Lee Josephson, PhD
Associate Professor (Chemistry)
Phone: 617-726-6478
Email: ljosephson@mgh.harvard.edu
My research focuses on the design and uses of magnetic nanoparticles, near infrared fluorescent (NIRF),
and magneto/optical probes for a wide range of questions in biology, chemistry and physics. As an early
worker in the field of nanotechnology, I collaborated with Dr. Weissleder to demonstrate that a magnetic
nanoparticle preparation could be used to determine the metastatic status of lymph nodes in an animal
model by MRI. Contrast agent enhanced imaging of lymph node status has now undergone extensive clinical
evaluation, see for example Harisinghani (2003) Noninvasive detection of clinically occult lymph-node
metastases in prostate cancer.
N Engl J Med, 348,2491-9.
Magnetic nanoparticles have been conjugated to membrane translocating peptides from the HIV tat protein,
and the resulting material is known as tat-CLIO. Remarkably, tat-CLIO causes the internalization of magnetic
iron oxide in a wide variety of non-phagocytic cells without toxicity. Tat-CLIO can be used to label and
track cells by MRI in three key areas of transplantation medicine. These are adoptive immunotherapy for
cancer (label T cells), implantation therapies for neurodegenerative disease (label neuroprogenitor cells),
and hematopoietic marrow reconstitution (label blood forming stem cells).
Apoptosis can be studied by many techniques, but few methods can be used to image apoptosis or quantify
apoptosis in living animals. Using annexin V, which binds to the externally facing phosphatidylserine of
apoptotic cells, superparamagnetic and near infrared fluorescence (NIRF) forms of annexin V have been
designed. Annexin V based probes are new and effective tools for imaging apoptosis, which plays a crucial
in the pathology and treatment of disease.
Finally, we have developed nanoparticles that are detectable by MRI and NIRF (magneto/optical probes), and
demonstrated their use as pre-operative MR contrast agents and intra-operative optical probes in important
clinical applications including lymph node delineation and brain tumor delineation.
Publications
Sheth RA, Tam JM, Maricevich MA, Josephson L, Mahmood U
Quantitative Endovascular Fluorescence-based Molecular Imaging through Blood of Arterial Wall Inflammation.
Koh I, Hong R, Weissleder R, Josephson L
Nanoparticle-Target Interactions Parallel Antibody-Protein Interactions.
Smith A, Blois J, Yuan H, Aikawa E, Ellson C, Figueiredo JL, Weissleder R, Kohler R, Yaffe MB, Cantley LC, Josephson L
The antiproliferative cytostatic effects of a self-activating viridin prodrug.
Mol Cancer Ther. 2009;8(6):1666-1675 - PMID: 19509266
Garanger E, Weissleder R, Josephson L
A Multifunctional Single-Attachment-Point Reagent for Controlled Protein Biotinylation.
Yuan H, Pupo MT, Blois J, Smith A, Weissleder R, Clardy J, Josephson L
A stabilized demethoxyviridin derivative inhibits PI3 kinase.
Bioorg Med Chem Lett. 2009;:ePub - PMID: 19523825
Islam T, Josephson L
Current state and future applications of active targeting in malignancies using superparamagnetic iron oxide nanoparticles.
Cancer Biomark. 2009;5(2):99-107 - PMID: 19414927
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Cortez-Retamozo V, Swirski FK, Waterman P, Yuan H, Figueiredo JL, Newton AP, Upadhyay R, Vinegoni C, Kohler R, Blois J, Smith A, Nahrendorf M, Josephson L, Weissleder R, Pittet MJ
Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation
Koh I, Hong R, Weissleder R, Josephson L
Sensitive NMR Sensors Detect Antibodies to Influenza.
Perez JM, Grimm J, Josephson L, Weissleder R
Integrated nanosensors to determine levels and functional activity of human telomerase.
Gee MS, Upadhyay R, Bergquist H, Alencar H, Reynolds F, Maricevich M, Weissleder R, Josephson L, Mahmood U
Human Breast Cancer Tumor Models: Molecular Imaging of Drug Susceptibility and Dosing during HER2/neu-targeted Therapy.
Radiology. 2008;248(3):925-35 - PMID: 18647846
Garanger E, Aikawa E, Reynolds F, Weissleder R, Josephson L
Simplified syntheses of complex multifunctional nanomaterials.
Blois J, Yuan H, Smith A, Pacold ME, Weissleder R, Cantley LC, Josephson L
Slow Self-Activation Enhances The Potency of Viridin Prodrugs.
Barnes KR, Blois J, Smith A, Yuan H, Reynolds F, Weissleder R, Cantley LC, Josephson L
Fate of a Bioactive Fluorescent Wortmannin Derivative in Cells.
