ANP  Vol.3 No.2 , May 2014
Contrast Agents and Cell Labeling Strategies for in Vivo Imaging
Abstract: Regenerative medicine has become a new therapeutic approach in which stem cells or genetically reprogrammed cells are delivered to diseased areas in the body with the intention that such multipotent cells will differentiate into healthy tissue and exchange damaged tissue. The success of such cell-based therapeutic approaches depends on precise dosing and delivery of the cells to the desired site in the human body. To determine the accuracy and efficacy of the therapy, tracking of the engrafted cells in an intact living organism is crucial. There is a great need for sensitive, noninvasive imaging methods, which would allow clinicians to monitor viability, migration dynamics, differentiation towards specific cell type, regeneration potential and integration of transplanted cells with host tissues for an optimal time period. Various in vivo tracking methods are currently used including: MRI (Magnetic Resonance Imaging), PET (Positron Emission Tomography), SPECT (Single Photon Emission Computer Tomography), optical imaging (OI), photoacoustic imaging (PAI) and ultrasound (US). In order to carry out the detection with each of the aforementioned techniques, the cells must be labeled either exogenously (ex vivo) or endogenously (in vivo). For tracking the administrated cells, scientists usually manipulate cells outside the living organism by incorporating imaging contrast agents (CAs) or reporter genes. Strategies for stem cell labeling using CAs will be reviewed in the light of various imaging techniques.
Cite this paper: Legacz, M. , Roepke, K. , Giersig, M. and Pison, U. (2014) Contrast Agents and Cell Labeling Strategies for in Vivo Imaging. Advances in Nanoparticles, 3, 41-53. doi: 10.4236/anp.2014.32007.

[1]   Bexell, D., Svensson, A. and Bengzon, J. (2013) Stem CellBased Therapy for Malignant Glioma. Cancer Treatment Reviews, 39, 358365.

[2]   Helmy, K.Y., Patel, S.A., Silverio, K., Pliner, L. and Rameshwar, P. (2010) Stem Cells and Regenerative Medicine: Accomplishments to Date and Future Promise. Therapeutic Delivery, 1, 693705.

[3]   Sadelain, M., Rivière, I. and Brentjens, R. (2003) Targeting Tumours with Genetically Enhanced T Lymphocytes. Nature Reviews Cancer, 3, 3545.

[4]   Jadczyk, T., Faulkner, A. and Madeddu, P. (2013) Stem Cell Therapy for Cardiovascular Disease: The Demise of Alchemy and Rise of Pharmacology. British Journal of Pharmacology, 169, 247268.

[5]   Yi, B.R., Kim, S.U. and Choi, K.C. (2013) Development and Application of Neural Stem Cells for Treating Various Human Neurological Diseases in Animal Models. Laboratory Animal Research, 29, 131137.

[6]   Rice, C.M., Kemp, K., Wilkins, A. and Scolding, N.J. (2013) Cell Therapy for Multiple Sclerosis: An Evolving Concept with Implications for Other Neurodegenerative Diseases. Lancet, 382, 12041213.

[7]   MartínezMorales, P.L., Revilla, A., Ocana, I., González, C., Sainz, P., McGuire, D. and Liste, I. (2013) Progress in Stem Cell Therapy for Major Human Neurological Disorders. Stem Cell Reviews, 9, 685699.

[8]   Van Brussel, I., Lee, W.P., Rombouts, M., Nuyts, A.H., Heylen, M., De Winter, B.Y., Cools, N. and Schrijvers, D.M. (2014) Tolerogenic Dendritic Cell Vaccines to Treat Autoimmune Diseases: Can the Unattainable Dream Turn into Reality? Autoimmunity Reviews, 13, 138150.

[9]   Shrestha, C., Zhao, L., Chen, K., He, H. and Mo, Z. (2013) Enhanced Healing of Diabetic Wounds by Subcutaneous Administration of Human Umbilical Cord Derived Stem Cells and Their Conditioned Media. International Journal of Endocrinology, 2013, Article ID: 592454.

[10]   Ojeh, N.O. and Navsaria, H.A. (2013) An in Vitro Skin Model to Study the Effect of Mesenchymal Stem Cells in Wound Healing and Epidermal Regeneration. Journal of Biomedical Materials Research Part A, 00A, 18.

[11]   Alison, M.R. and Islam, S. (2009) Attributes of Adult Stem Cells. The Journal of Pathology, 217, 144160.

