Superparamagnetische Eisenoxidpartikel: Aktueller Stand und zukünftige Entwicklungen

Zusammenfassung

Für Superparamagnetische Eisenoxidpartikel (SPIO) ist in den letzten 15 Jahren ein weites Anwendungsspektrum als Kontrastmittel für die MRT aufgezeigt worden. SPIO können mit verschiedenen Partikelgrößen und Oberflächenbeschichtungen hergestellt werden. SPIO mit größeren Partikeldurchmessern (50 - 150 nm) bewirken überwiegend eine Signalminderung bzw. T₂-Verkürzung, werden als Kontrastmittel in der MRT von Leber und Milz eingesetzt und führen zu einer hohen Genauigkeit vor allem im Nachweis von Lebermetastasen (zugelassene Substanzen: AMI-25 (Endorem bzw. Ferridex), SHU-555A (Resovist)). Kleinere Partikel (ca. 20 nm Durchmesser) zeigen eine andere Organverteilung und haben das Potenzial, die nicht-invasive Lymphknotendiagnostik zu verbessern oder vulnerable atherosklerotische Plaques zu charakterisieren (in der klinischen Prüfung: AMI-227 [Sinerem bzw. Combidex]). Partikel mit optimierter T₁-Relaxivität und verlängerter intravasaler Zirkulationszeit sind als Blutpool-Kontrastmittel für die MR-Angiographie einsetzbar. Als Indikationen werden derzeit die MR-Angiographie des Körperstamms, peripherer Arterien und der Koronararterien geprüft (z. B. SHU 555 C (Supravist), VSOP-C184). Weitere derzeit in der Prüfung befindliche Indikationen kleiner SPIO sind die MRT des Knochenmarks sowie die Bestimmung von Parametern der Perfusion von Tumoren oder z. B. des Myokards. Eine entsprechende Modifikation der Partikelhülle ermöglicht Ansätze der sogenannten Molekularen Bildgebung, z. B. Rezeptor-gerichtete Bildgebung, Markierung von Zellen zum in-vivo Monitoring der Zellmigration, z. B. von Stammzellen, Markierung von Genkonstrukten zur Lokalisationskontrolle in der Gentherapie. In der Tumortherapie können SPIO als Vermittler für die Hyperthermie eingesetzt werden. SPIO stellen ein wirkungsvolles MR-Kontrastmittel mit vielseitigen Einsatzmöglichkeiten in der Bildgebenden Diagnostik bis hin zur Molekularen Medizin dar.

Abstract

A wide range of applications for superparamagnetic iron oxide (SPIO) particles as contrast media for MRI has emerged over the last 15 years. SPIO particles can be manufactured with different particle sizes and surface coatings. Large SPIO particles (50 - 150 nm) predominantly produce a signal decrease or T₂-shortening and are used as contrast media for MRI of the liver and spleen. They have a high accuracy, especially in detecting liver metastases (approved for clinical use: AMI-25 (Endorem or Ferridex), SHU-555A (Resovist)). Smaller particles (about 20 nm in diameter) show a different organ distribution and have a potential for improving noninvasive lymph node assessment or characterizing vulnerable atherosclerotic plaques (in clinical trials: AMI-227 [Sinerem or Combidex]). Particles with an optimized T₁-relaxivity and prolonged intravascular circulation time can be used as blood pool contrast media for MR angiography. The currently investigated indications are MR angiography of the trunk, peripheral vessels, and coronary arteries (e.g., SHU-555 C (Supravist), VSOP-C 184). Other applications of small SPIO particles include MRI of the bone marrow and the determination of perfusion parameters in tumors or other tissues like the myocardium. SPIO particles with a modified coat can be used in so-called molecular imaging, such as receptor-directed imaging, cell labeling for in-vivo monitoring of cell migration, e.g., stem cell labeling, and labeling of gene constructs for localization in genetic therapy. In tumor therapy SPIO particles can serve as mediators for hyperthermia. SPIO is a powerful MR contrast medium with manifold applications ranging from diagnostic imaging to molecular medicine.

