Iron oxide nanoparticles for biomedical MR imaging
Professor Bernd Hamm MD, Director of the Institute of Radiology, at the Charité University of Medicine, Berlin and Matthias Taupitz MD, Head of the Department of Experimental Radiology within the Institute
Researchers open up new opportunities for cellular and molecular MR imaging.
Iron oxide nanoparticles are interesting and versatile markers for biomedical imaging. Their physical characteristic, superparamagnetism, leads to sensitive detectability of these nanoparticles through magnetic resonance imaging. Depending on the composition, or specific modification, iron oxide nanoparticles are suitable for use in functional MR imaging to display disease processes in vivo on the basis of cellular or molecular mechanisms. This is also known as cellular or molecular MR imaging.
From a pharmacokinetic point of view these substances, due to the character of their particles, are suitable for the marking of cells that are capable of phagocytosis. The nanoparticles, following phagocytosis in macrophages after i.v. injection, are predominantly absorbed in the liver. Here they cause a loss of signal intensity in the MR image in healthy tissue, i.e. normal liver tissue appears dark. Liver metastases, or primary liver tumours, do not absorb these particles and are therefore easier to detect. This principle makes MR diagnostics of the liver more accurate and reliable. Two substances based on iron oxide nanoparticles have been clinically licensed for the MR diagnosis of the liver (Endorem, manufactured by Guerbet, and Resovist, manufactured by Schering AG). In this area, the concept of cellular MR imaging is already in clinical use.
Through variation of the size and surface consistency of the particles the organ distribution can be systematically changed. Whereas the relatively large iron oxide nanoparticles (50 - 120 nm total diameter, Superparamagnetic Iron Oxide - SPIO) are absorbed in particular by the liver and spleen, smaller iron oxide nanoparticles (ca. 20 nm total diameter, Ultra-small SPIO- USPIO) remain in the bloodstream for longer. Following i.v. injection, this leads to increased accumulation of the nanoparticles in healthy lymph node tissue as well. In experimental and clinical studies it has been possible to show for one of these substances (Sinerem, manufactured by Guerbet) that small lymph nodes affected by metastases can also be detected. Consequently, it is conceivable that, in the future, we may be able to do without diagnostic lymph-adenectomies in oncological patients, or to achieve a better-directed removal of lymph nodes. Sinorem was extensively, clinically tested for intravenous MR lymphography and an application for clinical approval has been filed.
A further, promising approach for improved imaging diagnostics is based on the detection of phagocytosing immune cells through i.v. injected iron oxide nanoparticles. From a scientific and clinical point of view, an outstanding example for the in-vivo detection of inflammatory activity is the so-called vulnerable atherosclerotic plaques. Vulnerable plaques can cause sudden, life-threatening vascular obliterations through rupture and the formation of thrombi, particularly in the coronary vessels or in the arteries supplying the brain. Vulnerable plaques cannot necessarily be detected through conventional X-ray angiography because they may not be associated with stenoses. However, vulnerable atherosclerotic plaques are characterised by a high number of inflammatory cells, which, through the i.v. injection of iron oxide nanoparticles, can be marked in-vivo. Experimental and first clinical results show that i.v. injected iron oxide nanoparticles in combination with high resolution MR imaging can detect inflammatory changes in the arterial wall. However better understanding of the physiological basis of these effects is required before clinical use can be contemplated. Further interesting applications for SPIO and USPIO are currently being experimentally researched or, in some cases, even already clinically tested. This includes the display of inflammatory changes in the central nervous system, (in the detection of multiple sclerosis, for example) or the functional imaging of bone marrow, which could be of importance in tumour therapy.
Iron oxide nanoparticles can also be used for research into the effectiveness of cell-based therapies. Concepts for cell-based therapy are currently being developed, among others, for the treatment of Parkinson’s disease, spinal injuries or cardiac infarction. The fate of transplanted stem cells in the organism can be monitored for many months through prior labelling with iron oxide nanoparticles through MR imaging. With efficient labelling and the appropriate in vivo procedure the detection of just a few hundred cells is possible in-vivo.
Apart from these approaches for cellular in vivo imaging, iron oxide nanoparticles can also be coupled with target-specific molecules. This facilitates the in vivo visualisation of specific molecular structures or processes. An important example for this is the imaging of programmed cell death (apoptosis). In apoptosis, certain cell surface molecules propagate at a very early stage. Iron oxide nanoparticles, marked with the appropriate molecules, accumulate in apoptotic tissue after i.v. injection and make the occurrence of apoptosis visible on the MR image. With this detection of apoptosis through MRI in tumour therapy, in future we should be able to ascertain the effectiveness of therapies at an early stage. This makes for the improved, more targeted application of different therapy approaches, which are often expensive and sometimes also have many undesired side effects.
The Institute of Radiology is testing new approaches for superparamagnetic iron oxide nanoparticles. Whereas in all previous approaches for a potential in vivo use polymers, such as dextran, polyethylene glycol, or starch, have been used as coating material for the particles, the Charité, together with Ferropharm GmbH, a Brandenburg-based start-up company, have used nanoparticles that are coated with low-molecular weight organic molecules. This, compared with the above-mentioned USPIO, results in the development of even smaller nanoparticles with a diameter of around 7nm (Very Small Superparamagnetic Iron Oxide Particles - VSOP). Through this, so far unique size in combination with the surface coating, the researchers have opened up new opportunities for cellular and molecular MR imaging. They were able to show, on a few examples, that these VSOPs, compared with the previously used iron oxide nanoparticles, are much more suitable for cell marking. The Charité is carrying out examinations with stem cell therapy for the detection of inflammatory activity as well as in tumour diagnostics. One focus here is on the research into non-invasive characterisation of vulnerable atherosclerotic plaques. For molecular imaging these very small particles open up new opportunities as their size, combined with coupled, target-specific molecules, is sufficiently small to achieve good bio-availability within the desired target area. These very small particles, apart from being suitable for cellular and molecular imaging, can also be used as so-called blood-pool contrast media for high-resolution display of very small vessels in terms of MR angiography.
Research into these new iron oxide nanoparticles at the Charité is partially sponsored by the German Research Foundation (DFG), the Investment Bank Berlin (IBB) and the Technology Foundation Berlin (TSB), and by the Federal Ministry of Education and Research (BMBF) within their initiative ‘Nano for Life’. There is also a network with other institutions (the German Cancer Research Centre, in Heidelberg; Freiburg University; Mevis, a Bremen-based firm) and with companies such as Ferropharm GmbH in Teltow, Brandenburg, Siemens AG in Erlangen and Schering AG in Berlin).
01.05.2006
