Übersicht 1149 Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy Superparamagnetische Eisenoxid-Nanopartikel in der Biomedizin: Anwendungen und Entwicklungen in Diagnostik und Therapie Authors H. Ittrich, K. Peldschus, N. Raabe, M. Kaul, G. Adam Affiliation Diagnostic and Interventional Radiology Department and Clinic, Center für Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf Key words Abstract Key Points: " ● SPIO ! ▶ SPIO can be used for diagnosis, MR ima- ●" molecular imaging Superparamagnetic iron oxide nanoparticles ging, and treatment. ●" MRI (SPIO) can be used to image physiological pro- ▶ Monodisperse SPIO improve physicochem- ●" contrast media cesses and anatomical, cellular and molecular istry and pharmacodynamics. ●" iron oxide ●" nanoparticles changes in diseases. The clinical applications ▶ SPIO in targeted probes can be used in in- range from the imaging of tumors and metas- vitro diagnostic imaging (μNMR). tases in the liver, spleen and bone marrow, ▶ The potential to use SPIO in magnetic par- the imaging of lymph nodes and the CNS, ticle imaging (MPI) must be evaluated. MRA and perfusion imaging to atherosclero- Citation Format: tic plaque and thrombosis imaging. New ex- ▶ Ittrich H, Peldschus K, Raabe N et al. Super- perimental approaches in molecular imaging paramagnetic Iron Oxide Nanoparticles in describe undirected SPIO trapping (passive Biomedicine: Applications and Develop- targeting) in inflammation, tumors and asso- ments in Diagnostics and Therapy. Fortschr ciated macrophages as well as the directed Röntgenstr 2013; 185: 1149–1166 accumulation of SPIO ligands (active target- ing) in tumor endothelia and tumor cells, areas of apoptosis, infarction, inflammation and degeneration in cardiovascular and neu- Zusammenfassung rological diseases, in atherosclerotic plaques ! or thrombi. The labeling of stem or immune Mithilfe von Superparamagnetischen Eisenoxid- eingereicht 25.10.2012 akzeptiert 18.3.2013 cells allows the visualization of cell therapies Nanopartikeln (SPIO) können physiologische Ab- or transplant rejections. The coupling of SPIO läufe sowie anatomische, zelluläre und molekulare Bibliography to ligands, radio- and/or chemotherapeutics, Veränderungen in Krankheitsprozessen abgebildet DOI http://dx.doi.org/ embedding in carrier systems or activatable werden. Die klinischen Anwendungen reichen von 10.1055/s-0033-1335438 smart sensor probes and their externally con- der Tumor- und Metastasenbildgebung in Leber, Published online: 5.9.2013 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Fortschr Röntgenstr 2013; 185: trolled focusing (physical targeting) enable Milz und Knochenmark, über die Lymphknoten- 1149–1166 © Georg Thieme molecular tumor therapies or the imaging of und ZNS-Bildgebung, die MR-Angiografie und Per- Verlag KG Stuttgart · New York · metabolic and enzymatic processes. Mono- fusionsdiagnostik bis hin zur atherosklerotischen ISSN 1438-9029 disperse SPIO with defined physicochemical Plaque- und Thrombosebildgebung. Die experi- and pharmacodynamic properties may im- mentellen Anwendungsfelder in der Molekularen prove SPIO-based MRI in the future and as Bildgebung umfassen neben ungerichteter SPIO- Correspondence Dr. Harald Ittrich targeted probes in diagnostic magnetic reso- Anreicherung (Passive Targeting) in Entzündungs- Diagnostic and Interventional nance (DMR) using chip-based μNMR may regionen und Tumoren sowie assoziierten Makro- Radiology Department and significantly expand the spectrum of in vitro phagen die zielgerichtete Akkumulation von SPIO- Clinic, Center für Radiology and analysis methods for biomarker, pathogens Liganden (Active Targeting) an/in Tumorendothe- Endoscopy, University Medical and tumor cells. Magnetic particle imaging lien und Tumorzellen, Apoptose-, Infarkt-, Inflam- Center Hamburg-Eppendorf (MPI) as a new imaging modality offers new mations- und Degenerationsarealen in kardio- Martinistraße 52 applications for SPIO in cardiovascular, onco- vaskulären und neurologischen Erkrankungen, in 20246 Hamburg Tel.: ++ 49/40/4 28 03 31 16 logical, cellular and molecular diagnostics atherosklerotischen Plaques oder Thromben. Die Fax: ++ 49/40/4 28 03 67 99 and therapy. SPIO-Markierung von Stamm- oder Immunzellen [email protected] erlaubt die Visualisierung von Zelltherapien oder Ittrich H et al. Superparamagnetic Iron Oxide… Fortschr Röntgenstr 2013; 185: 1149–1166 1150 Übersicht Transplantat-Abstoßungen. Die Kopplung von SPIO an Liganden, field of molecular imaging describe on a cellular level the Radio- und/oder Chemotherapeutika, die Einbettung in Trägersys- in vitro labeling of cell types (e. g. macrophages, lympho- teme oder aktivierbare Sonden sowie deren extern