Angewandte

Chemie

DOI: 10.1002/anie.200604775
Imaging Agents

Development of a T1 Contrast Agent for Magnetic Resonance Imaging

Using MnO Nanoparticles**
Hyon Bin Na, Jung Hee Lee,* Kwangjin An, Yong Il Park, Mihyun Park, In Su Lee,
Do-Hyun Nam, Sung Tae Kim, Seung-Hoon Kim, Sang-Wook Kim, Keun-Ho Lim,
Ki-Soo Kim, Sun-Ok Kim, and Taeghwan Hyeon*

Nanometer-sized colloidal particles (nanoparticles) have tum dots) have been applied as fluorescent probes for cell
been extensively used in biomedical applications as a result labeling in optical imaging,[2] and gold nanoparticles derivat-
of their many useful electronic, optical, and magnetic proper- ized with oligonucleotides have been used for sensing
ties that are derived from their nanometer size and compo- complementary DNA strands.[3] Magnetic nanoparticles
sition.[1] Semiconductor nanoparticles (also known as quan- have been applied to contrast-enhancement agents for
magnetic resonance imaging (MRI), magnetic carriers for
drug-delivery systems, biosensors, and bioseparation.[4]
[*] Prof. J. H. Lee, Prof. S. T. Kim, Prof. S.-H. Kim MRI is one of the most powerful imaging techniques for
Department of Radiology, Samsung Medical Center living organisms as it provides images with excellent anatom-
Sungkyunkwan University School of Medicine ical details based on soft-tissue contrast and functional
Seoul 135-710 (Korea)
information in a non-invasive and real-time monitoring
Fax: (+ 82) 2-3410-0084
E-mail: junghee42.lee@smc.samsung.co.kr manner.[5] MRI has further advanced by the development of
H. B. Na, K. An, Y. I. Park, M. Park, Prof. T. Hyeon
contrast agents that enable more specific and clearer images
National Creative Research Initiative Center for Oxide Nanocrys- and enlargements of detectable organs and systems, leading to
talline Materials and School of Chemical and Biological Engineering a wide scope of applications of MRI not only for diagnostic
Seoul National University radiology but also for therapeutic medicine. Current MRI
Seoul 151-744 (Korea) contrast agents are in the form of either paramagnetic
Fax: (+ 82) 2-886-8457 complexes or magnetic nanoparticles.[6] Paramagnetic com-
E-mail: thyeon@snu.ac.kr
plexes, which are usually gadolinium (Gd3+) or manganese
Prof. I. S. Lee
(Mn2+) chelates, accelerate longitudinal (T1) relaxation of
Department of Chemistry and Advanced Material Science
Kyunghee University, Yongin 446-701 (Korea)
water protons and exert bright contrast in regions where the
complexes localize.[7] For instance, gadolinium diethylene-
Prof. D.-H. Nam
Department of Neurosurgery, Samsung Medical Center triaminepentaacetate (Gd-DTPA) has been the most widely
Sungkyunkwan University School of Medicine used of such complexes and its main clinical applications are
Seoul 135-710 (Korea) focused on detecting the breakage of the blood-brain barrier
Prof. S.-W. Kim (BBB) and changes in vascularity, flow dynamics, and
Department of Molecular Science and Technology perfusion.[8] Manganese-enhanced MRI (MEMRI), which
Ajou University, Suwon 443-749 (Korea) uses manganese ion (Mn2+) as a T1 contrast agent, is
K.-H. Lim applicable to animals only owing to the toxicity of Mn2+
NMR Laboratory, Asan Institutes for Life Science when it accumulates excessively in tissues and despite the
University of Ulsan, Seoul 138-736 (Korea)
increasing appreciation of this technique in neuroscience
Prof. K.-S. Kim research.[9]
Department of Pediatrics, Asan Medical Center
The recent development of molecular and cellular imag-
University of Ulsan, Seoul 138-736 (Korea)
ing to help visualize disease-specific biomarkers at the
Dr. S.-O. Kim
Biology and Clinical Pharmacology, Samyang R&D Center molecular and cellular levels has led to an increased interest
Daejeon 305-717 (Korea) in magnetic nanoparticles as MRI contrast agents. In partic-
[**] T.H. thanks the Korean Ministry of Science and Technology for ular, superparamagnetic iron oxide (SPIO) has emerged as
financial support through the National Creative Research Initiative the prevailing agent so far.[4, 10] However, the negative contrast
Program of the Korea Science and Engineering Foundation effect and magnetic susceptibility artifacts of iron oxide
(KOSEF). J.H.L. was supported by the Center for Biological nanoparticles are significant drawbacks of using SPIO in
Modulators of the 21st Century Frontier R&D Program. We thank MRI. The resulting dark signal can mislead the clinical
Sungman Jang and Heesouk Woo at the Samsung Medical Center
diagnosis in T2-weighted MRI because the signal is often
for help in the MRI measurements and TEM studies. We thank Dr.
Alan P. Koretsky at NINDS, NIH, and Dr. Seong-Gi Kim at the confused with the signals from bleeding, calcification, or
University of Pittsburgh for useful discussions. T1 refers to the metal deposits, and the susceptibility artifacts distort the
longitudinal relaxation time of water protons. background image.[4b]
Supporting information for this article is available on the WWW For the extensive applications of MRI to diagnostic
under http://www.angewandte.org or from the author. radiology and therapeutic medicine and to overcome the