Bioconjug Chem. 2008;19:130-137 - PMID: 17988080
Taktak S, Weissleder R, Josephson L
Electrode Chemistry Yields a Nanoparticle-Based NMR Sensor for Calcium.
Langmuir. 2008;24 (14):7596-7598 - PMID: 18558729
Hong R, Cima MJ, Weissleder R, Josephson L
Magnetic microparticle aggregation for viscosity determination by MR.
Magn Reson Med. 2008;59:515-520 - PMID: 18306403
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Sosnovik DE, Nahrendorf M, Deliolanis N, Novikov M, Aikawa E, Josephson L, Rosenzweig A, Weissleder R, Ntziachristos V
Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo.
Circulation. 2007;115:1384-1391 - PMID: 17339546
Yuan H, Barnes KR, Weissleder R, Cantley L, Josephson L
Covalent Reactions of Wortmannin under Physiological Conditions.
Chem Biol. 2007;14(3):321-8 - PMID: 17379147
Taktak S, Sosnovik D, Cima MJ, Weissleder R, Josephson L
Multiparameter Magnetic Relaxation Switch Assays.
Anal Chem. 2007;(79) 23:8863-9 - PMID: 17983206
Kim GY, Josephson L, Langer R, Cima MJ
Magnetic Relaxation Switch Detection of Human Chorionic Gonadotrophin.
Bioconjug Chem. 2007;18(6):2024-8 - PMID: 17892270
Gee MS, Upadhyay R, Bergquist H, Weissleder R, Josephson L, Mahmood U
Multiparameter noninvasive assessment of treatment susceptibility, drug target inhibition and tumor response guides cancer treatment.
Int J Cancer. 2007;(121) 11:2492-2500 - PMID: 17683072
Montet-Abou K, Montet X, Weissleder R, Josephson L
Cell internalization of magnetic nanoparticles using transfection agents.
Mol Imaging. 2007;(6) 1:1-9 - PMID: 17311760
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Sun EY, Weissleder R, Josephson L.
Continuous Analyte Sensing with Magnetic Nanoswitches
Small. 2006;(2) 10:1144-1147 - PMID: 17193579
Montet X, Montet-Abou K, Reynolds F, Weissleder R, Josephson L.
Nanoparticle Imaging of Integrins on Tumor Cells
Trehin R, Figueiredo JL, Pittet M, Weissleder R, Josephson L, Mahmood U.
Fluorescent Nanoparticle Uptake for Brain Tumor Visualization
Montet X, Funovics M, Montet-Abou K, Weissleder R, Josephson L.
Multivalent effects of RGD peptides obtained by nanoparticle display
Yuan H, Luo J, Weissleder R, Cantley L, Josephson L
Wortmannin-C20 Conjugates Generate Wortmannin.
J Med Chem. 2006;49(2):740-747 - PMID: 16420059
Montet X, Weissleder R, Josephson L.
Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas
Bioconjug Chem. 2006;17(4):905-911 - PMID: 16848396
Sun EY, Josephson L, Kelly KA, Weissleder R
Development of nanoparticle libraries for biosensing.
Bioconjug Chem. 2006;17(1):109-13 - PMID: 16417258
Montet X, Yuan H, Weissleder R, Josephson L
Enzyme-based visualization of receptor-ligand binding in tissues.
Lab Invest. 2006;86(5):517-25 - PMID: 16568109
Sun EY, Josephson L, Weissleder R.
Clickable nanoparticles for targeted imaging
Mol Imaging. 2006;(5) 2:122-128 - PMID: 16954026
Pittet M, Swirski F, Reynolds F, Josephson L, Weissleder R.
Labeling of immune cells for in vivo imaging using magnetofluorescent nanoparticles
Nat Protocols. 2006;1(1): 73-79
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Weissleder R, Kelly K, Sun E, Shtatland T, Josephson L.
Cell-specific targeting of nanoparticles by multivalent attachment of small molecules
Nat Biotechnol. 2005;23:1418-1423 - PMID: 16244656
Kelly KA, Allport JR, Tsourkas A, Shinde-Patil VR, Josephson L, Weissleder R.
Detection of Vascular Adhesion Molecule-1 Expression Using a Novel Multimodal Nanoparticle
Circ Res. 2005;96(3):327-36 - PMID: 15653572
Funovics M, Montet X, Reynolds F, Weissleder R, Josephson L.
Nanoparticles for the Optical Imaging of Tumor E-selectin
Neoplasia. 2005;7(10):904-11 - PMID: 16242073
Yuan H, Luo J, Field S, Weissleder R, Cantley L, Josephson L.
Synthesis and Activity of C11-Modified Wortmannin Probes for P13 Kinase
Bioconjug Chem. 2005;(3):669-675 - PMID: 15898736
Reynolds F, Weissleder R, Josephson L.