Key words

Magnetic resonance imaging - MRI - contrast medium - iron oxide particles - superparamagnetism

Literatur

• 1 Kobozev N I, Evdokimov V B, Zubovich I A, Mal'tsev A N. Magnetochemistry of active centers. I. Magnetic and catalytic properties of dilute layers.  Zhur Fiz Khim. 1952;  26 1349-1373
• 2 Bean C P, Jacobs I S. Magnetic granulometry and superparamagnetism.  J Appl Phys. 1956;  27 1448-1452
• 3 Kronick P, Gilpin R W. Use of superparamagnetic particles for isolation of cells.  J Biochem Biophys Methods. 1986;  12 73-80
• 4 Renshaw P F, Owen C S, Evans A E, Leigh J S. Immunospecific NMR contrast agents.  Magn Reson Imaging. 1986;  4 351-357
• 5 Hemmingsson A, Carlsten J, Ericsson A, Klaveness J, Sperber G O, Thuomas K A. Relaxation enhancement of the dog liver and spleen by biodegradable superparamagnetic particles in proton magnetic resonance imaging.  Acta Radiologica. 1987;  28 703-705
• 6 Saini S, Stark D D, Hahn P F, Wittenberg J, Brady T J, Ferrucci J T. Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system.  Radiology. 1987;  162 211-216
• 7 Wang Y X, Hussain S M, Krestin G P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging.  Eur Radiol. 2001;  11 2319-2331
• 8 Lawaczeck R, Bauer H, Frenzel T, Hasegawa M, Ito Y, Kito K, Miwa N, Tsutsui H, Vogler H, Weinmann H J. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting. Pre-clinical profile of SH U 555 A.  Acta Radiologica. 1997;  38 584-597
• 9 Widder D J, Greif W L, Widder K J, Edelman R R, Brady T J. Magnetite albumin microspheres: a new MR contrast material.  Am J Roentgenol. 1987;  148 399-404
• 10 Kreft B P, Tanimoto A, Leffler S, Finn J P, Oksendal A N, Stark D D. Contrast-enhanced MR imaging of diffuse and focal splenic disease with use of magnetic starch microspheres.  J Magn Reson Imaging. 1994;  4 373-379
• 11 Saeed M, Wendland M F, Engelbrecht M, Sakuma H, Higgins C B. Value of blood pool contrast agents in magnetic resonance angiography of the pelvis and lower extremities.  Eur Radiol. 1998;  8 1047-1053
• 12 Paeuser S, Reszka R, Wagner S, Wolf K-J, Buhr H-J, Berger G. Liposome-encapsulated superparamagnetic iron oxide particles as markers in an MRI-guided search for tumor-specific drug carriers.  Anti-Cancer Drug Design. 1997;  12 125-135
• 13 Taupitz M, Schnorr J, Abramjuk C, Wagner S, Pilgrimm H, Hunigen H, Hamm B. New generation of monomer-stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: preclinical results in rats and rabbits.  J Magn Reson Imaging. 2000;  12 905-911
• 14 Weissleder R, Stark D D, Engelstad B L, Bacon B R, Campton C C, White D L, Jacobs P, Lewis J. Superparamagnetic iron oxide: pharmacokinetics and toxicity.  Am J Roentgenol. 1989;  152 167-173
• 15 Knollmann F D, Bock J C, Rautenberg K, Beier J, Ebert W, Felix R. Differences in predominant enhancement mechanisms of superparamagnetic iron oxide and ultrasmall superparamagnetic iron oxide for contrast-enhanced portal magnetic resonance angiography: preliminary results of an animal study original investigation.  Invest Radiol. 1998;  33 637-643
• 16 Bremer C, Allkemper T, Baermig J, Reimer P. RES-specific iamging of the liver and spleen with iron oxide particles designed for blood pool MR-angiography.  J Magn Reson Imaging. 1999;  10 461-467
• 17 Oswald P, Clement O, Chambon C, Schouman-Claeys E, Frija G. Liver positive enhancement after injection of superparamagnetic nanoparticles: respective role of circulating and uptaken particles.  Magn Reon Imaging. 1997;  15 1025-1031
• 18 Hamm B, Reichel M, Vogl T, Taupitz M, Wolf K J. Superparamagnetische Eisenpartikel. Klinische Ergebnisse in der MR-Diagnostik von Lebermetastasen.  Fortschr Röntgenstr. 1994;  160 52-58
• 19 Kehagias D T, Gouliamos A D, Smyrniotis V, Vlahos L J. Diagnostic efficacy and safety of MRI of the liver with superparamagnetic iron oxide particles (SH U 555 A).  J Magn Reson Imaging. 2001;  14 595-601
• 20 Müller R D, Vogel K, Neumann K, Hirche H, Barkhausen J, Stoblen F, Henrich H, Langer R. SPIO-MR imaging versus double-phase spiral CT in detecting malignant lesions of the liver.  Acta Radiologica. 1999;  40 628-635