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2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5397
Communications
above-mentioned drawbacks of Gd3+- and Mn2+-based T1
contrast agents and SPIO-based T2 contrast agents, there
has been great demand for a new class of contrast agent that
satisfies the following characteristics: 1) positive (T1) contrast
ability, 2) intracellular uptake and accumulation for imaging
cellular distribution and functions, 3) nanoparticulate form
for easy surface modification and efficient labeling with
targeting agents for applications in molecular and cellular
imaging, and 4) favorable pharmacokinetics and dynamics for
easy delivery, efficient distribution to biomarkers, and safe
clearance from patients with minimal side effects. Here, we
report the development of a long-awaited T1 MRI contrast
agent that satisfies all of these desirable characteristics using
MnO nanoparticles.
Water-dispersible and biocompatible MnO nanoparticles
were prepared according to a reported method with some
modifications.[11, 12] First, uniformly sized MnO nanoparticles
(see Supporting Information) dispersed in nonpolar organic
solvent were synthesized by the thermal decomposition of
Mn-oleate complex.[11a] The particle size was controlled by
varying either the solvent or reaction time. The resulting
Figure 1. a) TEM images of water-dispersible MnO nanoparticles with
MnO nanoparticles dispersed in chloroform were then
particle sizes of 7, 15, 20, and 25 nm. b) T1-weighted MR image of
encapsulated in a polyethyleneglycol(PEG)-phospholipid MnO nanoparticles from a 3.0 T clinical MRI system.
shell to make them biocompatible.[12] Figure 1 a shows the
transmission electron microscopy (TEM) images of uniform
and water-dispersed MnO nanoparticles of various sizes. They specific relaxivity (change in the relaxation rate per unit
were highly crystalline and stable in water; they showed no concentration of an agent, meaning effectiveness as a MRI
degradation or aggregation in water over several months. contrast agent) is generally determined by measuring the
They are antiferromagnetic (see Supporting Information), relaxation rate as a function of concentration of the metal
which means that they do not exert the susceptibility artifacts ions. We calculated the specific relaxivity (r1) of the MnO
in MRI as observed with the SPIO-based T2 agent. nanoparticles with the different particle sizes (Table 1 and
To examine the possibility of using MnO nanoparticles as Supporting Information). Contrary to expectations, the r1
a MRI contrast agent, we measured relaxation times at a 3.0 T value was found to be higher for the smaller MnO nano-
human clinical scanner of the size-tuned nanoparticles particles. Consequently, we defined another form of relaxivity
prepared in test tubes. As shown in Figure 1 b, MnO nano- (r1(N)) based on the number of nanoparticles, given that the
particles with particle sizes of 7, 15, 20, and 25 nm at the same number of nanoparticles decreases as the size of the nano-
concentration of 5 mm (based on Mn concentration measured particles increases at the same metal content. The r1(N) value is
by inductively coupled plasma atomic emission spectroscopy higher for the larger MnO nanoparticles. Although the exact
(ICP-AES)) clearly showed bright signal enhancement in the knowledge of the contrast-enhancement mechanism of MnO
T1-weighted MRI, thus manifesting their potential applica- nanoparticles requires further investigation, we could spec-
tions as a T1 contrast agent. The smaller the size of the ulate that the paramagnetic Mn2+ ions on the surface of the
nanoparticles, the brighter the signal is in the T1-weighted MR nanoparticles seem to be responsible for the shortening of the
image, which indicates that the T1 shortening effect increases T1 relaxation times. This hypothesis is further supported by
as the size of the nanoparticles decreases (Table 1). The MnO the fact that another calculated relaxivity (r1(S)) based on the
nanoparticles clearly decreased both the longitudinal relax- total surface area of the nanoparticles is independent of the
ation time (T1) and the transverse relaxation time (T2). size of the nanoparticles. Furthermore, the r1 value of the
To further investigate the contrast effect, we measured the MnO/SiO2 coreshell nanoparticles (see TEM image in the
specific relaxivities (r1 or r2) of the MnO nanoparticles. The Supporting Information) was far lower than that of MnO

