Bernhard Gleich

Targeted delivery of magnetic aerosol droplets to the lung

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease1, cystic fibrosis2, respiratory infection3 and, more recently, lung cancer4. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date5,6. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles—so-called nanomagnetosols—in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.

Magnetic Nanoparticles in Magnetic Resonance Imaging and Diagnostics

ABSTRACTMagnetic nanoparticles are useful as contrast agents for magnetic resonance imaging (MRI). Paramagnetic contrast agents have been used for a long time, but more recently superparamagnetic iron oxide nanoparticles (SPIOs) have been discovered to influence MRI contrast as well. In contrast to paramagnetic contrast agents, SPIOs can be functionalized and size-tailored in order to adapt to various kinds of soft tissues. Although both types of contrast agents have a inducible magnetization, their mechanisms of influence on spin-spin and spin-lattice relaxation of protons are different. A special emphasis on the basic magnetism of nanoparticles and their structures as well as on the principle of nuclear magnetic resonance is made. Examples of different contrast-enhanced magnetic resonance images are given. The potential use of magnetic nanoparticles as diagnostic tracers is explored. Additionally, SPIOs can be used in diagnostic magnetic resonance, since the spin relaxation time of water protons differs, whether magnetic nanoparticles are bound to a target or not.

Design and Evaluation of Magnetic Fields for Nanoparticle Drug Targeting in Cancer

The retention of superparamagnetic nanoparticles under the influence of a high-gradient magnetic field was investigated. A simulation algorithm for prediction of the particles trajectories and, therefore, the total amount of adhered particles in an artificial vessel was developed. Comparisons between in vitro experiments and simulations showed that the required experimental magnetic moments were greater than the theoretically estimated magnetic moments. This paper presents a method for investigating magnetic fields and for determining the magnetic moment of particles by simulation of their trajectories. The detailed function of magnetic drug targeting is of great importance in animal studies and in human therapies

Magnetized Aerosols Comprising Superparamagnetic Iron Oxide Nanoparticles Improve Targeted Drug and Gene Delivery to the Lung

ABSTRACTPurposeTargeted delivery of aerosols could not only improve efficacy of inhaled drugs but also reduce side effects resulting from their accumulation in healthy tissue. Here we investigated the impact of magnetized aerosols on model drug accumulation and transgene expression in magnetically targeted lung regions of unanesthetized mice.MethodsSolutions containing superparamagnetic iron oxide nanoparticles (SPIONs) and model drugs (fluorescein or complexed plasmid DNA) were nebulized to unanesthetized mice under the influence of an external magnetic gradient directed to the lungs. Drug accumulation and transgene expression was subsequently measured at different time points.ResultsWe could demonstrate 2–3 fold higher accumulation of the model drug fluorescein and specific transgene expression in lung regions of mice which had been exposed to an external magnetic gradient during nebulization compared to the control mice without any exposure to magnetic gradient.ConclusionsMagnetized aerosols present themselves as an efficient approach for targeted pulmonary delivery of drugs and gene therapeutic agents in order to treat localized diseases of the deeper airways.

The Munich Compact Light Source: initial performance measures

While large-scale synchrotron sources provide a highly brilliant monochromatic X-ray beam, these X-ray sources are expensive in terms of installation and maintenance, and require large amounts of space due to the size of storage rings for GeV electrons. On the other hand, laboratory X-ray tube sources can easily be implemented in laboratories or hospitals with comparatively little cost, but their performance features a lower brilliance and a polychromatic spectrum creates problems with beam hardening artifacts for imaging experiments. Over the last decade, compact synchrotron sources based on inverse Compton scattering have evolved as one of the most promising types of laboratory-scale X-ray sources: they provide a performance and brilliance that lie in between those of large-scale synchrotron sources and X-ray tube sources, with significantly reduced financial and spatial requirements. These sources produce X-rays through the collision of relativistic electrons with infrared laser photons. In this study, an analysis of the performance, such as X-ray flux, source size and spectra, of the first commercially sold compact light source, the Munich Compact Light Source, is presented.

Perspectives on clinical magnetic particle imaging

Abstract After realizing the worlds’ first preclinical magnetic particle imaging (MPI) demonstrator, Philips is now realizing the worlds’ first whole-body clinical prototype to prove the feasibility of MPI for clinical imaging. After a brief introduction of the basic MPI imaging process, this contribution presents an overview on the determining factors for key properties, i.e., spatial resolution, acquisition speed, sensitivity, and quantitativeness, and how these properties are influenced by scaling up from preclinical to clinical instrumentation. Furthermore, it is discussed how this scale up affects the physiological compatibility of the method as well as hardware parameters such as power requirements for drive field generation, selection and focus field generation, and the design of the receive chain of the MPI device.

Targeted Endothelial Gene Delivery by Ultrasonic Destruction of Magnetic Microbubbles Carrying Lentiviral Vectors

ABSTRACTPurposeSite specific vascular gene delivery is a promising tool for treatment of cardiovascular diseases. By combining ultrasound mediated microbubble destruction with site specific magnetic targeting of lentiviruses, we aimed to develop a technique suitable for systemic application.MethodsThe magnetic nanoparticle coupling to lipid microbubbles was confirmed by absorbance measurements. Association of fluorescent lentivirus to magnetic microbubbles (MMB) was determined by microscopy and flow cytometry. Functionality and efficiency of GFP-encoding lentiviral MMB transduction was evaluated by endothelial (HMEC) GFP expression and cytotoxicity was measured by MTT reduction.ResultsMicrobubbles with a mean diameter of 4.3u2009±u20090.04xa0μm were stable for 2xa0days, readily magnetizable and magnetically steerable in vitro and efficiently associated with lentivirus. Exposure of eGFP-encoding lentiviral MMB to human endothelial cells followed by application of an external static magnetic field (30xa0min) and ultrasonic destruction of the microbubbles did not markedly affect cellular viability. Finally, this combination led to a 30-fold increase in transduction efficiency compared to application of naked virus alone.ConclusionsBy associating microbubbles with magnetic iron nanoparticles, these function as carriers for lentiviruses achieving tissue specific deposition at the site of interest.

Vascular Repair by Circumferential Cell Therapy Using Magnetic Nanoparticles and Tailored Magnets

Cardiovascular disease is often caused by endothelial cell (EC) dysfunction and atherosclerotic plaque formation at predilection sites. Also surgical procedures of plaque removal cause irreversible damage to the EC layer, inducing impairment of vascular function and restenosis. In the current study we have examined a potentially curative approach by radially symmetric re-endothelialization of vessels after their mechanical denudation. For this purpose a combination of nanotechnology with gene and cell therapy was applied to site-specifically re-endothelialize and restore vascular function. We have used complexes of lentiviral vectors and magnetic nanoparticles (MNPs) to overexpress the vasoprotective gene endothelial nitric oxide synthase (eNOS) in ECs. The MNP-loaded and eNOS-overexpressing cells were magnetic, and by magnetic fields they could be positioned at the vascular wall in a radially symmetric fashion even under flow conditions. We demonstrate that the treated vessels displayed enhanced eNOS expression and activity. Moreover, isometric force measurements revealed that EC replacement with eNOS-overexpressing cells restored endothelial function after vascular injury in eNOS(-/-) mice ex and in vivo. Thus, the combination of MNP-based gene and cell therapy with custom-made magnetic fields enables circumferential re-endothelialization of vessels and improvement of vascular function.

Site directed vascular gene delivery in vivo by ultrasonic destruction of magnetic nanoparticle coated microbubbles

UNLABELLEDnSite specific vascular gene delivery for therapeutic implications is favorable because of reduction of possible side effects. Yet this technology faces numerous hurdles that result in low transfection rates because of suboptimal delivery. Combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer could make it possible to use the systemic vasculature as the route of application and to magnetically trap these compounds at the target of interest. In this study we show that magnetic nanoparticle-coated microbubbles bind plasmid DNA and successfully deliver it to endothelial cells in vitro and more importantly transport their cargo through the vascular system and specifically deliver it to the vascular wall in vivo at sites where microbubbles are retained by magnetic force and burst by local ultrasound application. This resulted in a significant enhancement in site specific gene delivery compared with the conventional microbubble technique. Thus, this technology may have promising therapeutic potential.nnnFROM THE CLINICAL EDITORnThis work focuses on combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer to enable targeted gene delivery via the systemic vasculature and magnetic trapping of these compounds at the target of interest.

In-vivo X-ray Dark-Field Chest Radiography of a Pig

X-ray chest radiography is an inexpensive and broadly available tool for initial assessment of the lung in clinical routine, but typically lacks diagnostic sensitivity for detection of pulmonary diseases in their early stages. Recent X-ray dark-field (XDF) imaging studies on mice have shown significant improvements in imaging-based lung diagnostics. Especially in the case of early diagnosis of chronic obstructive pulmonary disease (COPD), XDF imaging clearly outperforms conventional radiography. However, a translation of this technique towards the investigation of larger mammals and finally humans has not yet been achieved. In this letter, we present the first in-vivo XDF full-field chest radiographs (32u2009×u200935u2009cm2) of a living pig, acquired with clinically compatible parameters (40u2009s scan time, approx. 80 µSv dose). For imaging, we developed a novel high-energy XDF system that overcomes the limitations of currently established setups. Our XDF radiographs yield sufficiently high image quality to enable radiographic evaluation of the lungs. We consider this a milestone in the bench-to-bedside translation of XDF imaging and expect XDF imaging to become an invaluable tool in clinical practice, both as a general chest X-ray modality and as a dedicated tool for high-risk patients affected by smoking, industrial work and indoor cooking.