• 21 Ba-Ssalamah A, Heinz-Peer G, Schima W, Schibany N, Schick S, Prokesch R W, Kaider A, Teleky B, Wrba F, Lechner G. Detection of focal hepatic lesions: comparison of unenhanced and SHU 555 A-enhanced MR imaging versus biphasic helical CTAP.  J Magn Reson Imaging. 2000;  11 665-672
• 22 Vogl T J, Hammerstingl R, Pegios W, Hamm B, Eibl-Eibesfeldt A, Woessmer B, Lissner J, Felix R. Wertigkeit des leberspezifischen superparamagnetischen Kontrastmittels AMI-25 für die Detektion und Differentialdiagnose lebereigener Tumoren versus Metastasen.  Fortschr Röntgenstr. 1994;  160 319-328
• 23 Grandin C, Van Beers B E, Robert A, Gigot J F, Geubel A, Pringot J. Benign hepatocellular tumors: MRI after superparamagnetic iron oxide administration.  J Comput Assist Tomogr. 1995;  19 412-418
• 24 Beets-Tan R G, Van Engelshoven J M, Greve J W. Hepatic adenoma and focal nodular hyperplasia: MR findings with superparamagnetic iron oxide-enhanced MRI.  Clin Imag. 1998;  22 211-215
• 25 Bartolotta T V, Midiri M, Galia M, Carcione A, De Maria M, Lagalla R. Benign hepatic tumors: MRI features before and after administration of superparamagnetic contrast media.  Radiologia Medica. 2001;  101 219-229
• 26 Saini S, Edelman R R, Sharma P, Li W, Mayo-Smith W, Slater G J, Eisenberg P J, Hahn P F. Blood-pool MR contrast material for detection and characterization of focal hepatic lesions: initial clinical experience with ultrasmall superparamagnetic iron oxide (AMI-227).  Am J Roentgenol. 1995;  164 1147-1152
• 27 Müller M, Reimer P, Wiedermann D, Allkemper T, Marx C, Tombach B, Rummeny E J, Shamsi K, Balzer T, Peters P E. T₁-gewichtete dynamische MRT mit neuen superparamagnetischen Eisenoxidpartikeln (Resovist): Ergebnisse einer Studie am Phantom sowie an 25 Patienten.  Fortschr Röntgenstr. 1998;  168 228-236
• 28 Saini S, Sharma R, Baron R L, Turner D A, Ros P R, Hahn P F, Small W C, Delange E E, Stillman A E, Edelman R R, Runge V M, Outwater E K. Multicentre dose-ranging study on the efficacy of USPIO ferumoxtran-10 for liver MR imaging.  Clin Radiol. 2000;  55 690-695
• 29 Clement O, Schouman-Claeys E, Frija G. Ferrite particles (AMI25): Influence of cirrhosis and chemotherapy on magnetic resonance imaging of metastasis.  Invest Radiol. 1990;  25 S61-S62
• 30 Kato N, Ihara S, Tsujimoto T, Miyazawa T. Effect of resovist on rats with different severities of liver cirrhosis.  Invest Radiol. 2002;  37 292-298
• 31 Lucidarme O, Baleston F, Cadi M, Bellin M F, Charlotte F, Ratziu V, Grenier P A. Non-invasive detection of liver fibrosis: Is superparamagnetic iron oxide particle-enhanced MR imaging a contributive technique?.  Eur Radiol. 2003;  13 467-474
• 32 Weissleder R, Elizondo G, Josephson L, Compton C C, Fretz C J, Stark D D, Ferrucci J T. Experimental lymph node metastases: enhanced detection with MR lymphography.  Radiology. 1989;  171 835-839
• 33 Hamm B, Taupitz M, Hussmann P, Wagner S, Wolf K J. MR lymphography with iron oxide particles: dose-response studies and pulse sequence optimization in rabbits.  Am J Roentgenol. 1992;  158 183-190
• 34 Taupitz M, Wagner S, Hamm B, Binder A, Pfefferer D. Interstitial MR lymphography with iron oxide particles: results in tumor-free and VX2 tumor-bearing rabbits.  Am J Roentgenol. 1993;  161 193-200
• 35 Weissleder R, Elizondo G, Wittenberg J, Lee A S, Josephson L, Brady T J. Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging.  Radiology. 1990;  175 494-498
• 36 Weissleder R, Elizondo G, Wittenberg J, Rabito C A, Bengele H H, Josephson L. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging.  Radiology. 1990;  175 489-493
• 37 Mühler A, Zhang X, Wang H, Lawaczeck R, Weinmann H J. Investigation of mechanisms influencing the accumulation of ultrasmall superparamagnetic iron oxide particles in lymph nodes.  Invest Radiol. 1995;  30 98-103
• 38 Elste V, Wagner S, Taupitz M, Pfefferer D, Kresse M, Hamm B, Berg R, Wolf K J, Semmler W. Magnetic resonance lymphography in rats: effects of muscular activity and hyperthermia on the lymph node uptake of intravenously injected superparamagnetic iron oxide particles.  Acad Radiol. 1996;  3 660-666