Protamine as an efficient membrane-translocating Peptide
Bioconjug Chem. 2005;16(5):1240-5 - PMID: 16173804
Choi HK, Yessayan D, Choi HJ, Schellenberger E, Bogdanov A, Josephson L, Weissleder R, Ntziachristos V.
Quantitative analysis of chemotherapeutic effects in tumors using in vivo staining and correlative histology
Cell Oncol. 2005;27(3):183-90 - PMID: 16037639
Mahmood U, Josephson L
Molecular MR Imaging Probes
Koch AM, Reynolds F, Merkle HP, Weissleder R, Josephson L.
Transport Of Surface-Modified Nanoparticles Through Cell Monolayers
Chembiochem. 2005;6(2):337-345 - PMID: 15651046
Wunder A, Schellenberger E, Mahmood U, Bogdanov A Jr, Muller-Ladner U, Weissleder R, Josephson L.
Methotrexate-induced accumulation of fluorescent annexin v in collagen-induced arthritis
Mol Imaging. 2005;4(1):1-6 - PMID: 15967121
Montet-Abou K, Montet X, Weissleder R, Josephson L.
Transfection agent induced nanoparticle cell loading
Mol Imaging. 2005;4(3):165-71 - PMID: 16194448
Sosnovik DE, Schellenberger EA, Nahrendorf M, Novikov MS, Matsui T, Dai G, Reynolds F, Grazette L, Rosenzweig A, Weissleder R, Josephson L.
Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical nanoparticle
Magn Reson Med. 2005;54(3):718-724 - PMID: 16086367
Reynolds F, O'loughlin T, Weissleder R, Josephson L.
Method of Determining Nanoparticle Core Weight
Anal Bioanal Chem. 2005;77(3):814-817 - PMID: 15679348
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Tsourkas A, Hofstetter O, Hofstetter H, Weissleder R, Josephson L
Magnetic Relaxation Switch Immunosensors Detect Enantiomeric Impurities
Angew Chem Int Edit. 2004;43(18):2395-2399 - PMID: 15114571
Perez JM, Simeone FJ, Tsourkas A, Josephson L, Weissleder R
Peroxidase substrate nanosensors for MR imaging
Ntziachristos V, Schellenberger EA, Ripoll J, Yessayan D, Graves E, Bogdanov A Jr, Josephson L, Weissleder R
Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.5 conjugate.
Grimm J, Perez JM, Josephson L, Weissleder R
Novel nanosensors for rapid analysis of telomerase activity
Cancer Res. 2004;64:639-43 - PMID: 14744779
Kircher MF, Weissleder R, Josephson L
A dual fluorochrome probe for imaging proteases
Bioconjug Chem. 2004;15:242-8 - PMID: 15025519
Schellenberger EA, Sosnovik D, Weissleder R, Josephson L
Magneto/Optical annexin v, a multimodal protein.
Bioconjug Chem. 2004;15(5):1062-7 - PMID: 15366960
Schellenberger EA, Reynolds F, Weissleder R, Josephson L
Surface-functionalized nanoparticle library yields probes for apoptotic cells
Chembiochem. 2004;5:275-9 - PMID: 14997519
Schellenberger EA, Weissleder R, Josephson L
Optimal modification of annexin v with fluorescent dyes
Chembiochem. 2004;5:271-4 - PMID: 14997518
Perez JM, Josephson L, Weissleder R
Use of magnetic nanoparticles as nanosensors to probe for molecular interactions
Chembiochem. 2004;5:261-4 - PMID: 14997516
Kelly KA, Reynolds F, Weissleder R, Josephson L
Fluorescein isothiocyanate-hapten immunoassay for determination of peptide-cell interactions.
Anal Biochem. 2004;330(2):181-5 - PMID: 15203322
Schellingerhout D, Josephson L
Molecular imaging of cell-based therapies.
Neuroimaging Clin N Am.. 2004;14(2):331-42 - PMID: 15182822
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Zhao M, Josephson L, Tang Y, Weissleder R
Magnetic sensors for protease assays
Angew Chem Int Edit. 2003;42:1375-8 - PMID: 12671972
Perez JM, Simeone FJ, Saeki Y, Josephson L, Weissleder R
Viral-induced self-assembly of magnetic nanoparticles allows the detection of viral particles in biological media
J Am Chem Soc. 2003;125:10192-3 - PMID: 12926940
Kircher MF, Mahmood U, King RS, Weissleder R, Josephson L
A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation
Cancer Res. 2003;63:8122-5 - PMID: 14678964
Petrovsky A, Schellenberger E, Josephson L, Weissleder R, Bogdanov A Jr
Near-infrared fluorescent imaging of tumor apoptosis
Cancer Res. 2003;63:1936-42 - PMID: 12702586
Kircher MF, Allport, JR, Graves EE, Love V, Josephson L, Lichtman AH, Weissleder R
In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors
Cancer Res. 2003;63:6838-46 - PMID: 14583481
Schellenberger EA, Bogdanov A Jr, Petrovsky A, Ntziachristos V, Weissleder R, Josephson L
Optical imaging of apoptosis as a biomarker of tumor response to chemotherapy
Hogemann-Savellano D, Bos E, Blondet C, Sato F, Abe T, Josephson L, Weissleder R, Gaudet J, Sgroi D, Peters PJ, Basilion JP.
