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Noninvasive cell-tracking methods

Abstract

Cell-based therapies, such as adoptive immunotherapy and stem-cell therapy, have received considerable attention as novel therapeutics in oncological research and clinical practice. The development of effective therapeutic strategies using tumor-targeted cells requires the ability to determine in vivo the location, distribution, and long-term viability of the therapeutic cell populations as well as their biological fate with respect to cell activation and differentiation. In conjunction with various noninvasive imaging modalities, cell-labeling methods, such as exogenous labeling or transfection with a reporter gene, allow visualization of labeled cells in vivo in real time, as well as monitoring and quantifying cell accumulation and function. Such cell-tracking methods also have an important role in basic cancer research, where they serve to elucidate novel biological mechanisms. In this Review, we describe the basic principles of cell-tracking methods, explain various approaches to cell tracking, and highlight recent examples for the application of such methods in animals and humans.

Key Points

  • Cell tracking has long been performed in the form of nonspecific labeling of white blood cells with either 111In-oxiquinolone or 99mTc-HMPAO, mostly to detect sites of infection

  • Novel cell-tracking techniques are based on vastly different principles and employ various detection methods, including MRI, PET, and optical imaging; each is associated with individual advantages and limitations

  • Direct labeling of cells only allows short-term tracking, whereas reporter genes (indirect labeling) can be employed for long-term tracking of transfected cells

  • Completed and ongoing clinical trials involve, for example, the direct labeling of blood cells with contrast agents or the indirect labeling of T cells with PET reporter genes

  • Future clinical applications of cell tracking will likely rely on PET, MRI, or combined MRI–PET to merge the complementary whole-body molecular, functional, and anatomical information provided by these methods

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Figure 1: Principles of direct and indirect labeling methods for cell tracking.
Figure 2: Example of in vivo cell tracking with MRI after ex vivo labeling and intravenous injection of labeled cells.
Figure 3: In vivo SPECT-CT monitoring of the distribution of CTLs after adoptive transfer.
Figure 4: Clinical cell tracking with MRI.
Figure 5: Brain MRI with and without superimposed PET of a patient after intracranial infusions of autologous cytolytic T cells expressing IL-13 zetakine and herpes simplex virus 1 thymidine kinase.
Figure 6: Bars indicate the characteristics of modalities for cell tracking, which strongly depend on individual experimental and clinical parameters.

References

  1. Rosenberg, S. A. et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).

    CAS  PubMed  Google Scholar 

  2. Weber, J. et al. White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. Clin. Cancer Res. 17, 1664–1673 (2011).

    CAS  PubMed  Google Scholar 

  3. Jha, P. et al. Monitoring of natural killer cell immunotherapy using noninvasive imaging modalities. Cancer Res. 70, 6109–6113 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Minn, A. J. et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J. Clin. Invest. 115, 44–55 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Grimm, J., Kircher, M. F. & Weissleder, R. Cell tracking. Principles and applications [German]. Radiologe 47, 25–33 (2007).

    CAS  PubMed  Google Scholar 

  6. Kircher, M. F. et al. In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res. 63, 6838–6846 (2003).

    CAS  PubMed  Google Scholar 

  7. Pittet, M. J. et al. In vivo imaging of T cell delivery to tumors after adoptive transfer therapy. Proc. Natl Acad. Sci. USA 104, 12457–12461 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Grimm, J., Swirski, F. K., Pittet, M., Josephson, L. & Weissleder, R. A nanoparticle-based cell labeling agent for cell tracking with SPECT/CT. Mol. Imaging 5, 364 (2006).

    Google Scholar 

  9. Zhou, R. et al. In vivo detection of stem cells grafted in infarcted rat myocardium. J. Nucl. Med. 46, 816–822 (2005).

    CAS  PubMed  Google Scholar 

  10. Moore, A., Grimm, J., Han, B. & Santamaria, P. Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes 53, 1459–1466 (2004).

    CAS  PubMed  Google Scholar 

  11. Bettegowda, C. et al. Imaging bacterial infections with radiolabeled 1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodouracil. Proc. Natl Acad. Sci. USA 102, 1145–1150 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Blasberg, R. G. & Gelovani, J. Molecular-genetic imaging: a nuclear medicine-based perspective. Mol. Imaging 1, 280–300 (2002).