Table 1: Relaxation properties of the MnO nanoparticles.

Nanoparticle Longitudinal relaxation Transversal relaxation
size T1[a] r1 r1(N) r1(S) T2[a] r2 r2(N) r2(S)
[nm] [ms] [mm 1 s 1] [mm 1 s 1] [m s 1] [ms] [mm 1 s 1] [mm 1 s 1] [m s 1]
7 481 0.37 3 33 85 1.74 14 154
15 624 0.18 15 34 95 0.57 46 121
20 707 0.13 25 33 120 0.52 99 102
25 752 0.12 46 39 132 0.44 165 139
[a] The longitudinal (T1) and transverse (T2) relaxation times were measured at 5 mm Mn (as measured by ICP-AES).

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 Angewandte
Chemie

nanoparticles, whereas the r2 values of these two kinds of 25 nm. In the T1-weighted MONEMRI of the brain (Fig-
nanoparticles were nearly the same (see Supporting Informa- ure 2 b and Supporting Information), the three orientations of
tion). the mouse brain show contrast-enhanced regions following
For in vivo MRI imaging, the 25 nm water-dispersible accumulation of MnO nanoparticles in the tissues which were
MnO nanoparticles (35 mg Mn (measured by ICP-AES) per clearly observed in the TEM image of the cortex obtained
kg of mouse body weight) were bolus-injected (rapid single 72 h after the injection (Figure 2 f, g and Supporting Informa-
shot) into a mouse through its tail vein. The body weights and tion). In comparison with non-contrast-enhanced images
possible changes in behavior of the animals were monitored (Figure 2 a), anatomic structures were clearly revealed in
for 3 weeks after the injection, and no signs of weight loss or the brain. Interestingly, no appreciable contrast enhancement
abnormal behaviors were observed (see Supporting Informa- in T2-weighted MRI was observed at the concentration of
tion). The cytotoxicity of MnO nanoparticles was evaluated in agent used in this study, despite the T2 shortening effect in the
eight human cell lines originating from various tissues. No in vitro measurement. The hippocampus structure, cortical
appreciable toxicity was observed with a MnO concentration layers, olfactory bulb layers, and cerebella gray matters
of less than 0.82 mm (based on the Mn concentration (zoomed images in Figure 2 cf) are distinctively depicted in
measured by ICP-AES) in human normal and cancer cell the MONEMRI. Such excellent brain MRI images that depict
lines such as lung fibroblast, embryonic kidney, and glioblas- clear anatomic structures were previously only obtained using
toma cells or at a MnO concentration of 82 mm in hepatoma, MEMRI, although a large dose of MnCl2 was needed and
large-cell lung cancer, breast adenocarcinoma, prostate injected slowly because of its low sensitivity and high
adenocarcinoma, and leukemia cells (see Supporting Infor- toxicity.[9] This clear anatomic imaging of various brain
mation). structures suggests potential applications not only for basic
Figure 2 shows the manganese oxide nanoparticle con- neuroscience research but also for managing clinical neuro-
trast-enhanced T1-weighted MRI (designated as MONE- logical diseases such as neurodegenerative diseases, including
MRI) of a mouse using the nanoparticles with a core size of AlzheimerDs disease and ParkinsonDs disease, and other
diseases that are accompanied by disturbances in neural cell
structures without disturbing the blood brain barrier, includ-
ing epilepsy and cortical dysplasia.
The fine anatomic structures of the renal pelvis, medullar,
and cortex were clearly revealed in kidney and the liver
parenchyma, thus indicating the intracellular uptake of the
nanoparticles in these organs as is supported by the TEM
images (Figures S6 and S8 in the Supporting Information).
The gray matter of the spinal cord was also clearly enhanced,
a task that is very challenging in diagnostic radiology for
managing neurodegenerative diseases.
For the selective imaging of disease-specific biomarkers in
brain disease, in which T1 contrast agents will certainly
outperform SPIO-based T2 contrast agents, we prepared
functionalized MnO nanoparticles by conjugating them with
Her-2/neu receptor antibody (Herceptin, Roche Pharma Ltd.)
to selectively target the epidermal growth factor receptors
(EGFRs) that are expressed at the cell surfaces of breast
cancer. Figure 3 a shows a series of MRI images of mouse
brain bearing the breast cancer brain metastatic tumor that
was intravenously injected with the Herceptin-functionalized
MnO nanoparticles. The breast cancer cells were selectively
enhanced in T1-weighted MRI because the functionalized
MnO nanoparticles with the EGFR-specific antibody were
delivered and accumulated at the EGFR of the cell surface of
Figure 2. a, b) Typical coronal (top), axial (middle), and sagittal
the breast cancer. As the blood brain barrier is destructed as a
(bottom) views of a T1-weighted 3D spin-echo MONEMRI before (a)
and after (b) the administration of the MnO nanoparticles: the images result of the tumor formation in this animal model, both the
in (b) show bright contrast enhancement in the brain structures owing functionalized and nonfunctionalized MnO nanoparticles
to the accumulated MnO nanoparticles. c) The hippocampus structure entered the tumor site initially but only the functionalized
is revealed showing the least-bright CA1, medium-bright CA2 and CA3, MnO accumulate at the tumor site for an extended time
and the brightest dentate gyrus (DG). d) Axial view of the mouse owing to the presence of the conjugated antibody. As shown
olfactory bulb, showing the layers in the olfactory bulb. e) The ammon in Figure 3 b, the nonfunctionalized MnO nanoparticles
head of dentate gyrus is clearly shown, and the cortical layers are
enhanced both the tumor and the normal brain tissues. To
visible. f) The cerebellum structure is clearly visible, and the gray
matters are enhanced. g, h) TEM images of the tissues taken from the be used as a contrast agent in the brain, a prerequisite of a
cortex (g) and the hippocampus (h) show the presence of the MnO potential agent is clear marginal detectability without
nanoparticles in the brain tissue. destroying anatomic background. A clear marginal detect-

