid-rich environment using dexamethasone-conjugated SPIONs may cause accelerated inflammatory response. Keywords: magnetic nanoparticles, magnetic drug targeting, rabbit model of atherosclerosis, dexamethasone, macrophage accumulation

Harald Unterweger,1,* Christina Janko,1,* Marc Schwarz,2 László Dézsi,3 Rudolf Urbanics,4 Jasmin Matuszak,1 Erik Őrfi,3 Tamás Fülöp,3 Tobias Bäuerle,2 János Szebeni,3,4 Clément Journé,5 Aldo R Boccaccini,6 Christoph Alexiou,1 Stefan Lyer,1 Iwona Cicha1 1Cardiovascular Nanomedicine Unit, Section of Experimental Oncology und Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, ENT Department, University Hospital Erlangen, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, 2Preclinical Imaging Platform Erlangen (PIPE), Institute of Radiology, University Hospital Erlangen, Erlangen, Germany; 3Nanomedicine Research and Education Center, Semmelweis University, 4SeroScience Ltd., Budapest, Hungary; 5Inserm U1148, Fédération de Recherche en Imagerie Multimodalités (FRIM), X Bichat Hospital, Paris Diderot University, Paris, France; 6Institute of Biomaterials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, Germany *These authors contributed equally to this work Abstract: Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size

Ralf P Friedrich,1 Christina Janko,1 Marina Poettler,1 Philipp Tripal,1 Jan Zaloga,1 Iwona Cicha,1 Stephan Dürr,1,2 Johannes Nowak,3 Stefan Odenbach,3 Ioana Slabu,4 Maik Liebl,4 Lutz Trahms,4 Marcus Stapf,5 Ingrid Hilger,5 Stefan Lyer,1 Christoph Alexiou1 1Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine, University hospital Erlangen, 2Department of Otorhinolaryngology, Head and Neck Surgery, Section of Phoniatrics and Pediatric Audiology, University hospital Erlangen, Erlangen, 3Technische Universität Dresden, Chair of Magnetofluiddynamics, Measuring and Automation Technology, Dresden, 4Physikalisch-Technische Bundesanstalt Berlin, Berlin, 5Department of Radiology, Division of Diagnostic and Interventional Radiology, Experimental Radiology, University hospital Jena, Jena, Germany Abstract: Due to their special physicochemical properties, iron nanoparticles offer new promising possibilities for biomedical applications. For bench to bedside translation of superparamagnetic iron oxide nanoparticles (SPIONs), safety issues have to be comprehensively clarified. To understand concentration-dependent nanoparticle-mediated toxicity, the exact quantification of intracellular SPIONs by reliable methods is of great importance. In the present study, we compared three different SPION quantification methods (ultraviolet spectrophotometry, magnetic particle spectroscopy, atomic adsorption spectroscopy) and discussed the shortcomings and advantages of each method. Moreover, we used those results to evaluate the possibility to use flow cytometric technique to determine the cellular SPION content. For this purpose, we correlated the side scatter data received from flow cytometry with the actual cellular SPION amount. We showed that flow cytometry provides a rapid and reliable method to assess the cellular SPION content. Our data also demonstrate that internalization of iron oxide nanoparticles in human umbilical vein endothelial cells is strongly dependent to the SPION type and results in a dose-dependent increase of toxicity. Thus, treatment with lauric acid-coated SPIONs (SEONLA) resulted in a significant increase in the intensity of side scatter and toxicity, whereas SEONLA with an additional protein corona formed by bovine serum albumin (SEONLA-BSA) and commercially available Rienso® particles showed only a minimal increase in both side scatter intensity and cellular toxicity. The increase in side scatter was in accordance with the measurements for SPION content by the atomic adsorption spectroscopy reference method. In summary, our data show that flow cytometry analysis can be used for estimation of uptake of SPIONs by mammalian cells and provides a fast tool for scientists to evaluate the safety of nanoparticle products. Keywords: low cytometry, side scatter, intracellular superparamagnetic iron oxide nanoparticles, quantification, spectroscopy