• 39 Clement O, Rety F, Cuenod C A, Siauve N, Carnot F, Bordat C, Siche M, Frija G. MR lymphography: evidence of extravasation of superparamagnetic nanoparticles into the lymph. Discussion S 183 - S 184.  Acad Radiol. 1998;  5 (Suppl 1) S170-S 172
• 40 Rety F, Clement O, Siauve N, Cuenod C A, Carnot F, Sich M, Buisine A, Frija G. MR lymphography using iron oxide nanoparticles in rats: pharmacokinetics in the lymphatic system after intravenous injection.  J Magn Reson Imaging. 2000;  12 734-739
• 41 Wagner S, Pfefferer D, Ebert W, Kresse M, Taupitz M, Hamm B, Lawaczeck R, Wolf K J. Intravenous MR lymphography with superparamagnetic iron oxide particles: Experimental studies in rats and rabbits.  Eur Radiol. 1995;  5 640-646
• 42 Bellin M F, Roy C, Kinkel K, Thoumas D, Zaim S, Vanel D, Tuchmann C, Richard F, Jacqmin D, Delcourt A, Challier E, Lebret T, Cluzel P. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles - initial clinical experience.  Radiology. 1998;  207 799-808
• 43 Harisinghani M G, Saini S, Weissleder R, Hahn P F, Yantiss R K, Tempany C, Wood B J, Mueller P R. MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic-pathologic correlation.  Am J Roentgenol. 1999;  172 1347-1351
• 44 Hoffman H T, Quets J, Toshiaki T, Funk G F, McCulloch T M, Graham S M, Robinson R A, Schuster M E, Yuh W T. Functional magnetic resonance imaging using iron oxide particles in characterizing head and neck adenopathy.  Laryngoscope. 2000;  110 1425-1430
• 45 Hudgins P A, Anzai Y, Morris M R, Lucas M A. Ferumoxtran-10, a superparamagnetic iron oxide as a magnetic resonance enhancement agent for imaging lymph nodes: a phase 2 dose study.  Am J Neuroradiol. 2002;  23 649-656
• 46 Mack M G, Balzer J O, Straub R, Eichler K, Vogl T J. Superparamagnetic iron oxide-enhanced MR imaging of head and neck lymph nodes.  Radiology. 2002;  222 239-244
• 47 Harisinghani M G, Saini S, Slater G J, Schnall M D, Rifkin M D. MR imaging of pelvic lymph nodes in primary pelvic carcinoma with ultrasmall superparamagnetic iron oxide (Combidex): preliminary observations.  J Magn Reson Imaging. 1997;  7 161-163
• 48 Pannu H K, Wang K P, Borman T L, Bluemke D A. MR imaging of mediastinal lymph nodes: evaluation using a superparamagnetic contrast agent.  J Magn Reson Imaging. 2000;  12 899-904
• 49 Sigal R, Vogl T, Casselman J, Moulin G, Veillon F, Hermans R, Dubrulle F, Viala J, Bosq J, Mack M, Depondt M, Mattelaer C, Petit P, Champsaur P, Riehm S, Dadashitazehozi Y, de Jaegere T, Marchal G, Chevalier D, Lemaitre L, Kubiak C, Helmberger R, Halimi P. Lymph node metastases from head and neck squamous cell carcinoma: MR imaging with ultrasmall superparamagnetic iron oxide particles (Sinerem MR) - results of a phase-III multicenter clinical trial.  Eur Radiol. 2002;  12 1104-1113
• 50 Seneterre E, Weissleder R, Jaramillo D, Reimer P, Lee A S, Brady T J, Wittenberg J. Bone marrow: ultrasmall superparamagnetic iron oxide for MR imaging.  Radiology. 1991;  179 529-533
• 51 Daldrup-Link H E, Rummeny E J, Ihssen B, Kienast J, Link T M. Iron-oxide-enhanced MR imaging of bone marrow in patients with non-Hodgkin's lymphoma: differentiation between tumor infiltration and hypercellular bone marrow.  Eur Radiol. 2002;  12 1557-1566
• 52 Daldrup H E, Link T M, Blasius S, Strozyk A, Konemann S, Jurgens H, Rummeny E J. Monitoring radiation-induced changes in bone marrow histopathology with ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI.  J Magn Reson Imaging. 1999;  9 643-652
• 53 Daldrup-Link H E, Reinlander C, Link T M, Richter K J, Konemann S, Rummeny E J. Experimentelle Untersuchungen zur Wertigkeit von SPIO für die MRT des Knochenmarks vor und nach Ganzkörperbestrahlung.  Fortschr Röntgenstr. 2001;  173 547-553
• 54 Fleige G, Nolte C, Synowitz M, Seeberger F, Kettenmann H, Zimmer C. Magnetic labeling of activated microglia in experimental gliomas.  Neoplasia. 2001;  3 489-499
• 55 Beckmann N, Joergensen J, Bruttel K, Rudin M, Schuurman H J. Magnetic resonance imaging for the evaluation of rejection of a kidney allograft in the rat.  Transplant International. 1996;  9 175-183