gesteuerter Fo- cytes, progenitor/stem cells) with SPIO (cell labeling) and kussierung (Physical Targeting) ermöglicht molekulare Tumorther- their diagnostic in vivo MR imaging and migration tracking apien sowie die Abbildung metabolischer und enzymatischer (tracking/migration monitoring) [20, 21]. Additional studies Prozesse. Monodisperse SPIO mit definierten physikochemischen on a molecular level describe the use of SPIO and specifical- und pharmakodynamischen Eigenschaften könnten die SPIO-un- ly targeted SPIO conjugates (targeted probes) for labeling terstützte MRT verbessern und zukünftig als zielgerichtete Sonden cell-surface molecules (e. g. cell receptors or antigens [22]) in der Diagnostischen Magnetresonanz (DMR) unter Nutzung von in combination with gene therapy, chemotherapeutic, or chipbasierten μNMR das Spektrum der In-vitro-Analysemethoden radiotherapeutic agents as a combined diagnostic-thera- für Biomarker, Pathogene und Tumorzellen entscheidend erwei- peutic agent (theranostics [23]) and tumor-thermoablative tern. Magnetic Particle Imaging (MPI) als neues Abbildungsverfah- use in hyperthermia [24]. The embedding of SPIO in na- ren könnte SPIO sowohl in der kardiovaskulären, onkologischen, noencapsulations or microencapsulations with different zellulären und molekularen Diagnostik und Therapie neue Anwen- controllable surface properties (e. g. in micelles or lipo- dungsfelder eröffnen. somes) recently made it possible to use SPIO in the imaging of metabolic processes (e. g. lipid metabolism [25, 26]). Moreover, the synthesis of novel, monodisperse SPIO with Introduction optimized physicochemical and pharmacodynamic proper- ! ties allows more precise addressing of target structures, The term superparamagnetic, first mentioned in the mid- greater accumulation in the target area, improved target- 1950 s [1], describes the ability of a ferrimagnetic or ferro- environment contrast, and more exact parametric or quan- magnetic material to be magnetized in the presence of an titative SPIO-MRI. external magnetic field and to completely lose this magne- In addition to the use of SPIO in diagnostic MRI and in the tization once the magnetic field is deactivated (no rema- treatment of diverse diseases, use in a new tomographic nent magnetization) [2]. This phenomenon is physically imaging modality currently undergoing preclinical evalua- based on the Brown and Neel relaxation [3]. tion, namely magnetic particle imaging (MPI) [27], is being Nanoparticles typically refer to particles with a size of tested and optimized. 1 – 100 nm, but the physical, chemical, and biological prop- Based on the statements of Taupitz et al. [28], the present erties can differ greatly compared to macroscopic material study is intended to provide a current overview of the mor- with the same composition [4]. phological, physical-chemical, and biological characteristics Superparamagnetic particles of iron oxide (SPIO) have an of different SPIO, the current status in clinical application, iron oxide core that is monomer- or polymer-coated/stabi- and the current and future preclinical experimental appli- lized. The advantages of SPIO, such as good suspensibility, a cation fields of SPIO in molecular imaging and treatment. highly reactive surface, uniform particle size distribution, and the possibility of additional coating modification by conjugating with specifically binding ligands (e. g. antibo- Particle types and particle properties dies) has made it possible to use these particles in biomedi- ! cine since the mid-1970 s in immunomagnetic cell separa- Definition and magnetic properties in MRI tion [5]. Superparamagnetic particles of iron oxide (SPIO) are a se- With the broad application of magnetic resonance imaging parate class of MR contrast agents that have a size spectrum (MRI) in medical diagnostics starting in the mid-1980 s, an- of only a few nanometers to several micrometers and influ- other SPIO application field developed, namely use as a neg- ence the spin-spin (T2) and spin-lattice (T1) relaxation. ative, i. e. signal-eliminating, contrast agent in MRI [6]. The After local accumulation, SPIO shorten the T2, T2* or T1 re- nonspecific uptake of SPIO in the mononuclear phagocyte laxation times of surrounding tissues. This causes a signal- system (MPS) or reticuloendothelial system (RES) after in- reducing T2 and T2* effect (negative contrast) or a signal-in- travenous application made it possible at the end of the creasing T1 effect (positive contrast). In general, the r2 or r2* 1980 s to use SPIO in preclinical and clinical diagnostic MRI relaxivity of SPIO as the reciprocal of the T2 or T2* relaxa- This document was downloaded for personal use only. Unauthorized