Jan Zaloga,1 Christina Janko,1 Johannes Nowak,2 Jasmin Matuszak,1 Sabine Knaup,1 Dietmar Eberbeck,3 Rainer Tietze,1 Harald Unterweger,1 Ralf P Friedrich,1 Stephan Duerr,1 Ralph Heimke-Brinck,4 Eva Baum,4 Iwona Cicha,1 Frank Dörje,4 Stefan Odenbach,2 Stefan Lyer,1 Geoffrey Lee,5 Christoph Alexiou1 1Department of Otorhinolaryngology, Head and Neck Surgery, Section for Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, University Hospital Erlangen, Erlangen, Germany; 2Measuring and Automation Technology, Technical University Dresden, Dresden, Germany; 3Physikalisch-Technische-Bundesanstalt, Berlin, Germany; 4Pharmacy Department, University Hospital Erlangen, Erlangen, Germany; 5Division of Pharmaceutics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany Abstract: The promising potential of superparamagnetic iron oxide nanoparticles (SPIONs) in various nanomedical applications has been frequently reported. However, although many different synthesis methods, coatings, and functionalization techniques have been described, not many core-shell SPION drug delivery systems are available for clinicians at the moment. Here, bovine serum albumin was adsorbed onto lauric acid-stabilized SPIONs. The agglomeration behavior, zeta potential, and their dependence on the synthesis conditions were characterized with dynamic light scattering. The existence and composition of the core-shell-matrix structure was investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements. We showed that the iron oxide cores form agglomerates in the range of 80 nm. Moreover, despite their remarkably low tendency to aggregate even in a complex media like whole blood, the SPIONs still maintained their magnetic properties and were well attractable with a magnet. The magnetic properties were quantified by vibrating sample magnetometry and a superconducting quantum interference device. Using flow cytometry, we further investigated the effects of the different types of nanoparticle coating on morphology, viability, and DNA integrity of Jurkat cells. We showed that by addition of bovine serum albumin, the toxicity of nanoparticles is greatly reduced. We also investigated the effect of the particles on the growth of primary human endothelial cells to further demonstrate the biocompatibility of the particles. As proof of principle, we showed that the hybrid-coated particles are able to carry payloads of up to 800 µg/mL of the cytostatic drug mitoxantrone while still staying colloidally stable. The drug-loaded system exhibited excellent therapeutic potential in vitro, exceeding that of free mitoxantrone. In conclusion, we have synthesized a biocompatible ferrofluid that shows great potential for clinical application. The synthesis is straightforward and reproducible and thus easily translatable into a good manufacturing practice environment. Keywords: iron oxide nanoparticles, drug delivery, protein corona, magnetic drug targeting, colloidal stability

Harald Unterweger,1 Rainer Tietze,1 Christina Janko,1 Jan Zaloga,1 Stefan Lyer,1 Stephan Dürr,1 Nicola Taccardi,2 Ourania-Menti Goudouri,3 Alexander Hoppe,3 Dietmar Eberbeck,4 Dirk W Schubert,5 Aldo R Boccaccini,3 Christoph Alexiou1 1ENT Department, Section of Experimental Oncology and Nanomedicine (SEON), Else Kroener-Fresenius-Stiftung-Professorship, University Hospital Erlangen, 2Chair of Chemical Engineering I (Reaction Engineering), 3Institute of Biomaterials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, 4Physikalisch-Technische Bundesanstalt, Berlin, 5Institute of Polymer Materials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, Erlangen, Germany Abstract: A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 µg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of –45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In conclusion, combination of dextran-coated SPIONs with hyaluronic acid and cisplatin represents a promising approach for magnetic drug targeting in the treatment of cancer. Keywords: magnetic drug targeting, superparamagnetic iron oxide nanoparticles, dextran, hyaluronic acid

Tissue-mimicking materials (TMMs) typically used for ultrasound phantoms include gelatin, agarose and polyvinyl alcohol (PVA). These materials have shown sufficient similarity in ultrasound parameters compared to human tissue. Despite their extensive use for years to generate ultrasound phantoms, no simple and easily reproducible way to generate complex, wall-less ultrasound flow phantoms has been introduced. Commercially available ultrasound flow phantoms are limited to simple flow geometries that do not reflect the complex blood flow in humans. Flow phantoms with complex geometries presented in scientific publications either have walls between TMMs and the flow channel, are limited to one material, or are complicated to produce. In this contribution, we present a method using 3D printing and soluble filament that allows for the reliable and consistent production of complex flow geometries with the typical materials used for ultrasound phantoms and without any walls.