• 56 Kanno S, Lee P C, Dodd S J, Williams M, Griffith B P, Ho C. A novel approach with magnetic resonance imaging used for the detection of lung allograft rejection.  J Thorac Cardiovasc Surg. 2000;  120 923-934
• 57 Kanno S, Wu Y J, Lee P C, Dodd S J, Williams M, Griffith B P, Ho C. Macrophage accumulation associated with rat cardiac allograft rejection detected by magnetic resonance imaging with ultrasmall superparamagnetic iron oxide particles.  Circulation. 2001;  104 934-938
• 58 Mühler A, Freise C E, Kuwatsuru R, Rosenau W, Liu T, Mintorovitch J, Clement O, Vexler V, Mahboubi S, Lang P. Acute liver rejection: evaluation with cell-directed MR contrast agents in a rat transplantation model.  Radiology. 1993;  186 139-146
• 59 Allkemper T, Bremer C, Matuszewski L, Ebert W, Reimer P. Contrast-enhanced blood-pool MR angiography with optimized iron oxides: effect of size and dose on vascular contrast enhancement in rabbits.  Radiology. 2002;  223 432-438
• 60 Urhahn R, Adam G, Busch N, Chen J H, Euringer W, Gunther R A. Superparamagnetische Eisenoxidpartikel: Welchen Stellenwert hat der T₁-Effekt für die MR-Diagnostik fokaler Leberläsionen?.  Fortschr Röntgenstr. 1996;  165 364-370
• 61 Knollmann F D, Böck J C, Teltenkotter S, Wlodarczyk W, Mühler A, Vogl T J, Felix R. Evaluation of portal MR angiography using superparamagnetic iron oxide.  J Magn Reson Imaging. 1997;  7 191-196
• 62 Reimer P, Marx C, Rummeny E J, Muller M, Lentschig M, Balzer T, Dietl K H, Sulkowski U, Berns T, Shamsi K, Peters P E. SPIO-enhanced 2D-TOF MR angiography of the portal venous system: results of an intraindividual comparison.  J Magn Reson Imaging. 1997;  7 945-949
• 63 Schmitz S A, Albrecht T, Jensen K, Wolf K J. SPIO-unterstützte MR- Angiographie des portalvenösen Systems.  Fortschr Röntgenstr. 2000;  172 51-54
• 64 Schmitz S A, Albrecht T, Wolf K J. MR angiography with superparamagnetic iron oxide: feasibility study.  Radiology. 1999;  213 603-607
• 65 Clarke S E, Weinmann H J, Dai E, Lucas A R, Rutt B K. Comparison of two blood pool contrast agents for 0.5-T MR angiography: experimental study in rabbits.  Radiology. 2000;  214 787-794
• 66 Kellar K E, Fujii D K, Gunther W H, Briley-Saebo K, Spiller M, Koenig S H. „NC100150”, a preparation of iron oxide nanoparticles ideal for positive-contrast MR angiography.  MAGMA. 1999;  8 207-213
• 67 Stillman A E, Wilke N, Li D, Haacke M, McLachlan S. Ultrasmall superparamagnetic iron oxide to enhance MRA of the renal and coronary arteries: studies in human patients.  J Comput Assist Tomogr. 1996;  20 51-55
• 68 Hofman M B, Henson R E, Kovacs S J, Fischer S E, Lauffer R B, Adzamli K, De Becker J, Wickline S A, Lorenz C H. Blood pool agent strongly improves 3D magnetic resonance coronary angiography using an inversion pre-pulse.  Magn Reson Med. 1999;  41 360-367
• 69 Johansson L O, Nolan M M, Taniuchi M, Fischer S E, Wickline S A, Lorenz C H. High-resolution magnetic resonance coronary angiography of the entire heart using a new blood-pool agent, NC100150 injection: comparison with invasive x-ray angiography in pigs.  J Cardiovasc Magn Reson. 1999;  1 139-143
• 70 Taupitz M, Schnorr J, Wagner S, Abramjuk C, Pilgrimm H, Kivelitz D, Schink T, Hansel J, Laub G, Hunigen H, Hamm B. Coronary MR angiography: experimental results with a monomer-stabilized blood pool contrast medium.  Radiology. 2002;  222 120-126
• 71 Sandstede J J, Pabst T, Wacker C, Wiesmann F, Hoffmann V, Beer M, Kenn W, Bauer W, Hahn D. Breath-hold 3D MR coronary angiography with a new intravascular contrast agent (feruglose) - first clinical experiences.  Magn Reson Imaging. 2001;  19 201-205
• 72 Bedaux W L, Hofman W B, Wielopolski P A, de Cock C C, Hoffmann V, Oudkerk M, de Feyter P J, van Rossum A C. Three-dimensional magnetic resonance coronary angiography using a new blood pool contrast agent: initial experience.  J Cardiovasc Magn Reson. 2002;  4 273-282
• 73 Knuesel P R, Nanz D, Wolfensberger U, Saranathan M, Lehning A, Luescher T F, Marincek B, Von Schulthess G K, Schwitter J. Multislice breath-hold spiral magnetic resonance coronary angiography in patients with coronary artery disease: Effect of intravascular contrast medium.  J Magn Reson Imaging. 2002;  16 660-667