    CAS  PubMed  Google Scholar 

  13. Ponomarev, V. et al. A novel triple-modality reporter gene for whole-body fluorescent, bioluminescent, and nuclear noninvasive imaging. Eur. J. Nucl. Med. Mol. Imaging 31, 740–751 (2004).

    CAS  PubMed  Google Scholar 

  14. Tannous, B. A. et al. Metabolic biotinylation of cell surface receptors for in vivo imaging. Nat. Methods 3, 391–396 (2006).

    CAS  PubMed  Google Scholar 

  15. Weissleder, R. et al. In vivo magnetic resonance imaging of transgene expression. Nat. Med. 6, 351–355 (2000).

    CAS  PubMed  Google Scholar 

  16. Krishnan, M. et al. Effects of epigenetic modulation on reporter gene expression: implications for stem cell imaging. FASEB J. 20, 106–108 (2006).

    CAS  PubMed  Google Scholar 

  17. Rudelius, M. et al. Highly efficient paramagnetic labelling of embryonic and neuronal stem cells. Eur. J. Nucl. Med. Mol. Imaging 30, 1038–1044 (2003).

    CAS  PubMed  Google Scholar 

  18. Bhorade, R., Weissleder, R., Nakakoshi, T., Moore, A. & Tung, C. H. Macrocyclic chelators with paramagnetic cations are internalized into mammalian cells via a HIV-tat derived membrane translocation peptide. Bioconjug. Chem. 11, 301–305 (2000).

    CAS  PubMed  Google Scholar 

  19. Heckl, S. et al. CNN-Gd(3+) enables cell nucleus molecular imaging of prostate cancer cells: the last 600 nm. Cancer Res. 62, 7018–7024 (2002).

    CAS  PubMed  Google Scholar 

  20. Kim, T. et al. Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells. J. Am. Chem. Soc. 133, 2955–2961 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ward, K. M., Aletras, A. H. & Balaban, R. S. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J. Magn. Reson. 143, 79–87 (2000).

    CAS  PubMed  Google Scholar 

  22. Aime, S., Carrera, C., Delli Castelli, D., Geninatti Crich, S. & Terreno, E. Tunable imaging of cells labeled with MRI-PARACEST agents. Angew. Chem. Int. Ed. Engl. 44, 1813–1815 (2005).

    CAS  PubMed  Google Scholar 

  23. Shen, T., Weissleder, R., Papisov, M., Bogdanov, A. Jr & Brady, T. J. Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn. Reson. Med. 29, 599–604 (1993).

    CAS  PubMed  Google Scholar 

  24. Jung, C. W. Surface properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Magn. Reson. Imaging 13, 675–691 (1995).

    CAS  PubMed  Google Scholar 

  25. Wagner, S., Schnorr, J., Pilgrimm, 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. 37, 167–177 (2002).

    CAS  PubMed  Google Scholar 

  26. Shapiro, E. M. et al. MRI detection of single particles for cellular imaging. Proc. Natl Acad. Sci. USA 101, 10901–10906 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Moore, A., Weissleder, R. & Bogdanov, A. Jr. Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J. Magn. Reson. Imaging 7, 1140–1145 (1997).

    CAS  PubMed  Google Scholar 

  28. Weissleder, R., Cheng, H. C., Bogdanova, A. & Bogdanov, A. Jr. Magnetically labeled cells can be detected by MR imaging. J. Magn. Reson. Imaging 7, 258–263 (1997).

    CAS  PubMed  Google Scholar 

  29. Zelivyanskaya, M. L. et al. Tracking superparamagnetic iron oxide labeled monocytes in brain by high-field magnetic resonance imaging. J. Neurosci. Res. 73, 284–295 (2003).

    CAS  PubMed  Google Scholar 

  30. Sipe, J. C. et al. Method for intracellular magnetic labeling of human mononuclear cells using approved iron contrast agents. Magn. Reson. Imaging 17, 1521–1523 (1999).

    CAS  PubMed  Google Scholar 

  31. de Vries, I. J. et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat. Biotechnol. 23, 1407–1413 (2005).

