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
Koh I, Hong R, Weissleder R, Josephson L
Sensitive NMR Sensors Detect Antibodies to Influenza.
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.
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.
Taktak S, Weissleder R, Josephson L
Electrode Chemistry Yields a Nanoparticle-Based NMR Sensor for Calcium.
Hong R, Cima MJ, Weissleder R, Josephson L
Magnetic microparticle aggregation for viscosity determination by MR.
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.
Yuan H, Barnes KR, Weissleder R, Cantley L, Josephson L
Covalent Reactions of Wortmannin under Physiological Conditions.
Chem Biol. 2007;14(3): 321-8
Taktak S, Sosnovik D, Cima MJ, Weissleder R, Josephson L
Multiparameter Magnetic Relaxation Switch Assays.
Anal Chem. 2007;(79) 23: 8863-9
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.
Kim GY, Josephson L, Langer R, Cima MJ
Magnetic Relaxation Switch Detection of Human Chorionic Gonadotrophin.
Bioconjug Chem. 2007;18(6): 2024-8
Montet-Abou K, Montet X, Weissleder R, Josephson L
Cell internalization of magnetic nanoparticles using transfection agents.
Mol Imaging. 2007;(6) 1: 1-9
Sun EY, Weissleder R, Josephson L.
Continuous Analyte Sensing with Magnetic Nanoswitches
Trehin R, Figueiredo JL, Pittet M, Weissleder R, Josephson L, Mahmood U.
Fluorescent Nanoparticle Uptake for Brain Tumor Visualization
Montet X, Montet-Abou K, Reynolds F, Weissleder R, Josephson L.
Nanoparticle Imaging of Integrins on Tumor Cells
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.
Montet X, Yuan H, Weissleder R, Josephson L
Enzyme-based visualization of receptor-ligand binding in tissues.
Sun EY, Josephson L, Kelly KA, Weissleder R
Development of nanoparticle libraries for biosensing.
Bioconjug Chem. 2006;17(1): 109-13
Montet X, Weissleder R, Josephson L.
Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas
Sun EY, Josephson L, Weissleder R.
Clickable nanoparticles for targeted imaging
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
Weissleder R, Kelly K, Sun E, Shtatland T, Josephson L.
Cell-specific targeting of nanoparticles by multivalent attachment of small molecules
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
Funovics M, Montet X, Reynolds F, Weissleder R, Josephson L.
Nanoparticles for the Optical Imaging of Tumor E-selectin
Reynolds F, Weissleder R, Josephson L.
Protamine as an efficient membrane-translocating Peptide
Bioconjug Chem. 2005;16(5): 1240-5
Yuan H, Luo J, Field S, Weissleder R, Cantley L, Josephson L.
Synthesis and Activity of C11-Modified Wortmannin Probes for P13 Kinase
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
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
Montet-Abou K, Montet X, Weissleder R, Josephson L.
Transfection agent induced nanoparticle cell loading
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
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
Reynolds F, O'loughlin T, Weissleder R, Josephson L.
Method of Determining Nanoparticle Core Weight
Anal Bioanal Chem. 2005;77(3): 814-817
Tsourkas A, Hofstetter O, Hofstetter H, Weissleder R, Josephson L
Magnetic Relaxation Switch Immunosensors Detect Enantiomeric Impurities
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.
P Natl Acad Sci U S A. 2004;101(33): 12294-9
Grimm J, Perez JM, Josephson L, Weissleder R
Novel nanosensors for rapid analysis of telomerase activity
Schellenberger EA, Sosnovik D, Weissleder R, Josephson L
Magneto/Optical annexin v, a multimodal protein.
Bioconjug Chem. 2004;15(5): 1062-7
Kircher MF, Weissleder R, Josephson L
A dual fluorochrome probe for imaging proteases
Bioconjug Chem. 2004;15: 242-8
Schellenberger EA, Weissleder R, Josephson L
Optimal modification of annexin v with fluorescent dyes
Chembiochem. 2004;5: 271-4
Perez JM, Josephson L, Weissleder R
Use of magnetic nanoparticles as nanosensors to probe for molecular interactions
Chembiochem. 2004;5: 261-4
Schellenberger EA, Reynolds F, Weissleder R, Josephson L
Surface-functionalized nanoparticle library yields probes for apoptotic cells
Chembiochem. 2004;5: 275-9
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
Schellingerhout D, Josephson L
Molecular imaging of cell-based therapies.
Neuroimaging Clin N Am.. 2004;14(2): 331-42
Zhao M, Josephson L, Tang Y, Weissleder R
Magnetic sensors for protease assays
Angew Chem Int Edit. 2003;42: 1375-8
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
Petrovsky A, Schellenberger E, Josephson L, Weissleder R, Bogdanov A Jr
Near-infrared fluorescent imaging of tumor apoptosis
Kircher MF, Mahmood U, King RS, Weissleder R, Josephson L
A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation
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
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.
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
Koch AM, Reynolds F, Kircher MF, Merkle HP, Weissleder R, Josephson L
Uptake and metabolism of a dual fluorochrome Tat-nanoparticle in HeLa cells
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
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
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
Hogemann D, Ntziachristos V, Josephson L, Weissleder R
High throughput magnetic resonance imaging for evaluating targeted nanoparticle probes
Bioconjug Chem. 2002;13: 116-21
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
Wunderbaldinger P, Josephson L, Weissleder R
Tat peptide directs enhanced clearance and hepatic permeability of magnetic nanoparticles
Bioconjug Chem. 2002;13: 264-8
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
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
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
Kircher MF, Josephson L, Weissleder R
Ratio imaging of enzyme activity using dual wavelength optical reporters
Mol Imaging. 2002;1: 89-95
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
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
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
Moore A, Josephson L, Bhorade RM, Basilion JP, Weissleder R
Human transferrin receptor gene as a marker gene for MR imaging
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
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
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
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