• 74 Amano Y, Herfkens R J, Shifrin R Y, Alley M T, Pelc N J. Three-dimensional cardiac cine magnetic resonance imaging with an ultrasmall superparamagnetic iron oxide blood pool agent (NC100150).  J Magn Reson Imaging. 2000;  11 81-86
• 75 Schmitz S A, Coupland S E, Gust R, Winterhalter S, Wagner S, Kresse M, Semmler W, Wolf K J. Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits.  Invest Radiol. 2000;  35 460-471
• 76 Ruehm S G, Corot C, Vogt P, Kolb S, Debatin J F. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits.  Circulation. 2001;  103 415-422
• 77 Schmitz S A, Taupitz M, Wagner S, Wolf K J, Beyersdorff D, Hamm B. Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles.  J Magn Reson Imaging. 2001;  14 355-361
• 78 Schmitz S A, Winterhalter S, Schiffler S, Gust R, Wagner S, Kresse M, Coupland S E, Semmler W, Wolf K J. USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits.  Radiology. 2001;  221 237-243
• 79 Johansson L O, Bjornerud A, Ahlstrom H K, Ladd D L, Fujii D K. A targeted contrast agent for magnetic resonance imaging of thrombus: implications of spatial resolution.  J Magn Reson Imaging. 2001;  13 615-618
• 80 Wacker F K, Reither K, Ebert W, Wendt M, Lewin J S, Wolf K J. MR Image-guided Endovascular Procedures with the Ultrasmall Superparamagnetic Iron Oxide SH U 555 C as an Intravascular Contrast Agent: Study in Pigs.  Radiology. 2003;  226 459-464
• 81 Weishaupt D, Hilfiker P R, Schmidt M, Debatin J F. Pulmonary hemorrhage: imaging with a new magnetic resonance blood pool agent in conjunction with breathhold three-dimensional magnetic resonance angiography.  Cardiovasc Intervent Radiol. 1999;  22 321-325
• 82 Turetschek K, Huber S, Floyd E, Helbich T, Roberts T P, Shames D M, Tarlo K S, Wendland M F, Brasch R C. MR imaging characterization of microvessels in experimental breast tumors by using a particulate contrast agent with histopathologic correlation.  Radiology. 2001;  218 562-569
• 83 Turetschek K, Huber S, Helbich T, Floyd E, Tarlo K S, Roberts T PL, Shames D M, Wendland M F, Brasch R C. Dynamic MRI enhanced with albumin-(Gd-DTPA)30 or ultrasmall superparamagnetic iron oxide particles (NC100150 injection) for the measurement of microvessel permeability in experimental breast tumors.  Acad Radiol. 2002;  9 (Suppl 1) S 112-S 114
• 84 Turetschek K, Roberts T P, Floyd E, Preda A, Novikov V, Shames D M, Carter W O, Brasch R C. Tumor microvascular characterization using ultrasmall superparamagnetic iron oxide particles (USPIO) in an experimental breast cancer model.  J Magn Reson Imaging. 2001;  13 882-888
• 85 Daldrup-Link H E, Brasch R C. Macromolecular contrast agents for MR mammography: current status.  Eur Radiol. 2003;  13 354-365
• 86 Ichikawa T, Arbab A S, Araki T, Touyama K, Haradome H, Hachiya J, Yamaguchi M, Kumagai H, Aoki S. Perfusion MR imaging with a superparamagnetic iron oxide using T₂-weighted and susceptibility-sensitive echoplanar sequences: evaluation of tumor vascularity in hepatocellular carcinoma.  Am J Roentgenol. 1999;  173 207-213
• 87 Rozenman Y, Zou X M, Kantor H L. Magnetic resonance imaging with superparamagnetic iron oxide particles for the detection of myocardial reperfusion.  Magn Reson Imaging. 1991;  9 933-939
• 88 Bjerner T, Johansson L, Ericsson A, Wirkstrom G, Hemmingsson A, Ahlstrom H. First-pass myocardial perfusion MR imaging with outer-volume suppression and the intravascular contrast agent NC100150 injection: preliminary results in eight patients.  Radiology. 2001;  221 822-826
• 89 Panting J R, Taylor A M, Gatehouse P D, Keegan J, Yang G Z, McGill S, Francis J M, Burman E D, Firmin D N, Pennell D J. First-pass myocardial perfusion imaging and equilibrium signal changes using the intravascular contrast agent NC100150 injection.  J Magn Reson Imaging. 1999;  10 404-410
• 90 Bjerner T, Ericsson A, Wikstrom G, Johansson L, Nilsson S, Ahlstrom H, Hemmingsson A. Evaluation of nonperfused myocardial ischemia with MRI and an intravascular USPIO contrast agent in an ex vivo pig model.  J Magn Reson Imaging. 2000;  12 866-872