Magnetic nanoparticles guided by an external magnetic field can be used to deliver drugs (e.g., chemotherapeutics) to malignant regions (e.g., tumor tissue). Some nonmagnetic, sonosensitive nanoparticles are known to generate cavitation induced by focused ultrasound. This can can be used to monitor spatial/temporal particle distribution and to stimulate local drug release in target regions. Little to nothing is known about the sonosensitivity of magnetic nanoparticles. Therefore, we investigated this physical phenomenon in the present contribution. We showed that certain magnetic nanoparticles have high cavitation potential and are promising for further research in this regard.

Various medical procedures make use of magnetic nanoparticles, such as Magnetic Drug Targeting (MDT), which boosts the demand for imaging modalities that are capable of in vivo visualizing this kind of particles. Magnetomotive Ultrasound is an imaging technique that can detect tissue, which is perfused by magnetic nanoparticles. In this contribution, we investigate the suitability of Magnetomotive Ultrasound to serve as a monitoring system during MDT. With the conducted measurements, it was possible for the first time to observe in vivo the accumulation of iron-oxide nanoparticles during a Magnetic Drug Targeting cancer treatment applied to a small animal (rabbit).

Magnetic Drug Targeting (MDT) is a cancer treatment technique that enables a local chemotherapy. In MDT, chemotherapeutic drugs are bound to magnetic nanoparticles and are accumulated in the tumor area by means of an external magnetic field. Unfortunately, a single magnet can only generate a pulling magnetic force. However, in some applications a pushing force on the nanoparticles could be advantageous. One way to realize pushing forces is to exploit the acoustic radiation force based on the nonlinearity of sound propagation in fluid media generated by a high intensity focused ultrasonic transducer. In this context, we built a test setup was built to investigate the utility of High Intensity Focused Ultrasound (HIFU) to generate a pushing force on the magnetic nanoparticles. The results show that the acoustic radiation force can be employed for particle guidance to achieve concentration differences similar to those obtained by using an electromagnet.

Magnetomotive Ultrasound is an imaging technique that is capable to detect tissue, which is perfused by magnetic nanoparticles. However, this modality is restricted to qualitative imaging only. Therefore, we present an extended Magnetomotive Ultrasound algorithm, which allows the quantitative determination of the spatial distribution of magnetic nanoparticle density in tissue. The algorithm is based on an iterative adjustment of simulated data to measurements. Experiments with tissue-mimicking phantoms reveal that the presented method leads to the spatial particle concentration in the correct order of magnitude.

Research in biomedical nanotechnology led already to a variety of applications of nanoparticles in diagnosis as well as in therapy. One of these medical applications is Magnetic Drug Targeting, a promising cancer treatment technique. The aim of this medical attendance is a local chemotherapeutic treatment of the cancerous tissue. For this purpose, chemotherapeutic drugs are bound to magnetic nanoparticles and accumulated in the tumor area by means of an external static magnetic field. Hereby, a well-defined particle concentration in the cancerous tissue requires monitoring of the particle accumulation. Therefore, we present an ultrasound imaging technique that is capable of detecting quantitatively the concentration of iron oxide nanoparticles in biological tissue. The evaluation is based on the variation of the speed of sound of an induced shear wave with respect to the particle concentration.

