Chip NMR biosensor for molecular analysis of cells

Summary

Principal Investigator: R Weissleder
Affiliation: Harvard University
Country: USA
Abstract: DESCRIPTION (provided by applicant): One of the major challenges in medicine is the rapid and accurate measurement of protein bio- markers, cells and organisms in different biological samples. During the prior funding period we had developed a broadly applicable, novel, point-of-care diagnostic platform using "magnetic relaxation switches" as a proximity sensor to amplify molecular interactions. We have shown that highly sensitive and selective measurements (e.g. DNA, mRNA, proteins, metabolites, drugs, bacteria, cells) can be obtained on small volume of unprocessed biological samples. One of the critical limitations of the approach however, was the need for bulky and/or complex NMR systems to carry out the measurements. We have now achieved a technological breakthrough by miniaturizing an entire NMR system onto a single, integrated circuit (IC) chip (dubbed DMR for "diagnostic magnetic resonance"). In preliminary feasibility experiments, we have shown that we can already achieve detection sensitivities of 10-12 M surpassing those of many traditional, time consuming assays. The goal of this competing renewal is to further mature DMR into a cutting-edge detection technology and apply it to molecular and cellular sensing and profiling of cells. Using cancer cells as a specific sensing target, we propose three specific aims to refine and further validate the DMR technology: 1) optimize particle constructs for high efficiency detection of cancer cells;2) determine the detection threshold and specificity for cancer cells and 3) develop real time molecular analysis of cells in biological samples. This proposal addresses a number of unmet needs and aims at optimizing, validating and further improving the novel DMR biodetection platform. PUBLIC HEALTH RELEVANCE: We are developing a handheld sensor to quickly assay blood and tissue samples in cancer patients. Based on fundamentally new designs, this technology allows sensing and rapid profiling of cancer cells in blood.
Funding Period: 2004-09-01 - 2011-08-31
more information: NIH RePORT

Top Publications

  1. pmc Magnetic Ligation Method for Quantitative Detection of MicroRNAs
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital Harvard Medical School, 185 Cambridge St, Boston, MA, 02114, USA
    Adv Healthc Mater 3:1015-9. 2014
  2. pmc Sensitive and direct detection of circulating tumor cells by multimarker µ-nuclear magnetic resonance
    Arezou A Ghazani
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Neoplasia 14:388-95. 2012
  3. pmc Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy
    Carlos Tassa
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Acc Chem Res 44:842-52. 2011
  4. pmc Enhancing navigation in biomedical databases by community voting and database-driven text classification
    Timo Duchrow
    Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
    BMC Bioinformatics 10:317. 2009
  5. pmc Development of a bioorthogonal and highly efficient conjugation method for quantum dots using tetrazine-norbornene cycloaddition
    Hee Sun Han
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 4307, USA
    J Am Chem Soc 132:7838-9. 2010
  6. pmc Nanoparticle-mediated measurement of target-drug binding in cancer cells
    Adeeti V Ullal
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
    ACS Nano 5:9216-24. 2011
  7. pmc In vivo imaging in cancer
    John Condeelis
    Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Program in Microenvironment and Metastasis, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA
    Cold Spring Harb Perspect Biol 2:a003848. 2010
  8. pmc Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction
    Florian Leuschner
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, USA
    Circ Res 107:1364-73. 2010
  9. pmc Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation
    Mark R Karver
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA
    Bioconjug Chem 22:2263-70. 2011
  10. pmc Mechanism of magnetic relaxation switching sensing
    Changwook Min
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    ACS Nano 6:6821-8. 2012

