Molekulare MR-Bildgebung

Zusammenfassung.

Die medizinisch-biologische Grundlagenforschung erbrachte in den letzten Jahren einen rasanten Erkenntnisfortschritt für das funktionelle Verständnis über physiologische und pathologische Prozesse bis hinab auf molekulares Niveau. Gleichzeitig haben sich auch verschiedene bildgebende Techniken von der ursprünglichen Organdarstellung der Zellebene genähert und sind im Begriff, die Sichtbarmachung auch von molekularen Vorgängen zu etablieren. Neben anderen Verfahren wie PET und Nahinfrarotfluoreszenz weist die MRT einige vielversprechende Optionen und bereits heute erprobte Einsatzmöglichkeiten in der molekularen Bildgebung auf, wie z. B. die Visualisierung von Enzymaktivitäten, die Darstellung der Expression bestimmter Gene, die Sichtbarmachung von Oberflächenrezeptoren oder die spezifische Visualisierung von Zellen im Rahmen der Immunantwort. Gegenüber den anderen Modalitäten mit zum Teil höherer Sensitivität bietet die molekulare Magnetresonanztomographie (mMRT) insbesondere den Vorteil eines hohen räumlichen Auflösungsvermögens. Für die mMRT ist die weitere Verbesserung der Auflösung und die Entwicklung von molekular angreifenden Markern mit erhöhter Sensitivität und Spezifität eine wesentliche Voraussetzung. Der Stand der Entwicklung der mMRT wird anhand einer Literaturübersicht bisher durchgeführter experimenteller Studien und eigener Forschungsergebnisse an Gliomen dargestellt.

Molecular MR Imaging.

Basic medicobiological research in recent years has made rapid advances in the functional understanding of normal and pathological processes down to the molecular level. At the same time, various imaging modalities have developed from the depiction of organs to approaching the depiction of the cellular level and are about to make the visualization of molecular processes an established procedure. Besides other modalities like PET and near-infrared fluorescence, MR imaging offers some promising options for molecular imaging as well as some applications that have already been tested such as the visualization of enzyme activity, the depiction of the expression of certain genes, the visualization of surface receptors, or the specific demonstration of cells involved in the body's immune response. A major advantage of molecular magnetic resonance imaging (mMRI) over other more sensitive modalities is its high spatial resolution. However, the establishment of mMRI crucially relies on further improvements in resolution and the development of molecular markers for improving its sensitivity and specificity. The state of the art of mMRI is presented by giving a survey of the literature on experimental studies and reporting the results our study group obtained during investigation on gliomas.

Molekulare Bildgebung - Magnetresonanztomographie - Gliome - Mikroglia - Makrophagen

Molecular imaging - Magnetic resonance imaging - Gliomas - Microglia - Macrophages