• 91 Weissleder R, Reimer P, Lee A S, Wittenberg J, Brady T J. MR receptor imaging: ultrasmall iron oxide particles targeted to asialoglycoprotein receptors.  Am J Roentgenol. 1990;  155 1161-1167
• 92 Schaffer B K, Linker C, Papisov M, Tsai E, Nossiff N, Shibata T, Bogdanov A, Brady T J, Weissleder R. MION-ASF: biokinetics of an MR receptor agent.  Magn Reson Imaging. 1993;  11 411-417
• 93 Reimer P, Weissleder R, Lee A S, Wittenberg J, Brady T J. Receptor imaging: application to MR imaging of liver cancer.  Radiology. 1990;  177 729-734
• 94 Reimer P, Weissleder R, Brady T J, Yeager A E, Baldwin B H, Tennant B C, Wittenberg J. Experimental hepatocellular carcinoma: MR receptor imaging.  Radiology. 1991;  180 641-645
• 95 Leveille-Webster C R, Rogers J, Arias I M. Use of an asialoglycoprotein receptor-targeted magnetic resonance contrast agent to study changes in receptor biology during liver regeneration and endotoxemia in rats.  Hepatology. 1996;  23 1631-1641
• 96 Reimer P, Weissleder R, Shen T, Knoefel W T, Brady T J. Pancreatic receptors. Initial feasibility studies with a targeted contrast agent for MR imaging.  Radiology. 1994;  193 527-531
• 97 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
• 98 Schellenberger E A, Bogdanov A, Hogemann D, Tait J, Weissleder R, Josephson L. Annexin V-CLIO: an nanoparticle for detecting apoptosis by MRI.  Molecular Imaging. 2002;  1 102-107
• 99 Zhang Y, Kohler N, Zhang M. Intracellular uptake of poyl(ethylene glycol) and folic acid modified magnetite nanoparticles.  Mat Res Soc Symp Proceedings. 2002;  676 Y 981-Y 985
• 100 Cerdan S, Lotscher H R, Kunnecke B, Seelig J. Monoclonal antibody-coated magnetite particles as contrast agents in magnetic resonance imaging of tumors.  Magn Reson Med. 1989;  12 151-163
• 101 Remsen L G, McCormick C I, Roman-Goldstein S, Nilaver G, Weissleder R, Bogdanov A, Hellstrom I, Kroll R A, Neuweit E A. MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis.  Am J Neuroradiol. 1996;  17 411-418
• 102 Weissleder R, Lee A S, Fischman A J, Reimer P, Shen T, Wilkinson R, Callahan R J, Brady T J. Polyclonal human immunoglobulin G labeled with polymeric iron oxide: antibody MR imaging.  Radiology. 191;  181 245-249
• 103 Weissleder R, Lee A S, Khaw B A, Shen T, Brady T J. Antimyosin-labeled monocrystalline iron oxide allows detection of myocardial infarct: MR antibody imaging.  Radiology. 1992;  182 381-385
• 104 Kang H W, Josephson L, Petrovsky A, Weissleder R, Bogdanov A. Magnetic Resonance Imaging of Inducible E-Selectin Expression in Human Endothelial Cell Culture.  Bioconjugate Chemistry. 2002;  13 122-127
• 105 Tiefenauer L X, Kuehne G, Andres R Y. Antibody-magnetite nanoparticles: In vitro characterization of a potential tumor-specific contrast agent for magnetic resonance imaging.  Bioconjugate Chemistry. 1993;  4 347-352
• 106 Suzuki M, Honda H, Kobayashi T, Wakabayashi T, Yoshida J, Takahashi M. Development of a target-directed magnetic resonance contrast agent using monoclonal antibody-conjugated magnetic particles.  Noshuyo Byori. 1996;  13 127-132
• 107 Suwa T, Ozawa S, Ueda M, Ando N, Kitajima M. Magnetic resonance imaging of esophageal squamous cell carcinoma using magnetite particles coated with anti-epidermal growth factor receptor antibody.  Int J Cancer. 1998;  75 626-634
• 108 Schulze E, Ferrucci J T, Poss K, Lapointe L, Bogdanova A, Weissleder R. Cellular uptake and trafficking of a prototypical magnetic iron oxide label in vitro.  Invest Radiol. 1995;  30 604-610
• 109 Weissleder R, Cheng H C, Bogdanova A, Bogdanova A J. Magnetically labeled cells can be detected by MR imaging.  J Magn Reson Imaging. 1997;  7 258-263
• 110 Fleige G, Seeberger F, Laux D, Kresse M, Taupitz M, Pilgrimm H, Zimmer C. In Vitro Characterization of Two Different Ultrasmall Iron Oxide Particles for Magnetic Resonance Cell Tracking.  Invest Radiol. 2002;  37 482-488
• 111 Franklin R J, Blaschuk K L, Bearchell M C, Prestoz L L, Setzu A, Brindle K M. FrenchConstant C: Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain.  Neuroreport. 1999;  10 3961-3965