Scientific Experts

  • David Sosnovik
  • Ralph Weissleder
  • Hakho Lee
  • Monty Liong
  • David Issadore
  • Cesar M Castro
  • Jaehoon Chung
  • Lee Josephson
  • Huilin Shao
  • Jered B Haun
  • Changwook Min
  • Arezou A Ghazani
  • Vanessa M Peterson
  • Hyun Jung Chung
  • Mark R Karver
  • Tae Jong Yoon
  • Thomas Reiner
  • Carlos Tassa
  • Scott A Hilderbrand
  • Isaac Koh
  • Rui Hong
  • Sonia Taktak
  • Hyungsoon Im
  • Adeeti V Ullal
  • Karin Montet-Abou
  • Rostic Gorbatov
  • Neal K Devaraj
  • Junsung Rho
  • Marta Fernandez-Suarez
  • Sarit S Agasti
  • Sarah M Fortune
  • Mehmet Toner
  • Stanley Y Shaw
  • Brett S Marinelli
  • John Condeelis
  • Florian Leuschner
  • Hee Sun Han
  • Mikael J Pittet
  • Aleksey Chudnovskiy
  • Filip K Swirski
  • Matthias Nahrendorf
  • Elisabeth Garanger
  • Timo Duchrow
  • Moritz Wildgruber
  • Michael J Cima
  • Eric Yi Sun
  • Xavier Montet
  • Hushan Yuan
  • Fred Reynolds
  • Matthew Sebas
  • Aaron D Aguirre
  • Maulik D Majmudar
  • Nil Gural
  • Rupal R Shah
  • Melina Pectasides
  • Rushdy Ahmad
  • Maria D Castano
  • Michael J Birrer
  • Christopher B Ford
  • Richard T Penson
  • Mari Mino-Kenudson
  • Anh N Hoang
  • Nathan C Miller
  • Shaunagh McDermott
  • Matt Sebas
  • Xandra O Breakefield
  • Fred H Hochberg
  • Leonora Balaj
  • Bob S Carter
  • Alain Charest
  • Darell D Bigner
  • Andita Newton
  • Katherine S Yang
  • Mikael Pittet
  • Rui Wang
  • Ghyslain Budin
  • Isabel Chico-Calero
  • Won Woo Lee
  • Brett Marinelli
  • Jose Luiz Figueiredo
  • Moungi G Bawendi
  • Jungmin Lee
  • Virna Cortez-Retamozo
  • Peter Waterman
  • Takuya Ueno
  • Yoshiko Iwamoto
  • Peter Panizzi
  • Daniel Guettler
  • Peter Libby
  • Stefan Kramer