    CAS  PubMed  Google Scholar 

  32. Saudek, F. et al. Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation 90, 1602–1606 (2010).

    PubMed  Google Scholar 

  33. Smirnov, P. et al. In vivo single cell detection of tumor-infiltrating lymphocytes with a clinical 1.5 Tesla MRI system. Magn. Reson. Med. 60, 1292–1297 (2008).

    PubMed  Google Scholar 

  34. Bulte, J. W. et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc. Natl Acad. Sci. USA 96, 15256–15261 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ahrens, E. T., Feili-Hariri, M., Xu, H., Genove, G. & Morel, P. A. Receptor-mediated endocytosis of iron-oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging. Magn. Reson. Med. 49, 1006–1013 (2003).

    CAS  PubMed  Google Scholar 

  36. Rettenbacher, L. & Galvan, G. Anaphylactic shock after repeated injection of 99mTc-labeled CEA antibody [German]. Nuklearmedizin 33, 127–128 (1994).

    CAS  PubMed  Google Scholar 

  37. Bulte, J. W. et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat. Biotechnol. 19, 1141–1147 (2001).

    CAS  PubMed  Google Scholar 

  38. Modo, M., Hoehn, M. & Bulte, J. W. Cellular MR imaging. Mol. Imaging 4, 143–164 (2005).

    PubMed  Google Scholar 

  39. Daldrup-Link, H. E. et al. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging. Eur. Radiol. 15, 4–13 (2005).

    PubMed  Google Scholar 

  40. Walczak, P., Kedziorek, D. A., Gilad, A. A., Lin, S. & Bulte, J. W. Instant MR labeling of stem cells using magnetoelectroporation. Magn. Reson. Med. 54, 769–774 (2005).

    CAS  PubMed  Google Scholar 

  41. Josephson, L., Tung, C. H., Moore, A. & Weissleder, R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug. Chem. 10, 186–191 (1999).

    CAS  PubMed  Google Scholar 

  42. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol. 18, 410–414 (2000).

    CAS  PubMed  Google Scholar 

  43. Koch, A. M. et al. Uptake and metabolism of a dual fluorochrome Tat-nanoparticle in HeLa cells. Bioconjug. Chem. 14, 1115–1121 (2003).

    CAS  PubMed  Google Scholar 

  44. Zhao, M., Kircher, M. F., Josephson, L. & Weissleder, R. Differential conjugation of Tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake. Bioconjug. Chem. 13, 840–844 (2002).

    CAS  PubMed  Google Scholar 

  45. Vianello, F. et al. Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control. J. Immunol. 176, 2902–2914 (2006).

    CAS  PubMed  Google Scholar 

  46. Suzuki, Y. et al. In vivo serial evaluation of superparamagnetic iron-oxide labeled stem cells by off-resonance positive contrast. Magn. Reson. Med. 60, 1269–1275 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ahrens, E. T., Flores, R., Xu, H. & Morel, P. A. In vivo imaging platform for tracking immunotherapeutic cells. Nat. Biotechnol. 23, 983–987 (2005).

    CAS  PubMed  Google Scholar 

  48. Partlow, K. C. et al. 19F magnetic resonance imaging for stem/progenitor cell tracking with multiple unique perfluorocarbon nanobeacons. FASEB J. 21, 1647–54 (2007).

    CAS  PubMed  Google Scholar 

  49. Gustafsson, B., Youens, S. & Louie, A. Y. Development of contrast agents targeted to macrophage scavenger receptors for MRI of vascular inflammation. Bioconjug. Chem. 17, 538–547 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Swirski, F. K. et al. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc. Natl Acad. Sci. USA 103, 10340–10345 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Harisinghani, M. G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491–2499 (2003).

    PubMed  Google Scholar 

  52. Guimaraes, A. R. et al. Pilot study evaluating use of lymphotrophic nanoparticle-enhanced magnetic resonance imaging for assessing lymph nodes in renal cell cancer. Urology 71, 708–712 (2008).