Literatur

• 1 Weissleder R. Molecular imaging: exploring the next frontier.  Radiology. 1999;  212 609-614
• 2 Service R F. New probes open windows on gene expression.  Science. 1998;  280 1010-1011
• 3 Alfke H, Klose K J. Eine Einführung in die Molekulare Radiologie.  Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr. 2000;  172 Supplement 6
• 4 Weissleder R, Tung C H, Mahmood U, Bogdanov A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.  Nat Biotechnol. 1999;  17 375-378
• 5 Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions.  Prog Neurobiol. 1998;  56 149-171
• 6 Contag P R, Olomu I N, Stevenson D K, Contag C H. Bioluminescent indicators in living mammals.  Nat Med. 1998;  4 245-247
• 7 Tjuvajev J G, Chen S H, Joshi A, Joshi R, Guo Z S, Balatoni J. et al . Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo.  Cancer Res. 1999;  59 5186-5193
• 8 Gambhir S S, Barrio J R, Phelps M E, Iyer M, Namavari M, Satyamurthy N. et al . Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography.  Proc Natl Acad Sci USA. 1999;  96 2333-2338
• 9 Kornblum H I, Araujo D M, Annala A J, Tatsukawa K J, Phelps M E, Cherry S R. In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET).  Nat Biotechnol. 2000;  18 655-660
• 10 Phelps M E. Inaugural article: positron emission tomography provides molecular imaging of biological processes.  Proc Natl Acad Sci USA. 2000;  97 9226-9233
• 11 Wu A M, Yazaki P J, Tsai S, Nguyen K, Anderson A L, McCarthy D W. et al . High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper- 64-labeled engineered antibody fragment.  Proc Natl Acad Sci USA. 2000;  97 8495-8500
• 12 Bowtell R W, Peters A, Sharp J C, Mansfield P, Hsu E W, Aiken N. et al . NMR microscopy of single neurons using spin echo and line narrowed 2DFT imaging.  Magn Reson Med. 1995;  33 790-794
• 13 Jacobs R E, Fraser S E. Magnetic resonance microscopy of embryonic cell lineages and movements.  Science. 1994;  263 681-684
• 14 Johnson G A, Benveniste H, Black R D, Hedlund L W, Maronpot R R, Smith B R. Histology by magnetic resonance microscopy.  Magn Reson Q. 1993;  9 1-30
• 15 Remsen L G, McCormick C I, Roman G S, Nilaver G, Weissleder R, Bogdanov A. et al . MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis.  AJNR Am J Neuroradiol. 1996;  17 411-418
• 16 Kresse M, Wagner S, Pfefferer D, Lawaczeck R, Elste V, Semmler W. Targeting of ultrasmall superparamagnetic iron oxide (USPIO) particles to tumor cells in vivo by using transferrin receptor pathways.  Magn Reson Med. 1998;  40 236-242
• 17 Zhao M, Beauregard D A, Davletov B A, Brindle K M. Detection of Apoptosis by MRI Using SPIO-Conjugated C2 Domain of Synaptotagmin I.  Proc Intl Sot Mag Reson Med. 2000;  8 40
• 18 Johansson L O, Kellar K E, Ahlström H K, Bjornerud A, Douty B, Ladd D L. et al . Targeted Contrast Agents for Magnetic Resonance Imaging: Possibilities and Limitations.  Proc Intl Sot Mag Reson Med. 2000;  8 203
• 19 Sipkins D A, Cheresh D A, Kazemi M R, Nevin L M, Bednarski M D, Li K C. Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.  Nat Med. 1998;  4 623-626
• 20 Moore A, Marecos E, Bogdanov A, Weissleder R. Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model.  Radiology. 2000;  214 568-574
• 21 Dodd S J, Williams M, Suhan J P, Williams D S, Koretsky A P, Ho C. Detection of single mammalian cells by high-resolution magnetic resonance imaging.  Biophys J. 1999;  76 103-109
• 22 Schoepf U, Marecos E M, Melder R J, Jain R K, Weissleder R. Intracellular magnetic labeling of lymphocytes for in vivo trafficking studies.  Biotechniques. 1998;  24 642-6, 648
• 23 Weissleder R, Cheng H C, Bogdanova A, Bogdanov A. Magnetically labeled cells can be detected by MR imaging.  J Magn Reson Imaging. 1997;  7 258-263
• 24 Yeh T C, Zhang W, Ildstad S T, Ho C. Intracellular labeling of T-cells with superparamagnetic contrast agents.  Magn Reson Med. 1993;  30 617-625
• 25 Yeh T C, Zhang W, Ildstad S T, Ho C. In vivo dynamic MRI tracking of rat T-cells labeled with superparamagnetic iron-oxide particles.  Magn Reson Med. 1995;  33 200-208
• 26 Josephson L, Tung C H, Moore A, Weissleder R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates.  Bioconjug Chem. 1999;  10 186-191
• 27 Lewin M, Carlesso N, Tung C H, Tang X W, Cory D, Scadden D T. et al . Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.  Nat Biotechnol. 2000;  18 410-414
• 28 Moats R. et al .A "smart" magnetic resonance imaging agent that reports on specific enzymatic activity. Angew Chem Int Ed Engl 1997: 726