Detail Information

Publications49

  1. pmc Magnetic Ligation Method for Quantitative Detection of MicroRNAs
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital Harvard Medical School, 185 Cambridge St, Boston, MA, 02114, USA
    Adv Healthc Mater 3:1015-9. 2014
    ..The sandwich probes assay can be adapted to analyze a panel of microRNAs associated with cardiovascular diseases in heart tissue samples. ..
  2. pmc Sensitive and direct detection of circulating tumor cells by multimarker µ-nuclear magnetic resonance
    Arezou A Ghazani
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Neoplasia 14:388-95. 2012
    ..We also confirm these results in a comparative trial of patients with ovarian cancer. This platform could potentially benefit a broad range of applications in clinical oncology...
  3. pmc Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy
    Carlos Tassa
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Acc Chem Res 44:842-52. 2011
    ..Finally, the targeted delivery of a photodynamic therapy agent as part of a theranostic nanoparticle successfully increased local cell toxicity and minimized systemic side effects...
  4. pmc Enhancing navigation in biomedical databases by community voting and database-driven text classification
    Timo Duchrow
    Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
    BMC Bioinformatics 10:317. 2009
    ..Here, we introduce and apply community voting, database-driven text classification, and visual aids as a means to incorporate distributed expert knowledge, to automatically classify database entries and to efficiently retrieve them...
  5. pmc Development of a bioorthogonal and highly efficient conjugation method for quantum dots using tetrazine-norbornene cycloaddition
    Hee Sun Han
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 4307, USA
    J Am Chem Soc 132:7838-9. 2010
    ..We have applied this method to the in situ targeting of norbornene-coated QDs to live cancer cells labeled with tetrazine-modified proteins...
  6. pmc Nanoparticle-mediated measurement of target-drug binding in cancer cells
    Adeeti V Ullal
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
    ACS Nano 5:9216-24. 2011
    ....
  7. pmc In vivo imaging in cancer
    John Condeelis
    Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Program in Microenvironment and Metastasis, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA
    Cold Spring Harb Perspect Biol 2:a003848. 2010
    ..Examples of new insights derived from the different scales of imaging and relevant probes are discussed in the context of cancer progression and metastasis...
  8. pmc Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction
    Florian Leuschner
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, USA
    Circ Res 107:1364-73. 2010
    ..Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin (Ang) II signaling...
  9. pmc Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation
    Mark R Karver
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA
    Bioconjug Chem 22:2263-70. 2011
    ..One promising, highly stable, and water-soluble derivative was used in pretargeted cancer cell labeling studies, confirming its utility as a bioorthogonal moiety...
  10. pmc Mechanism of magnetic relaxation switching sensing
    Changwook Min
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA
    ACS Nano 6:6821-8. 2012
    ..4). Importantly, a new model for transverse relaxation was constructed that accurately recapitulates observed MRSw phenomena and predicts the MRSw detection sensitivities and dynamic ranges...
  11. pmc Ultrasensitive clinical enumeration of rare cells ex vivo using a micro-hall detector
    David Issadore
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, MA 02114, USA
    Sci Transl Med 4:141ra92. 2012
    ..This cost-effective, single-cell analytical technique is well suited to perform molecular and cellular diagnosis of rare cells in the clinic...
  12. pmc Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy
    Huilin Shao
    Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
    Nat Med 18:1835-40. 2012
    ..This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials...
  13. pmc Ascites analysis by a microfluidic chip allows tumor-cell profiling
    Vanessa M Peterson
    Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114
    Proc Natl Acad Sci U S A 110:E4978-86. 2013
    ....
  14. pmc Magnetic nanosensor for detection and profiling of erythrocyte-derived microvesicles
    Junsung Rho
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States
    ACS Nano 7:11227-33. 2013
    ..By advancing our understanding of MV biology, we expect that the developed platform will lead to improved blood product quality and transfusion safety. ..
  15. pmc Miniaturized nuclear magnetic resonance platform for detection and profiling of circulating tumor cells
    Cesar M Castro
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Lab Chip 14:14-23. 2014
    ..Recent advances in the sensing technology will be summarized, followed by the description of the dynamic interplay between our preclinical and clinical CTC studies. ..
  16. pmc A magneto-DNA nanoparticle system for rapid detection and phenotyping of bacteria
    Hyun Jung Chung
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
    Nat Nanotechnol 8:369-75. 2013
    ..The generic platform described could be used to rapidly identify and phenotype pathogens for a variety of applications...
  17. pmc Microfluidic cell sorter (μFCS) for on-chip capture and analysis of single cells
    Jaehoon Chung
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
    Adv Healthc Mater 1:432-6. 2012
    ..The potential clinical application of the technology is demonstrated by capturing and genetically analyzing CTCs in tumor-bearing mice...
  18. pmc Magnetic barcode assay for genetic detection of pathogens
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Nat Commun 4:1752. 2013
    ..tuberculosis-positive patient specimens. Combined with portable systems, the magnetic barcode assay holds promise to become a sensitive, high-throughput and low-cost platform for point-of-care diagnostics...
  19. ncbi Comparison of select cancer biomarkers in human circulating and bulk tumor cells using magnetic nanoparticles and a miniaturized micro-NMR system
    Arezou A Ghazani
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
    Nanomedicine 9:1009-17. 2013
    ..We show a weak correlation between each paired sample, suggesting that use of CTC as "liquid biopsies" and proxies to metastatic solid lesions could be misleading...
  20. pmc Supramolecular host-guest interaction for labeling and detection of cellular biomarkers
    Sarit S Agasti
    Center for Systems Biology, Massachusetts General Hospital Harvard Medical School, 185 Cambridge St, Boston, MA 02114, USA
    Angew Chem Int Ed Engl 51:450-4. 2012
    ....
  21. pmc Ubiquitous detection of gram-positive bacteria with bioorthogonal magnetofluorescent nanoparticles
    Hyun Jung Chung
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
    ACS Nano 5:8834-41. 2011
    ..This bioorthogonal labeling method could ultimately be applied to a variety of other small molecules with specificity for infectious pathogens, enabling their detection and diagnosis...