    PubMed  Google Scholar 

  53. Weissleder, R., Kelly, K., Sun, E. Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23, 1418–1423 (2005).

    CAS  PubMed  Google Scholar 

  54. Long, C. M., van Laarhoven, H. W., Bulte, J. W. & Levitsky, H. I. Magnetovaccination as a novel method to assess and quantify dendritic cell tumor antigen capture and delivery to lymph nodes. Cancer Res. 69, 3180–3187 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Genove, G., DeMarco, U., Xu, H., Goins, W. F. & Ahrens, E. T. A new transgene reporter for in vivo magnetic resonance imaging. Nat. Med. 11, 450–454 (2005).

    CAS  PubMed  Google Scholar 

  56. Cohen, B. et al. MRI detection of transcriptional regulation of gene expression in transgenic mice. Nat. Med. 13, 498–503 (2007).

    CAS  PubMed  Google Scholar 

  57. Gilad, A. A. et al. Artificial reporter gene providing MRI contrast based on proton exchange. Nat. Biotechnol. 25, 217–219 (2007).

    CAS  PubMed  Google Scholar 

  58. Mempel, T. R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).

    CAS  PubMed  Google Scholar 

  59. von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).

    CAS  PubMed  Google Scholar 

  60. Ntziachristos, V., Bremer, C., Graves, E. E., Ripoll, J. & Weissleder, R. In vivo tomographic imaging of near-infrared fluorescent probes. Mol. Imaging 1, 82–88 (2002).

    PubMed  Google Scholar 

  61. Liu, H. et al. Molecular optical imaging with radioactive probes. PLoS ONE 5, e9470 (2010).

    PubMed  PubMed Central  Google Scholar 

  62. Ruggiero, A., Holland, J. P., Lewis, J. S. & Grimm, J. Cerenkov luminescence imaging of medical isotopes. J. Nucl. Med. 51, 1123–1130 (2010).

    CAS  PubMed  Google Scholar 

  63. Shah, K. & Weissleder, R. Molecular optical imaging: applications leading to the development of present day therapeutics. NeuroRx 2, 215–225 (2005).

    PubMed  PubMed Central  Google Scholar 

  64. Ntziachristos, V., Ripoll, J., Wang, L. V. & Weissleder, R. Looking and listening to light: the evolution of whole-body photonic imaging. Nat. Biotechnol. 23, 313–320 (2005).

    CAS  PubMed  Google Scholar 

  65. Lim, Y. T. et al. Selection of quantum dot wavelengths for biomedical assays and imaging. Mol. Imaging 2, 50–64 (2003).

    CAS  PubMed  Google Scholar 

  66. Contag, P. R., Olomu, I. N., Stevenson, D. K. & Contag, C. H. Bioluminescent indicators in living mammals. Nat. Med. 4, 245–247 (1998).

    CAS  PubMed  Google Scholar 

  67. Welsh, D. K. & Kay, S. A. Bioluminescence imaging in living organisms. Curr. Opin. Biotechnol. 16, 73–78 (2005).

    CAS  PubMed  Google Scholar 

  68. Tang, Y. et al. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum. Gene Ther. 14, 1247–1254 (2003).

    CAS  PubMed  Google Scholar 

  69. Shcherbo, D. et al. Bright far-red fluorescent protein for whole-body imaging. Nat. Methods 4, 741–746 (2007).

    CAS  PubMed  Google Scholar 

  70. Borovjagin, A. V. et al. Noninvasive monitoring of mRFP1- and mCherry-labeled oncolytic adenoviruses in an orthotopic breast cancer model by spectral imaging. Mol. Imaging 9, 59–75 (2010).

    CAS  PubMed  Google Scholar 

  71. Massoud, T. F. & Gambhir, S. S. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 17, 545–580 (2003).

    CAS  PubMed  Google Scholar 

  72. Adonai, N. et al. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc. Natl Acad. Sci. USA 99, 3030–3035 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bhargava, K. K., Gupta, R. K., Nichols, K. J. & Palestro, C. J. In vitro human leukocyte labeling with 64Cu: an intraindividual comparison with 111In-oxine and 18F-FDG. Nucl. Med. Biol. 36, 545–549 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Brenner, W. et al. 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J. Nucl. Med. 45, 512–518 (2004).