The transferrin receptor: a potential molecular imaging marker for human cancer.
Koch AM, Reynolds F, Kircher MF, Merkle HP, Weissleder R, Josephson L
Uptake and metabolism of a dual fluorochrome Tat-nanoparticle in HeLa cells
Bioconjug Chem. 2003;14:1115-21 - PMID: 14624624
Josephson L, Mahmood U, Wunderbaldinger P, Tang Y, Weissleder R
Pan and sentinel lymph node visualization using a near-infrared fluorescent probe
Mol Imaging. 2003;2:18-23 - PMID: 12926234
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Perez JM, Josephson L, O'Loughlin T, Hogemann D, Weissleder R
Magnetic relaxation switches capable of sensing molecular interactions
Nat Biotechnol. 2002;20:816-20 - PMID: 12134166
Perez JM, O'Loughin T, Simeone F J, Weissleder R, Josephson L
DNA-based magnetic nanoparticle assembly acts as a magnetic relaxation nanoswitch allowing screening of DNA-cleaving agents
J Am Chem Soc. 2002;124:2856-7 - PMID: 11902860
Wunderbaldinger P, Josephson L, Weissleder R
Tat peptide directs enhanced clearance and hepatic permeability of magnetic nanoparticles
Bioconjug Chem. 2002;13:264-8 - PMID: 11906263
Josephson L, Kircher MF, Mahmood U, Tang Y, Weissleder R
Near-infrared fluorescent nanoparticles as combined MR/optical imaging probes
Bioconjug Chem. 2002;13:554-60 - PMID: 12009946
Hogemann D, Ntziachristos V, Josephson L, Weissleder R
High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes
Bioconjug Chem. 2002;13:116-21 - PMID: 11792186
Kang HW, Josephson L, Petrovsky A, Weissleder R, Bogdanov A Jr
Magnetic resonance imaging of inducible E-selectin expression in human endothelial cell culture
Bioconjug Chem. 2002;13:122-7 - PMID: 11792187
Zhao M, Kircher MF, Josephson L, Weissleder R
Differential conjugation of tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake
Bioconjug Chem. 2002;13:840-4 - PMID: 12121140
Schellenberger EA, Bogdanov A Jr, Hogemann D, Tait J, Weissleder R, Josephson L
Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI
Mol Imaging. 2002;1:102-7 - PMID: 12920851
Kircher MF, Josephson L, Weissleder R
Ratio imaging of enzyme activity using dual wavelength optical reporters
Mol Imaging. 2002;1:89-95 - PMID: 12920849
Wunderbaldinger P, Josephson L, Bremer C, Moore A, Weissleder R
Detection of lymph node metastases by contrast-enhanced MRI in an experimental model
Magn Reson Med. 2002;47:292-7 - PMID: 11810672
Wunderbaldinger P, Josephson L, Weissleder R
Crosslinked iron oxides (CLIO): a new platform for the development of targeted MR contrast agents
Acad Radiol. 2002;9 Suppl 2:S304-6 - PMID: 12188255
Schellenberger EA, Hogemann D, Josephson L, Weissleder R
Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI
Acad Radiol. 2002;9 Suppl 2:S310-1 - PMID: 12188257
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Moore A, Josephson L, Bhorade RM, Basilion JP, Weissleder R
Human transferrin receptor gene as a marker gene for MR imaging
Radiology. 2001;221:244-50 - PMID: 11568347
Dodd CH, Hsu HC, Chu WJ, Yang P, Zhang HG, Mountz JD Jr, Zinn K, Forder J, Josephson L, Weissleder R, Mountz JM, Mountz JD
Normal T-cell response and in vivo magnetic resonance imaging of T cells loaded with HIV transactivator-peptide-derived superparamagnetic nanoparticles
J Immunol Methods. 2001;256:89-105 - PMID: 11516758
2
Hogemann D, Josephson L, Weissleder R, Basilion JP
Improvement of MRI probes to allow efficient detection of gene expression
Bioconjug Chem. 2000;11:941-6 - PMID: 11087345
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Josephson L, Tung CH, Moore A, Weissleder R
High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates
Bioconjug Chem. 1999;10:186-91 - PMID: 10077466
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