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Communications
1998, 281, 2016; c) S. Kim, Y. T. Lim, E. G. Soltesz, A. M.
De Grand, J. Lee, A. Nakayama, J. A. Parker, T. Mihaljevic,
R. G. Laurence, D. M. Dor, L. H. Cohn, M. G. Bawendi, J. V.
Frangioni, Nat. Biotechnol. 2004, 22, 93; d) K. E. Sapsford, L.
Berti, I. L. Medintz, Angew. Chem. 2006, 118, 4676; Angew.
Chem. Int. Ed. 2006, 45, 4562; e) I. L. Medintz, H. T. Uyeda,
E. R. Goldman, H. Mattoussi, Nat. Mater. 2005, 4, 435; f) X.
Michalet, F. F. Pinaud, L. A. Bentolila, J. M. Tsay, S. Doose, J. J.
Li, G. Sundaresan, A. M. Wu, S. S. Gambhir, S. Weiss, Science
2005, 307, 538; g) J. M. Klostranec, W. C. W. Chan, Adv. Mater.
2006, 18, 1953; h) X. Gao, Y. Cui, R. M. Levenson, L. W. K.
Chung, S. Nie, Nat. Biotechnol. 2004, 22, 969; i) H. Mattoussi,
J. M. Mauro, E. R. Goldman, G. P. Anderson, V. C. Sundar, F. V.
Mikulec, M. G. Bawendi, J. Am. Chem. Soc. 2000, 122, 12 142;
j) I. L. Medintz, A. R. Clapp, J. S. Melinger, J. R. Deschamps, H.
Mattoussi, Adv. Mater. 2005, 17, 2450; k) L. Medintz, A. R.
Clapp, H. Mattoussi, E. R. Goldman, B. Fisher, J. M. Mauro,
Figure 3. a) Breast cancer cells were selectively enhanced in T1- Nat. Mater. 2003, 2, 630; l) E. B. Voura, J. K. Jaiswal, H.
weighted MRI because the Herceptin-functionalized MnO nanoparti- Mattoussi, S. M. Simon, Nat. Med. 2004, 10, 993.
cles were delivered and accumulated at the EGFR at the surfaces of [3] a) T. A. Taton, C. A. Mirkin, R. L. Letsinger, Science 2000, 289,
the breast cancer cells. b) The nonfunctionalized MnO nanoparticles 1757; b) J.-M. Nam, C. S. Thaxton, C. A. Mirkin, Science 2003,
enhanced both the tumor and the normal brain tissue. 301, 1884; c) Y. W. C. Cao, R. Jin, C. A. Mirkin, Science 2002,
297, 1536; d) S.-J. Park, T. A. Taton, C. A. Mirkin, Science 2002,
295, 1503; e) M. S. Han, A. K. R. Lytton-Jean, B.-K. Oh, J. Heo,
ability with preserved anatomic background images was C. A. Mirkin, Angew. Chem. 2006, 118, 1839; Angew. Chem. Int.
observed using the MnO nanoparticles, which is a remarkable Ed. 2006, 45, 1807; f) P. Hazarika, B. Ceyhan, C. M. Niemeyer,
advantage over SPIO and suggests the use of MnO nano- Small 2005, 1, 844; g) C. M. Niemeyer, B. Ceyhan, P. Hazarika,
particles for treating brain diseases. Angew. Chem. 2003, 115, 5944; Angew. Chem. Int. Ed. 2003, 42,
5766; h) C. M. Niemeyer, B. Ceyhan, Angew. Chem. 2001, 113,