    CAS  PubMed  Google Scholar 

  75. Kircher, M. F. et al. Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions. Circulation 117, 388–395 (2008).

    PubMed  PubMed Central  Google Scholar 

  76. Brenner, W. et al. 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J. Nucl. Med. 45, 512–518 (2004).

    CAS  PubMed  Google Scholar 

  77. Monteiro-Riviere, N. A., Inman, A. O. & Zhang, L. W. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol. Appl. Pharmacol. 234, 222–235 (2009).

    CAS  PubMed  Google Scholar 

  78. de Vries, E. F., Roca, M., Jamar, F., Israel, O. & Signore, A. Guidelines for the labelling of leucocytes with 99mTc-HMPAO. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur. J. Nucl Med. Mol. Imaging 37, 842–848 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Chalfie, M., Tu, Y., Euskirchen, G., Ward, W. W. & Prasher, D. C. Green fluorescent protein as a marker for gene expression. Science 263, 802–805 (1994).

    CAS  PubMed  Google Scholar 

  80. Rabinovich, B. A. et al. Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer. Proc. Natl Acad. Sci. USA 105, 14342–14346 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Acton, P. D. & Zhou, R. Imaging reporter genes for cell tracking with PET and SPECT. Q. J. Nucl. Med. Mol. Imaging 49, 349–360 (2005).

    CAS  PubMed  Google Scholar 

  82. Mettler, F. A. Jr. & Guiberteau, M. J. Essentials of nuclear medicine imaging 5th Edition (Saunders/Elsevier, Philadelphia, 2006).

    Google Scholar 

  83. Gambhir, S. S. et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc. Natl Acad. Sci. USA 97, 2785–2790 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Massoud, T. F., Singh, A. & Gambhir, S. S. Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications. AJNR Am. J. Neuroradiol. 29, 409–418 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Massoud, T. F., Singh, A. & Gambhir, S. S. Noninvasive molecular neuroimaging using reporter genes: part I, principles revisited. AJNR Am. J. Neuroradiol. 29, 229–234 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Serganova, I., Mayer-Kukuck, P., Huang, R. & Blasberg, R. Molecular imaging: reporter gene imaging. Handb. Exp. Pharmacol. 185, 167–223 (2008).

    CAS  Google Scholar 

  87. Yaghoubi, S. S. et al. Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat. Clin. Pract. Oncol. 6, 53–58 (2009).

    CAS  PubMed  Google Scholar 

  88. De, A., Lewis, X. Z. & Gambhir, S. S. Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice. Mol. Ther. 7, 681–691 (2003).

    CAS  PubMed  Google Scholar 

  89. Kohn, D. B., Sadelain, M. & Glorioso, J. C. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat. Rev. Cancer 3, 477–488 (2003).

    CAS  PubMed  Google Scholar 

  90. Papapetrou, E. P. et al. Genomic safe harbors permit high beta-globin transgene expression in thalassemia induced pluripotent stem cells. Nat. Biotechnol. 29, 73–78 (2011).

    CAS  PubMed  Google Scholar 

  91. Lam, A. P & Dean, D. A. Progress and prospects: nuclear import of nonviral vectors. Gene Ther. 17, 439–447 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Min, J. J. & Gambhir, S. S. Molecular imaging of PET reporter gene expression. Handb. Exp. Pharmacol. 185/2, 277–303 (2008).

    Google Scholar 

  93. Koehne, G. et al. Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes. Nat. Biotechnol. 21, 405–413 (2003).

    CAS  PubMed  Google Scholar 

  94. Ponomarev, V. et al. Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo. Neoplasia 3, 480–488 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Dobrenkov, K. et al. Monitoring the efficacy of adoptively transferred prostate cancer-targeted human T lymphocytes with PET and bioluminescence imaging. J. Nucl. Med. 49, 1162–1170 (2008).

    PubMed  Google Scholar 

  96. Cao, F. et al. Molecular imaging of embryonic stem cell misbehavior and suicide gene ablation. Cloning Stem Cells 9, 107–117 (2007).