  22. pmc Specific pathogen detection using bioorthogonal chemistry and diagnostic magnetic resonance
    Monty Liong
    Center for Systems Biology, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts 02114, United States
    Bioconjug Chem 22:2390-4. 2011
    ..Considering the short assay times and the portability of the necessary instrumentation, it is feasible that this approach could be adapted for clinical use in resource-limited settings...
  23. pmc Bioorthogonal reaction pairs enable simultaneous, selective, multi-target imaging
    Mark R Karver
    Center for Systems Biology, Massachusetts General Hospital Harvard Medical School, 185 Cambridge Street, Suite 5 210, Boston, MA 02114 USA http csb mgh harvard edu
    Angew Chem Int Ed Engl 51:920-2. 2012
    ..These small-molecule probes show good chemical reactivity and can be readily incorporated into biological systems...
  24. pmc Orthogonal amplification of nanoparticles for improved diagnostic sensing
    Vanessa M Peterson
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States
    ACS Nano 6:3506-13. 2012
    ..With its high sensitivity and simplified assay steps, this technique will likely have broad utility in nanomaterial-based diagnostics...
  25. pmc Miniature magnetic resonance system for point-of-care diagnostics
    David Issadore
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA
    Lab Chip 11:2282-7. 2011
    ..The clinical potential of the new system is demonstrated by detecting trace amounts of proteins and as few as 10 bacteria (Staphylococcus aureus) in a short time frame (<30 min)...
  26. pmc Nanoparticle-target interactions parallel antibody-protein interactions
    Isaac Koh
    Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Boston, Massachusetts 02129, USA
    Anal Chem 81:3618-22. 2009
    ....
  27. doi Magnetic nanoparticle biosensors
    Jered B Haun
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Wiley Interdiscip Rev Nanomed Nanobiotechnol 2:291-304. 2010
    ....
  28. pmc Bioorthogonal chemistry amplifies nanoparticle binding and enhances the sensitivity of cell detection
    Jered B Haun
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA
    Nat Nanotechnol 5:660-5. 2010
    ..This method also supports amplification of biomarker signals, making it superior to alternative targeting techniques including avidin/biotin...
  29. pmc Self-assembled magnetic filter for highly efficient immunomagnetic separation
    David Issadore
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA
    Lab Chip 11:147-51. 2011
    ....
  30. pmc Micro-NMR for rapid molecular analysis of human tumor samples
    Jered B Haun
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Sci Transl Med 3:71ra16. 2011
    ..Our quantitative point-of-care micro-NMR technique shows potential for cancer diagnosis in the clinic...
  31. pmc Probing intracellular biomarkers and mediators of cell activation using nanosensors and bioorthogonal chemistry
    Jered B Haun
    Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA
    ACS Nano 5:3204-13. 2011
    ..We expect the described method will have broad applications in nanomaterial-based diagnostics and therapeutics...
  32. ncbi Transfection agent induced nanoparticle cell loading
    Karin Montet-Abou
    Center for Molecular Imaging Research and Harvard Medical School, Charlestown, MA 02129, USA
    Mol Imaging 4:165-71. 2005
    ..However, we found that the conditions used to label cells with Feridex and transfection agents need to be carefully selected to avoid the problems of surface adsorption and nanoparticle precipitation...
  33. ncbi Wortmannin-C20 conjugates generate wortmannin
    Hushan Yuan
    Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Med Chem 49:740-7. 2006
    ....
  34. ncbi Continuous analyte sensing with magnetic nanoswitches
    Eric Yi Sun
    Center for Molecular Imaging Research, Massachusetts General Hospital, Building 149, 13th St, Room 5410, Charlestown, MA 02129, USA
    Small 2:1144-7. 2006
  35. ncbi Cell internalization of magnetic nanoparticles using transfection agents
    Karin Montet-Abou
    Center for Molecular Imaging Research Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    Mol Imaging 6:1-9. 2007
    ..Conditions for loading cells with Feridex and a TFA need to be carefully selected to minimize nanoparticle precipitation and dextran adsorption to the cell surface...
  36. ncbi Molecular magnetic resonance imaging in cardiovascular medicine
    David E Sosnovik
    Center for Molecular Imaging Research, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129, USA
    Circulation 115:2076-86. 2007
  37. ncbi Multiparameter magnetic relaxation switch assays
    Sonia Taktak
    Center for Molecular Imaging Research and Department of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA
    Anal Chem 79:8863-9. 2007
    ..The T1/T2 and T2 replication interrogation methods illustrate how MRSw assays can employ multiple parameters, instead of relying only on T2, to obtain information about the reaction of NPs with molecular targets...
  38. pmc Magnetic microparticle aggregation for viscosity determination by MR
    Rui Hong
    Center for Molecular Imaging Research, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    Magn Reson Med 59:515-20. 2008
    ....
  39. pmc Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications
    David E Sosnovik
    Center for Molecular Imaging Research, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, 02129, USA
    Basic Res Cardiol 103:122-30. 2008
    ..First generation MNP are already in clinical use and second generation agents, with longer blood half lives, are likely to be approved for routine clinical use in the near future...
  40. pmc Sensitive NMR sensors detect antibodies to influenza
    Isaac Koh
    Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Boston, MA 02129, USA
    Angew Chem Int Ed Engl 47:4119-21. 2008
  41. pmc A multifunctional single-attachment-point reagent for controlled protein biotinylation
    Elisabeth Garanger
    Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Boston, Massachusetts 02129, USA
    Bioconjug Chem 20:170-3. 2009
    ..The MSAP peptide-scaffold approach allows fluorophores, chromophores, or reactive groups to be combined with biotin and provides a broad approach to obtain multifunctional biotin-based reagents...
  42. ncbi Protamine as an efficient membrane-translocating peptide
    Fred Reynolds
    Center for Molecular Imaging Research, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts 02129, USA
    Bioconjug Chem 16:1240-5. 2005
    ..In addition, the fluorescent protamines developed here might be used to further our understanding of this important pharmaceutical...
  43. pmc Monocyte subset dynamics in human atherosclerosis can be profiled with magnetic nano-sensors
    Moritz Wildgruber
    Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 4:e5663. 2009
    ....
  44. pmc Electrode chemistry yields a nanoparticle-based NMR sensor for calcium
    Sonia Taktak
    Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Langmuir 24:7596-8. 2008
    ..Our work suggests that the many chemistries of nonbiological origin, such as those employed for ion-selective electrodes, can be adapted to obtain NMR-based sensors for ions...