• 29 Louie A Y, Huber M M, Ahrens E T, Rothbacher U, Moats R, Jacobs R E. et al . In vivo visualization of gene expression using magnetic resonance imaging.  Nat Biotechnol. 2000;  18 321-325
• 30 de Marco G, Bogdanov A, Marecos E, Moore A, Simonova M, Weissleder R. MR imaging of gene delivery to the central nervous system with an artificial vector.  Radiology. 1998;  208 65-71
• 31 Weissleder R, Bogdanov A, Zimmer C. Dextran stabilized iron oxides allow gene delivery into neuron-like cells. Seventh international symposium on recent advances in drug delivery systems. Salt Lake City; 1995: 165-166
• 32 Kayyem J F, Kumar R M, Fraser S E, Meade T J. Receptor-targeted co-transport of DNA and magnetic resonance contrast agents.  Chem Biol. 1995;  2 615-620
• 33 Stegman L D, Rehemtulla A, Beattie B, Kievit E, Lawrence T S, Blasberg R G. et al . Noninvasive quantitation of cytosine deaminase transgene expression in human tumor xenografts with in vivo magnetic resonance spectroscopy.  Proc Natl Acad Sci USA. 1999;  96 9821-9826
• 34 Bogdanov A, Weissleder R. The development of in vivo imaging systems to study gene expression.  Trends Biotechnol. 1998;  16 5-10
• 35 Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca E A. et al . In vivo magnetic resonance imaging of transgene expression.  Nat Med. 2000;  6 351-355
• 36 Weissleder R, Simonova M, Bogdanova A, Bredow S, Enochs W S, Bogdanov A J. MR imaging and scintigraphy of gene expression through melanin induction.  Radiology. 1997;  204 425-429
• 37 Rossi M L, Hughes J T, Esiri M M, Coakham H B, Brownell D B. Immunohistological study of mononuclear cell infiltrate in malignant gliomas.  Acta Neuropathol Berl. 1987;  74 269-277
• 38 Wood G W, Morantz R A. Immunohistologic evaluation of the lymphoreticular infiltrate of human central nervous system tumors.  J Natl Cancer Inst. 1979;  62 485-491
• 39 Morimura T, Neuchrist C, Kitz K, Budka H, Scheiner O, Kraft D. et al . Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation.  Acta Neuropathol Berl. 1990;  80 287-294
• 40 Badie B, Schartner J M. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas.  Neurosurgery. 2000;  46 957-961
• 41 Roggendorf W, Strupp S, Paulus W. Distribution and characterization of microglia/macrophages in human brain tumors.  Acta Neuropathol Berl. 1996;  92 288-293
• 42 Morioka T, Baba T, Black K L, Streit W J. Response of microglial cells to experimental rat glioma.  Glia. 1992;  6 75-79
• 43 Moffett J R, Els T, Espey M G, Walter S A, Streit W J, Namboodiri M A. Quinolinate immunoreactivity in experimental rat brain tumors is present in macrophages but not in astrocytes.  Exp Neurol. 1997;  144 287-301
• 44 Kettenmann H. Beyond the neuronal circuitry.  Trends Neurosci. 1996;  19 305-306
• 45 van den Hauwe L, Parizel P M, Martin J J, Cras P, De Deyn P, De Schepper A M. Postmortem MRI of the brain with neuropathological correlation.  Neuroradiology. 1995;  37 343-349
• 46 Eis M, Els T, Hoehn B M, Hossmann K A. Quantitative diffusion MR imaging of cerebral tumor and edema.  Acta Neurochir Suppl Wien. 1994;  60 344-346
• 47 Banati R B, Goerres G W, Myers R, Gunn R N, Turkheimer F E, Kreutzberg G W. et al . [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis.  Neurology. 1999;  53 2199-2203
• 48 Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T. et al . PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis.  J Neurosci Res. 1997;  50 345-353
• 49 Olivero W C, Dulebohn S C, Lister J R. The use of PET in evaluating patients with primary brain tumours: is it useful?.  J Neurol Neurosurg Psychiatry. 1995;  58 250-252
• 50 Dousset V, Gomez C, Petry K G, Delalande C, Caille J M. Dose and scanning delay using USPIO for central nervous system macrophage imaging.  MAGMA. 1999;  8 185-189
• 51 Dousset V, Delalande C, Ballarino L, Quesson B, Seilhan D, Coussemacq M. et al . In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance.  Magn Reson Med. 1999;  41 329-333
• 52 Egelhof T, Delbeck N, Hartmann M, Roth S U, Elste V, Heiland S. et al . Can superparamagnetic contrast media improve MRI-tomographic images of experimental gliomas?.  Radiologe. 1998;  38 943-947
• 53 Zimmer C, Weissleder R, Poss K, Bogdanova A, Wright S C, Enochs W S. MR imaging of phagocytosis in experimental gliomas.  Radiology. 1995;  197 533-538
• 54 Zimmer C, Weissleder R, O'Connor D, Lapointe L, Brady T J, Enochs W S. Cerebral iron oxide distribution: in vivo mapping with MR imaging.  Radiology. 1995;  196 521-527