    CAS  PubMed  Google Scholar 

  97. Brader, P. et al. Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging. Clin. Cancer Res. 14, 2295–2302 (2008).

    CAS  PubMed  Google Scholar 

  98. Rogers, B. E., Chaudhuri, T. R., Reynolds, P. N., Della Manna, D. & Zinn, K. R. Non-invasive gamma camera imaging of gene transfer using an adenoviral vector encoding an epitope-tagged receptor as a reporter. Gene Ther. 10, 105–114 (2003).

    CAS  PubMed  Google Scholar 

  99. Zhang, H. et al. Imaging expression of the human somatostatin receptor subtype-2 reporter gene with 68Ga-DOTATOC. J. Nucl. Med. 52, 123–131 (2011).

    CAS  PubMed  Google Scholar 

  100. Moroz, M. A. et al. Imaging hNET reporter gene expression with 124I-MIBG. J. Nucl. Med. 48, 827–836 (2007).

    CAS  PubMed  Google Scholar 

  101. Auricchio, A. et al. In vivo quantitative noninvasive imaging of gene transfer by single-photon emission computerized tomography. Hum. Gene Ther. 14, 255–261 (2003).

    CAS  PubMed  Google Scholar 

  102. Kummer, C. et al. Multitracer positron emission tomographic imaging of exogenous gene expression mediated by a universal herpes simplex virus 1 amplicon vector. Mol. Imaging 6, 181–192 (2007).

    CAS  PubMed  Google Scholar 

  103. MacLaren, D. C. et al. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther. 6, 785–791 (1999).

    CAS  PubMed  Google Scholar 

  104. Huang, M. et al. Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer. Cancer Gene Ther. 8, 612–618 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Doubrovin, M. M. et al. In vivo imaging and quantitation of adoptively transferred human antigen-specific T cells transduced to express a human norepinephrine transporter gene. Cancer Res. 67, 11959–11969 (2007).

    CAS  PubMed  Google Scholar 

  106. Kim, Y. H. et al. Reversing the silencing of reporter sodium/iodide symporter transgene for stem cell tracking. J. Nucl. Med. 46, 305–311 (2005).

    CAS  PubMed  Google Scholar 

  107. Terrovitis, J. et al. Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J. Am. Coll. Cardiol. 52, 1652–1660 (2008).

    PubMed  PubMed Central  Google Scholar 

  108. Hwang do, W. et al. Noninvasive in vivo monitoring of neuronal differentiation using reporter driven by a neuronal promoter. Eur. J. Nucl. Med. Mol. Imaging 35, 135–145 (2008).

    PubMed  Google Scholar 

  109. Soenen, S. J. & De Cuyper, M. Assessing cytotoxicity of (iron oxide-based) nanoparticles: an overview of different methods exemplified with cationic magnetoliposomes. Contrast Media Mol. Imaging 4, 207–219 (2009).

    CAS  PubMed  Google Scholar 

  110. Zhang, L. W., Baumer, W. & Monteiro-Riviere, N. A. Cellular uptake mechanisms and toxicity of quantum dots in dendritic cells. Nanomedicine 6, 777–791 (2011).

    CAS  PubMed  Google Scholar 

  111. Zanzonico, P. et al. [131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity. Eur. J. Nucl. Med. Mol. Imaging 33, 988–997 (2006).

    CAS  PubMed  Google Scholar 

  112. Mercier-Letondal, P. et al. Early immune response against retrovirally-transduced Herpes Simplex Virus-thymidine kinase-expressing gene-modified T cells coinfused with a T cell-depleted marrow graft: an altered immune response? Hum. Gene Ther. 19, 937–950 (2008).

    CAS  PubMed  Google Scholar 

  113. Wu, J. C. et al. Transcriptional profiling of reporter genes used for molecular imaging of embryonic stem cell transplantation. Physiol. Genomics 25, 29–38 (2006).

    PubMed  Google Scholar 

  114. Segal, A. W., Arnot, R. N., Thakur, M. L. & Lavender, J. P. Indium-111-labelled leucocytes for localisation of abscesses. Lancet 2, 1056–1058 (1976).

    CAS  PubMed  Google Scholar 

  115. Muller, C., Zielinski, C. C., Linkesch, W., Ludwig, H. & Sinzinger, H. In vivo tracing of indium-111 oxine-labeled human peripheral blood mononuclear cells in patients with lymphatic malignancies. J. Nucl. Med. 30, 1005–1011 (1989).