In summary, we have reported the first biocompatible
3798; Angew. Chem. Int. Ed. 2001, 40, 3685.
nanoparticulate T1 MRI contrast agent for various body [4] a) R. Weissleder, K. Kelly, E. Y. Sun, T. Shtatland, L. Josephson,
organs. We obtained clear T1-weighted MR images of the Nat. Biotechnol. 2005, 23, 1418; b) J. W. M. Bulte, D. L. Kraitch-
brain, liver, kidney, and spinal cord from 5 days to 3 weeks man, NMR Biomed. 2004, 17, 484; c) J. W. M. Bulte, S.-C. Zhang,
after the administration of MnO nanoparticles which depicted P. van Gelderen, V. Herynek, E. K. Jordan, I. D. Duncan, J. A.
fine anatomic structures. Furthermore, we have shown here Frank, Proc. Natl. Acad. Sci. USA 1999, 96, 15 256; d) Y.-W. Jun,
that functionalized MnO nanoparticles prepared by conjuga- Y.-M. Huh, J.-S. Choi, J.-H. Lee, H.-T. Song, S. Kim, S. Yoon, K.-
S. Kim, J.-S. Shin, J.-S. Suh, J. Cheon, J. Am. Chem. Soc. 2005,
tion with a tumor-specific antibody can also be used for
127, 5732; e) H. Gu, P.-L. Ho, K. W. T. Tsang, L. Wang, B. Xu, J.
selectively imaging breast cancer cells in the metastatic brain Am. Chem. Soc. 2003, 125, 15 702; f) C. Xu, K. Xu, H. Gu, X.
tumor. Easy delivery, clearance from the body organs and Zhong, Z. Guo, R. Zheng, X. Zhang, B. Xu, J. Am. Chem. Soc.
tissues, and a tolerable cellular toxicity range give us hope to 2004, 126, 3392; g) J. Won, M. Kim, Y.-W. Yi, Y. H. Kim, N. Jung,
develop this agent for future human clinical application as T. K. Kim, Science 2005, 309, 121; h) C. Xu, K. Xu, H. Gu, R.
well. This new class of MRI contrast agent will open up a new Zheng, H. Liu, X. Zhang, Z. Guo, B. Xu, J. Am. Chem. Soc. 2004,
direction in the applications of MR imaging for biomedical 126, 9938; i) H. Gu, K. Xu, C. Xu, B. Xu, Chem. Commun. 2006,
941; j) H.-T. Song, J.-S. Choi, Y.-M. Huh, S. Kim, Y.-W. Jun, J.-S.
research and targeted therapy using molecular and cellular
Suh, J. Cheon, J. Am. Chem. Soc. 2005, 127, 9992; k) Y.-M. Huh,
imaging in future medicine. Y.-W. Jun, H.-T. Song, S. Kim, J.-S. Choi, J.-H. Lee, S. Yoon, K.-S.
Kim, J.-S. Shin, J.-S. Suh, J. Cheon, J. Am. Chem. Soc. 2005, 127,
Received: November 24, 2006 12 387; l) J.-H. Lee, Y.-W. Jun, S.-I. Yeon, J.-S. Shin, J. Cheon,
Revised: January 19, 2007 Angew. Chem. 2006, 118, 8340; Angew. Chem. Int. Ed. 2006, 45,
Published online: March 13, 2007 8160; m) I. S. Lee, N. Lee, J. Park, B.-H. Kim, Y.-W. Yi, T. Kim,

.
Keywords: contrast agents imaging agents
magnetic resonance imaging manganese nanoparticles
T. K. Kim, I. H. Lee, S. R. Paik, T. Hyeon, J. Am. Chem. Soc.
2006, 128, 10 658; n) J. Kim, S. Park, J. E. Lee, S. M. Jin, J. H. Lee,
I. S. Lee, I. Yang, J.-S. Kim, S. K. Kim, M.-H. Cho, T. Hyeon,
Angew. Chem. 2006, 118, 7918; Angew. Chem. Int. Ed. 2006, 45,
7754; o) J. Kim, J. E. Lee, J. Lee, J. H. Yu, B. C. Kim, K. An, Y.
Hwang, C. H. Shin, J. G. Park, J. Kim, T. Hyeon, J. Am. Chem.
[1] a) C. M. Niemeyer, C. A. Mirkin, Nanobiotechnology: Concepts, Soc. 2006, 128, 688.
Applications and Perspectives, Wiley-VCH, Weinheim, 2004; [5] a) D. W. McRobbie, E. A. Moore, M. J. Graves, M. R. Prince,
b) A. P. Alivisatos, Nat. Biotechnol. 2004, 22, 47; c) K. J. Kla- MRI from Picture to Proton, Cambridge University Press,
bunde, Nanoscale Materials in Chemistry, Wiley-Interscience, Cambridge, 2002; b) M. A. Brown, R. C. Semelka, MRI: Basic
New York, 2001; d) T. Hyeon, Chem. Commun. 2003, 927; e) J. Principles and Applications, Wiley-Liss, New York, 2003.
Wang, Small 2005, 1, 1036; f) N. L. Rosi, C. A. Mirkin, Chem. [6] U. HMfeli, W. SchNtt, J. Teller, M. Zborowski, Scientific and
Rev. 2005, 105, 1547; g) C. M. Niemeyer, Angew. Chem. 2001, Clinical Applications of Magnetic Carriers, Plenum, New York,
113, 4254; Angew. Chem. Int. Ed. 2001, 40, 4128. 1997.
[2] a) M. Bruchez, Jr., M. Moronne, P. Gin, S. Weiss, A. P. Alivisa- [7] P. Caravan, J. J. Ellison, T. J. McMurry, R. B. Lauffer, Chem. Rev.
tos, Science 1998, 281, 2013; b) W. C. W. Chan, S. Nie, Science 1999, 99, 2293.

5400 www.angewandte.org
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 5397 5401
 Angewandte
Chemie

[8] H.-J. Weinmann, W. Ebert, B. Misselwitz, H. Schmitt-Willich, W. M. Deserno, S. Tabatabaei, C. H. van de Kaa, J. de la Rosette,
Eur. J. Radiol. 2003, 46, 33. R. Weissleder, N. Engl. J. Med. 2003, 348, 2491.
[9] a) J. H. Lee, A. C. Silva, H. Merkle, A. P. Koretsky, Magn. [11] a) J. Park, K. An, Y. Hwang, J.-G. Park, H.-J. Noh, J.-Y. Kim, J.-
Reson. Med. 2005, 53, 640; b) A. C. Silva, J. H. Lee, I. Aoki, A. P. H. Park, N.-M. Hwang, T. Hyeon, Nat. Mater. 2004, 3, 891; b) M.
Koretsky, NMR Biomed. 2004, 17, 532. Yin, S. ODBrien, J. Am. Chem. Soc. 2003, 125, 10 180; c) W. S. Seo,
[10] a) A. S. Arbab, G. T. Yocum, H. Kalish, E. K. Jordan, S. A. H. H. Jo, K. Lee, B. Kim, S. J. Oh, J. T. Park, Angew. Chem. 2004,
Anderson, A. Y. Khakoo, E. J. Read, J. A. Frank, Blood 2004, 116, 1135; Angew. Chem. Int. Ed. 2004, 43, 1115; d) J. Park, E.
104, 1217; b) J. W. M. Bulte, T. Douglas, B. Witwer, S.-C. Zhang, Kang, C. J. Bae, J. G. Park, H. J. Noh, J. Y. Kim, J. H. Park, H. M.
E. Strable, B. K. Lewis, H. Zywicke, B. Miller, P. van Gelderen, Park, T. Hyeon, J. Phys. Chem. B 2004, 108, 13 598.
B. M. Moskowitz, I. D. Duncan, J. A. Frank, Nat. Biotechnol. [12] B. Dubertret, P. Skourides, D. J. Norris, V. Noireaux, A. H.
2001, 19, 1141; c) M. G. Harisinghani, J. Barentsz, P. F. Hahn, Brivanlou, A. Libchaber, Science 2002, 298, 1759.

Angew. Chem. Int. Ed. 2007, 46, 5397 5401

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