Atherosclerosis results from the accumulation of the modified lipoproteins within the artery walls, which triggers complex vascular inflammatory processes. Although the pharmacologic agents for the treatment of clinical manifestations of atherosclerosis are available, their systemic delivery has serious disadvantages, such as considerable side effects or low efficacy at tolerated doses. Moreover, the treatment of atherosclerosis using the interventional techniques bears further shortcomings: the implanted stents require a lengthy antiplatelet therapy and carry the risk of in-stent restenosis. In the surgical approach to atherosclerosis, apart from the overall risk of open heart surgery, the lack of adequate venous material for bypasses constitutes a common problem. The nanotechnology has the potential to overcome the disadvantages of the current therapy of atherosclerosis, e.g., by the formation of nanosized assemblies for the earlier detection of atherosclerotic lesions and for cell-specific delivery of therapeutics. Replacing the current systemic pharmacological approach by a locally targeted treatment of plaques can substantially minimize the adverse effects, by lowering the drug cytotoxicity and reducing the required dosage. Moreover, a new generation of nanotechnological approaches to the revascularization procedures is now emerging, e.g., vascular tissue engineering utilizing the magnetic nanoparticles or the design of stents with the reduced risk of thrombosis and restenosis. This review discusses the possible applications of the nanomedical approaches in the treatment of cardiovascular diseases.

Cancer is one of the biggest challenges facing the medical research in our time. The goals are to improve not only the therapeutic outcome, even in the cases of advanced and metastatic cancer, but also the methods of treatment, which often have considerable adverse effects. In addition, the current developments, such as demographic change, population growth, and increasing healthcare costs, have to be taken into consideration. In all likelihood, nanotechnology and, in particular, the use of magnetic nanoparticles consisting of the elements nickel, cobalt, and iron can make a significant contribution. The greatest potential can be ascribed to the drug delivery systems: magnetic nanoparticles are functionalized by binding them to various substances, including chemotherapeutic agents, radionuclides, nucleic acids, and antibodies. They can then be guided and accumulated using a magnetic field. Hyperthermia can be induced with an alternating magnetic field, providing another therapeutic option. Magnetic nanoparticles may be useful in overcoming cancer drug resistance. They also contribute to realizing a combination of diagnostic investigation and therapy in the field of “theranostics”. The multifaceted and promising results of research in the recent years offer the prospect of a real advance in cancer therapy in the near future.

As an interdisciplinary field, tissue engineering (TE) aims to regenerate tissues by combining the principles of cell biology, material science, and biomedical engineering. Nanotechnology creates new materials that might enable further tissue-engineering applications. In this context, the introduction of nanotechnology and nanomaterials promises a biomimetic approach by mimicking nature. This review summarizes the current scope of nanotechnology implementation possibilities in the field of tissue engineering of bone, muscle, and vascular grafts with forms on nanofibrous structures.

Collagen is increasingly attracting attention for bone tissue engineering applications. However, due to its low mechanical properties, applications including mechanical loads or requiring structural integrity are limited. To tackle this handicap, collagen can be combined with (nanoscale) silica in a variety of composite materials that are attractive for bone tissue engineering. Considering research carried out in the past 15 years, this article reviews the literature discussing the development of silica/collagen composites that have been synthesized by adding silica from different sources as inorganic bioactive material to collagen as organic matrix. Different routes for the fabrication of collagen/silica composites are presented, focusing on nanocomposites. In vitro cell bioactivity studies demonstrated the osteogenic and, in some cases, angiogenic potential of the composites. Relevant in vivo studies discussing integration of the materials in bone tissue are discussed. Due to the understanding of possible interaction between silicon species and collagen, the effect of different silica precursors on the collagen self-assembly process is also discussed. On the basis of literature results and as discussed in this review, collagen/silica nanocomposites and hybrids represent attractive biomaterials for bone regeneration applications.

The use of nanoparticles in tumor imaging, molecular imaging, and drug delivery has significantly expanded in the last few years. The relatively new field of “theranostics” combines their capacity for drug delivery with their potential as contrast agents. Depending on the imaging modality used, several types of nanoparticles are available, such as gold for optical imaging or superparamagnetic iron oxide for magnetic resonance imaging. This review will give a short overview of the different types of nanoparticles as well as their development and potential application in recent years. Furthermore, it describes the research on classic imaging modalities as well as on new techniques to image nanoparticles in vivo and focuses on magnetic-based imaging modalities.

Abstract Background Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. fls485 coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze fls485 expression in human small intestinal mucosa. Methods fls485 expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several in situ techniques and usage of newly synthesized mouse monoclonal antibodies. Results fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c. Conclusions Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible.