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J. Zaloga, C. Janko, J. Nowak, J. Matuszak, Sabine Knaup, D. Eberbeck, R. Tietze, H. Unterweger, R. Friedrich, Stephan Duerr, Ralph Heimke-Brinck, Evan Baum, I. Cicha, F. Dörje, S. Odenbach, S. Lyer, Geoffrey Lee, C. Alexiou (2014)Development of a lauric acid/albumin hybrid iron oxide nanoparticle system with improved biocompatibility
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R. Tietze, S. Lyer, S. Dürr, T. Struffert, T. Engelhorn, M. Schwarz, Elisabeth Eckert, T. Göen, S. Vasylyev, W. Peukert, F. Wiekhorst, L. Trahms, A. Dörfler, C. Alexiou (2013)Efficient drug-delivery using magnetic nanoparticles--biodistribution and therapeutic effects in tumour bearing rabbits.
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DE GRUYTER Current Directions in Biomedical Engineering 2020;6(3): 20203139 Michael Fink*, Stefan J. Rupitsch, Stefan Lyer, and Helmut Ermert In Vivo Study on Magnetomotive Ultrasound Imaging in the Framework of Nanoparticle based Magnetic Drug Targeting Abstract: Various medical procedures make use of magnetic MDT seems to be a suitable and promising alternative to nanoparticles, such as Magnetic Drug Targeting (MDT), conventional chemotherapy. which boosts the demand for imaging modalities that are To control the particle concentration in the cancerous tissue, capable of in vivo visualizing this kind of particles. an imaging system to visualize the particle accumulation is Magnetomotive Ultrasound is an imaging technique that can essential. Indeed, there are imaging modalities that are detect tissue, which is perfused by magnetic nanoparticles. In capable of detecting magnetic nanoparticles in tissue, which this contribution, we investigate the suitability of are already in clinical use, such as MRI (Magnetic Resonance Magnetomotive Ultrasound to serve as a monitoring system Imaging). MRI is a well-known technique and serves as a during MDT. With the conducted measurements, it was standard imaging procedure in hospitals . There are also possible for the first time to observe in vivo the accumulation imaging techniques under development that can visualize of iron-oxide nanoparticles during a Magnetic Drug tissue, contaminated with magnetic nanoparticles, such as Targeting cancer treatment applied to a small animal (rabbit). MPI (Magnetic Particle Imaging). MPI exploits superparamagnetic nanoparticles as contrast agents . Keywords: Magnetic Drug Targeting, Magnetomotive Unfortunately, both modalities have in common that they Ultrasound, iron-oxide nanoparticles, ultrasonic imaging. require large technical equipment and are cost-intensive. However, the most significant drawback is that simultaneous https://doi.org/10.1515/cdbme-2020-3139 MDT and imaging with the mentioned procedures is not possible, as these procedures require the patient to take place inside a cramped scanner device. But due to lack of space, 1 Introduction the necessary equipment for MDT cannot be placed inside this scanner device. Consequently, these imaging modalities Magnetic nanoparticles enable novel medical treatment are not suitable to serve as a monitoring system during MDT modalities, such as Magnetic Drug Targeting (MDT), a treatment. cancer treatment procedure that allows local In contrast, it is indeed possible to perform ultrasonic chemotherapeutic intervention. Contrary to traditional imaging of the target tissue while MDT. Moreover, chemotherapeutic treatment, MDT is attended by decreasing ultrasound is a widely used and a comparatively low-cost the overall dose of drugs, which leads to reduced side effects. imaging technique. Besides, it is portable and offers several It is worth mentioning that at the same time, an increased diagnostic options. However, the size of nanoparticles poses dosage of chemotherapeutic drugs in the tumor area can be a massive challenge for ultrasound-based detection, as the achieved . For this purpose, chemotherapeutic drugs stick particles are not depictable directly due to their weak acoustic to magnetic nanoparticles, which are applied intra-arterially backscattering. close to the tumor. An external magnetic field can enrich the particle density (and, therefore, also the drug concentration) in the tumor area. A high efficiency of MDT in cancer therapy has been proven in animal studies . Therefore, ______ *Corresponding author: Michael Fink, Stefan J. Rupitsch, Helmut Ermert: Department of Sensor Technology, Friedrich - Alexander - University Erlangen - Nuremberg, Paul - Gordan - Strasse 3/5, Erlangen, Germany, firstname.lastname@example.org Stefan Lyer: Section of Experimental Oncology and Figure 1: Magnetic fl ux density field of the electromagnet, used Nanomedicine, University Hospital Erlangen, Erlangen, Germany in this contribution. The arrows mark the direction of the flux density gradient. Open Access. © 2020 Michael Fink et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 License. M. Fink et al., In Vivo Study on Magnetomotive Ultrasound Imaging — 2 Nevertheless, Oh et al.  have demonstrated that ultrasound imaging techniques can be exploited to detect nanoparticle laden tissue. This sonographic detection of magnetic nanoparticles is known as Magnetomotive Ultrasound (MMUS). MMUS rests on nanoparticle movement excitations, employing an external time-variable magnetic field. This particle movement leads to tissue motion, which can be observed sonographically and which serves as an indicator for the presence of magnetic nanoparticles. Consequently, MMUS is indeed an imaging modality that can be employed to display the distribution of the drug carriers during an MDT treatment. 2 Simultaneous MDT Treatment and MMUS Imaging The cost-efficiency of medical devices increases the potential to be adapted in clinical routines. Hence, with a view to clinical applications, it is reasonable that the magnet used for MDT (to accumulate the particles) shall also be employed for MMUS imaging to generate the alternating magnetic field. However, this request raises two problems: The target of an MDT magnet design is to create a static magnetic field (for local particle accumulation). In the case of a high-frequency coil current (for particle movement excitation), the effective magnetic field Figure 2: In vivo measurement setup to investigate clinical suffers from eddy current losses. The MMUS procedure MMUS imaging in the framework of Magnetic Drug Targeting (a) is, therefore, limited to low field frequencies. In the low and two-dimensional geometrical arrangement of ultrasonic frequency range, however, there are also other transducer and electromagnet to apply simultaneous MDT treatment and MMUS imaging (b). movements such as respiratory movements. These other tissue movements possibly impede the detection of particle-induced tissue motions. The latter issue requires consideration of the geometrical conditions. Therefore, we must note that the qualitative Due to the arrangement of the electromagnet and the particle distribution (which MMUS shall determine) is ultrasonic transducer, both components perceive the related to the tissue displacement that occurs towards the target tissue under different directions, which can positive magnetic field gradient, as the magnetic force F is complicate signal processing or which may even disable proportional to the gradient of the absolute magnetic flux the detection of the particle-induced tissue movements density B via MMUS. 𝐅 ∝ ∇|𝐁 | . (1) We may overcome the first-mentioned issue by using coded magnetic excitation signals. In doing so, the particle-induced Fig. 1 shows the magnetic flux density field around the pole tissue movement provides a much more pronounced tip of the electromagnet that is used to perform the recognition value . This makes it much easier to identify measurements in this contribution (see Fig. 2a). Moreover, the target movement and to distinguish it from breathing Fig. 1 shows the direction of the flux density gradient. As can movements, heartbeat movements, or motions caused by be seen, the direction of the field gradient is locally muscle contraction. dependent, and so is the direction of the tissue shift. M. Fink et al., In Vivo Study on Magnetomotive Ultrasound Imaging — 3 However, the sonography measurement only provides the tissue displacement u in the axial direction of the ultrasonic || transducer (see Fig. 2b). Therefore, the measured tissue displacement u must be converted to the actual tissue || displacement u to provide the qualitative mapping of the nanoparticle distribution. For reasons of simplification, in Fig. 2b, the scenario is illustrated via a two-dimensional setup, although the actual configuration is, of course, three-dimensional. According to Figure 3: Schematic representation of the target tissue in the Fig. 2b, the actual tissue displacement u can be composed of image plane of the ultrasonic transducer (a) and angle between the vector u|| that points into the direction of the ultrasonic image plane and the magnetic force direction (b). transducer and the vector u that points perpendicular to it. The component u cannot be determined via MMUS. Therefore, we compute the relevant tissue displacement u 3 Measurements and Results exploiting the trigonometric identity |𝐮 | || We have performed in vivo MMUS measurements in the |u| = . (2) () framework of an MDT animal study. Therefore, a tumor was implanted subcutaneously into the left hind limb of a rabbit. Although the angle α is locally dependent, it is known for any Within the framework of the experiments, we apply drug- location within the image plane. Under consideration of the laden iron-oxide nanoparticles intra-arterially, and we enrich trigonometric identity (2), the determination of the relevant the particles in the tumor tissue employing an electromagnet, tissue displacement u will be only possible if the ultrasonic which has been designed for MDT applications (see ). transducer is not arranged perpendicular to the tissue The Section of Experimental Oncology and Nanomedicine displacement. Fig. 3 shows a schematic image of the target (SEON) of the University Hospital Erlangen, Germany, has tissue within the image plane of the ultrasonic transducer as produced the superparamagnetic nanoparticles used in this well as the locally dependent angle between the image plane contribution. The particles consist of 5 - 15 nm diameter iron- and the direction to which the local magnetic force points. At oxide cores, surrounded by lauric acid layers. The outer an angle of 90°, the actual tissue displacement cannot be layers serve as linkages to the medical drug as well as determined, resulting in a blind spot. biocompatible coating, as the naked iron-oxide nanoparticles Besides the local tissue shift u, we have to consider the local exhibit intrinsic toxicity and are not stable in blood . magnetic field gradient ∇|B| to obtain a measure for During the enrichment process, we observed the target tissue describing the qualitative representation of the particle sonographically, utilizing the medical ultrasonic system density distribution. As, according to (1), the magnetic force Ultrasonix Touch. A linear array (Ultrasonix 4DL-14-5/38) is proportional to the magnetic field gradient, we specify a was applied as ultrasonic transducer to collect the rf-data. quantity d Fig. 2a shows the main components of the measurement setup (electromagnet and ultrasonic transducer). Moreover, |𝐮 | d = , (3) the measurement setup includes a signal generator to shape ∇|𝐁| the excitation signal waveform and a power amplifier to induce the coil current. which can be seen as a measure to represent the particle The magnetic excitation signal is chosen to be a 4-bit Barker distribution. However, d does not provide a technically code (the fundamental frequency is 1 Hz) to distinguish reasonable interpretation. That is the reason why we utilize in particle-induced tissue motions from other tissue movements. this contribution the normalized parameter d norm The recorded rf-data were evaluated according to the presented MMUS principle. Fig. 4 shows the qualitative d = , (4) norm () particle distribution at different time steps throughout the whole particle accumulation process. The particles are to assess the local particle density. administered at a low rate over a long period to avoid a shock In the following, the simultaneous applicability of MDT and reaction of the animal. Hence, the accumulation process takes MMUS with a single electromagnet will be investigated by 45 minutes. means of in vivo measurements. M. Fink et al., In Vivo Study on Magnetomotive Ultrasound Imaging — 4 Figure 4: B-mode image of the tumor in the left hind limb of a rabbit and MMUS evaluation of the collected rf-data at different time steps, while the applied iron-oxide nanoparticles are accumulated in the target area using an MDT magnet. MMUS. Furthermore, the possibilities of real-time imaging will be investigated. 4 Conclusion References This study demonstrates a suitable setup to perform MMUS imaging simultaneously to MDT treatment. In particular, we  P. Kheirkhah, S. Denyer, A.D. Bhimani, G.D. Arnone, D.R. Esfahani, et al. Magnetic Drug Targeting: A Novel Treatment could show that MMUS imaging is possible despite the for Intramedullary Spinal Cord Tumors , Scien. Rep. 8, Art. angular offset between electromagnet and ultrasonic Num. 11417, 2018. transducer. With the measurements carried out in this thesis,  R. Tietze, S. Lyer, S. Duerr, T. Struffert, T. Engelhorn,et al. the enrichment of the target tissue with nanoparticles during Efficient Drug-Delivery Using Magnetic Nanoparticles - Biodistribution and Therapeutic Effects in Tumour Bearing MDT could be observed for the first time. The presented Rabbits, Nanomedicine vol. 9(7): 961-971, 2013. imaging procedure can be performed with the equipment  D.L. Bushnell and R.P. Baum, Standard Imaging Techniques already used for MDT and a standard medical ultrasonic for Neuroendocrine Tumors, Endocrinology and Metabolism device. Thus, MMUS seems to be a promising modality for Clinics vol. 40(1): 153-162, 2011.  K. Luedtke-Buzug, J. Haegele, S. Biederer, T.F. Sattel, M. mapping the particle distribution (i. e., drug distribution) in Erbe, et al. Comparison of Commercial Iron Oxide Based MDT applications. MRI Contrast Agents With Synthesized Highperformance However, we can identify two artifacts when considering the MPI Tracers, Biomed. Eng. vol. 58(6): 527-533, 2013. results:  J. Oh, M.D. Feldman, J. Kim, C. Condit, S. Emelianov and Tissue oscillations can also be noted in the tumor's T.E. Milner, Detection of Magnetic Nanoparticles in Tissue Using Magnetomotive Ultrasound, Nanotechnology vol. 17: neighboring tissue (especially at timestep 35 min). Since 4183-4190, 2006. these movements disappear thereafter, we think that  M. Fink, H. Ermert, C. Alexiou and S. Lyer, Sonographic these tissue motions may be caused by particles that are Detection of Magnetic Nanoparticles for Magnetic Drug still circulating in the bloodstream system. Targeting Using Coded Magnetic Fields, Proc. IEEE IUS Throughout the whole enrichment process, the area close  C. Alexiou, D. Diel, P. Henninger, H. Iro, R. Roecklein, W. to the ultrasonic transducer is detected as particle-free. Schmidt and H. Weber, A high field gradient magnet for In this area, the tissue oscillates approximately magnetic drug targeting, IEEE Trans. Appl. Supercond. 16, perpendicular to the image plane of the ultrasonic 1527-1530, 2006.  J. Zaloga, C. Janko, J. Nowak, J. Matuszak, S. Knaup, et al. transducer, resulting in a blind spot. In order to avoid Development of a lauric acid/album hybrid iron oxide such a blind spot, a second measurement would have to nanoparticle system with improved biocompatibility, Intern. be carried out, viewing this blind spot from a different Journ. Nanomed. 9, 4847-4866, 2014.magnetic drug angle. targeting, IEEE Trans. Appl. Supercond. 16, 1527-1530, In future contributions, we will focus on the potential of 2006. three-dimensional imaging of the particle distribution using
Current Directions in Biomedical Engineering – de Gruyter
Published: Sep 1, 2020
Keywords: Magnetic Drug Targeting; Magnetomotive Ultrasound; iron-oxide nanoparticles; ultrasonic imaging
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