    CAS  PubMed  Google Scholar 

  116. Youssef, P. P. et al. Neutrophil trafficking into inflamed joints in patients with rheumatoid arthritis, and the effects of methylprednisolone. Arthritis Rheum. 39, 216–225 (1996).

    CAS  PubMed  Google Scholar 

  117. Blocklet, D. et al. 111In-oxine and 99mTc-HMPAO labelling of antigen-loaded dendritic cells: in vivo imaging and influence on motility and actin content. Eur. J. Nucl. Med. Mol. Imaging 30, 440–447 (2003).

    CAS  PubMed  Google Scholar 

  118. Bulte, J. W. In vivo MRI cell tracking: clinical studies. AJR Am. J. Roentgenol. 193, 314–325 (2009).

    PubMed  PubMed Central  Google Scholar 

  119. Stuber, M. et al. Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with ON-resonant water suppression (IRON). Magn. Reson. Med. 58, 1072–1077 (2007).

    PubMed  Google Scholar 

  120. Pichler, B. J., Kolb, A., Nagele, T. & Schlemmer, H. P. PET/MRI: paving the way for the next generation of clinical multimodality imaging applications. J. Nucl. Med. 51, 333–336 (2010).

    PubMed  Google Scholar 

  121. Patel, D. et al. The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents. Biomaterials 32, 1167–1176 (2011).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

Authors

Contributions

M. F. Kircher and J. Grimm researched data for the article and provided substantial contributions to the discussion of content. All authors wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jan Grimm.

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Competing interests

S. S. Gambhir is stockholder/director of Cellsight, Endra, Enlight, ImaginAB, and Visual Sonics. S. S. Gambhir also received grant/research support from GE Healthcare. M. F. Kircher and J. Grimm declare no competing interests.

Supplementary information

Supplementary Video 1

3D Animation of serial MRI data obtained after adoptive transfer of CLIO-HD-labeled, OT I transgenic CD8+ T cells into a mouse carrying both B16F0 melanomas (in the left side of the body) and B16-OVA melanomas (in the right side of the body). Reproduced with permission from the American Association for Cancer Research © Kircher, M. F. et al. Cancer Res. 63, 6838-6843 (2003). (MOV 2491 kb)

Supplementary Video 2

3D-virtual rendering shows that cytotoxic lymphocytes (CTLs) localize in the lung 2 h after injection. HA-specific CTLs were labeled with 111In-oxine and injected to mice with HA-positive and HA-negative tumor cells. The animation is a representative reconstruction and fusion in OsiriX of the SPECT and CT recordings. Reprinted with permission from the National Academy of Sciences © Pittet, M. J. et al. Proc. Natl Acad. Sci. USA 104, 12457–12461 (2007). (MOV 353 kb)

Supplementary Video 3

3D-virtual rendering shows that a large fraction of administered cytotoxic lymphocytes (CTLs) accumulate in the spleen, liver, and kidney 24 h after injection. HA-specific CTLs were labeled with 111In-oxine and injected to mice with HA-positive and HA-negative tumor cells. The animation is a representative reconstruction in OsiriX of the SPECT and CT recordings. Reprinted with permission from the National Academy of Sciences © Pittet, M. J. et al. Proc. Natl Acad. Sci. USA 104, 12457–12461 (2007). (MOV 324 kb)

Supplementary Video 4

3D-virtual rendering shows that cytotoxic lymphocytes (CTLs) preferentially accumulate in HA-positive tumors 24 h after injection. HA-specific CTLs were labeled with 111In-oxine and injected to mice with HA-positive and HA-negative tumor cells. The animation is a representative reconstruction in OsiriX of the SPECT and CT recordings. Reprinted with permission from the National Academy of Sciences © Pittet, M. J. et al. Proc. Natl Acad. Sci. USA 104, 12457–12461 (2007). (MOV 401 kb)

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Kircher, M., Gambhir, S. & Grimm, J. Noninvasive cell-tracking methods. Nat Rev Clin Oncol 8, 677–688 (2011). https://doi.org/10.1038/nrclinonc.2011.141

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