• 112 Lewin M, Carlesso N, Tung C H, Tang X W, Cory D, Scadden D T, Weissleder R. Tat peptide derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.  Nature Biotechnology. 2000;  18 410-414
• 113 Bulte J WM, Douglas T, Witwer B, Zhang S-C, Strable E, Lewis B K, Zywicke H, Miller B, van Gelderen P, Moskowitz B M, Duncan L D, Frank J A. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells.  Nature Biotechnology. 2001;  19 1141-1147
• 114 Bulte J WM, Duncan I D, Frank J A. In vivo magnetic resonance tracking of magnetically labeled cells after transplantation.  J Cerebr Blood Flow Metabol. 2002;  22 899-907
• 115 Chan T W, Eley C, Liberti P, So A, Kressel H Y. Magnetic resonance imaging of abscesses using lipid-coated iron oxide particles.  Invest Radiol. 1992;  27 443-449
• 116 Yeh T C, Zhang W, Ilstad S T, Ho C. Intracellular labeling of T-cells with superparamagnetic contrast agents.  Magn Reson Med. 1993;  30 617-625
• 117 Krieg F M, Andres R Y, Winterhalter K H. Superparamagnetically labelled neutrophils as potential abscess-specific contrast agent for MRI.  Magn Reson Imaging. 1995;  13 393-400
• 118 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
• 119 Lonnemark M, Hemmingsson A, Bach-Gansmo T, Ericsson A, Oksendal A, Nyman R, Moxnes A. Effect of superparamagnetic particles as oral contrast medium at magnetic resonance imaging. A phase I clinical study.  Acta Radiologica. 1989;  30 193-196
• 120 Briggs R W, Wu Z, Mladinich C RJ, Stoupis C, Gauger J, Liebig T, Ros P R, Ballinger J R, Kubilis P. In vivo animal tests of an artifact-free contrast agent for gastrointestinal MRI.  Magn Reson Imaging. 1997;  15 559-566
• 121 D'Arienzo A, Scaglione G, Vicinanza G, Manguso F, Bennato R, Belfiore G, Imbriaco M, Mazzacca G. Magnetic resonance imaging with ferumoxil, a negative superparamagnetic oral contrast agent, in the evaluation of ulcerative colitis.  Am J Gastroenterol. 2000;  95 720-724
• 122 Pauser S, Reszka R, Wagner S, Wolf K J, Buhr H J, Berger G. Liposome-encapsulated superparamagnetic iron oxide particles as markers in an MRI-guided search for tumor-specific drug carriers.  Anti-Cancer Drug Design. 1997;  12 125-135
• 123 Kim D K, Zhang Y, Voit W, Rao K V, Kehr J, Bjelke B, Muhammed M. Superparamagnetic iron oxide nanoparticles for bio-medical applications.  Scripta Materialia. 2001;  44 1713-1717
• 124 Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca E A, Basilion J P. In vivo magnetic resonance imaging of transgene expression.  Nature Medicine. 2000;  6 351-354
• 125 Scherer F, Anton M, Schillinger U, Henke J, Bergemann C, Kruger A, Gansbacher B, Plank C. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo.  Gene Therapy. 2002;  9 102-109
• 126 von Ardenne M, Kirsch R. (On the methodology of extreme hyperthermia, with special reference to multi-step cancer chemotherapy).  Dtsch Gesundheitsw. 1965;  20 1935-1940 contd
• 127 Sako M, Hirota S. Embolotherapy of hepatomas using ferromagnetic microspheres, its clinical evaluation and the prospect of its use as a vehicle in chemoembolo-hyperthermic therapy.  Gan to Kagaku Ryoho (Japanese J Cancer Chemother). 1986;  13 1618-1624
• 128 Moroz P, Jones S K, Winter J, Gray B N. Targeting liver tumors with hyperthermia: Ferromagnetic embolization in a rabbit liver tumor model.  J Surg Oncol. 2001;  78 22-29
• 129 Moroz P, Jones S K, Gray B N. Tumor response to arterial embolization hyperthermia and direct injection hyperthermia in a rabbit liver tumor model.  J Surg Oncol. 2002;  80 149-156
• 130 Jung C W, Jacobs P. Physical and chemical properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil.  Magn Reson Imaging. 1995;  13 661-674
• 131 Tanimoto A, Yuasa Y, Hiramatsu K. Enhancement of phase-contrast MR angiography with superparamagnetic iron oxide.  J Magn Reson Imaging. 1998;  8 446-450
• 132 Wagner S, Schnorr J, Pilgrim H, Hamm B, Taupitz M. Monomer-coated very small superparamagnetic iron oxide particles as contrast medium for magnetic resonance imaging: Preclinical in vivo characterization.  Invest Radiol. 2002;  37 167-177