[12]   Marsh, M. and Helenius, A. (2006) Virus Entry: Open Sesame. Cell, 124, 729740.

[13]   Shapiro, E.M., Skrtic, S., Sharer, K., Hill, J.M., Dunbar, C.E. and Koretsky, A.P. (2004) MRI Detection of Single Particles for Cellular Imaging. Proceedings of the National Academy of Sciences of the United States of America, 101, 1090110906.

[14]   Al Faraj, A., Luciani, N., KolosnjajTabi, J., Mattar, E., Clement, O., Wilhelm, C. and Gazeau, F. (2013) RealTime HighResolution Magnetic Resonance Tracking of Macrophage Subpopulations in a Murine Inflammation Model: A Pilot Study with a Commercially Available Cryogenic Probe. Contrast Media & Molecular Imaging, 8, 193203.

[15]   Jacobs, R.E. and Cherry, S.R. (2001) Complementary Emerging Techniques: HighResolution PET and MRI. Current Opinion in Neurobiology, 11, 621629.

[16]   Macintosh, B.J. and Graham, S.J. (2013) Magnetic Resonance Imaging to Visualize Stroke and Characterize Stroke Recovery: A Review. Frontiers in Neurology, 27, 60.

[17]   Bulte, J.W. and Kraitchman, D.L. (2004) Iron Oxide MR Contrast Agents for Molecular and Cellular Imaging. NMR in Biomedicine, 17, 484499.

[18]   Geraldes, C.F. and Laurent, S. (2009) Classification and Basic Properties of Contrast Agents for Magnetic Resonance Imaging. Contrast Media & Molecular Imaging, 4, 123.

[19]   Frangioni, J.V. and Hajjar, R.J. (2004) In Vivo Tracking of Stem Cells for Clinical Trials in Cardiovascular Disease. Circulation, 110, 33783383.

[20]   Mills, P.H. and Ahrens, E.T. (2009) Enhanced PositiveContrast Visualization of Paramagnetic Contrast Agents Using Phase Images. Magnetic Resonance in Medicine, 62, 13491355.

[21]   Leung, K. (2010) 99mTcDiethylenetriamine Pentaacetic Acid Superparamagnetic Iron Oxide Nanoparticles Conjugated with Lactobionic Acid. Molecular Imaging and Contrast Agent Database (MICAD).

[22]   Aime, S. and Caravan, P. (2009) Biodistribution of GadoliniumBased Contrast Agents, Including Gadolinium Deposi tion. Journal of Magnetic Resonance Imaging, 30, 12591267.

[23]   Guenoun, J., Ruggiero, A., Doeswijk, G., Janssens, R.C., Koning, G.A., Kotek, G., Krestin, G.P. and Bernsen, M.R. (2013) In Vivo Quantitative Assessment of Cell Viability of Gadolinium or IronLabeled Cells Using MRI and Biolu minescence Imaging. Contrast Media & Molecular Imaging, 8, 165174.

[24]   Kalish, H., Arbab, A.S., Miller, B.R., Lewis, B.K., Zywicke, H.A., Bulte, J.W., Bryant Jr., L.H. and Frank, J.A. (2003) Combination of Transfection Agents and Magnetic Resonance Contrast Agents for Cellular Imaging: Relationship be tween Relaxivities, Electrostatic Forces, and Chemical. Magnetic Resonance in Medicine, 50, 275282.

[25]   Rudelius, M., DaldrupLink, H.E., Heinzmann, U., Piontek, G., Settles, M., Link, T.M. and Schlegel, J. (2003) Highly Efficient Paramagnetic Labelling of Embryonic and Neuronal Stem Cells. European Journal of Nuclear Medicine and Molecular Imaging, 30, 10381044.

[26]   Bhorade, R., Weissleder, R., Nakakoshi, T., Moore, A. and Tung, C.H. (2000) Macrocyclic Chelators with Paramagne tic Cations Are Internalized into Mammalian Cells via a HIVTat Derived Membrane Translocation Peptide. Bioconju gate Chemistry, 11, 301305.

[27]   Prantner, A.M., Sharma, V., Garbow, J.R. and PiwnicaWorms, D. (2003) Synthesis and Characterization of a Gd DOTADPermeation Peptide for Magnetic Resonance Relaxation Enhancement of Intracellular Targets. Molecular Imaging, 2, 333341.

[28]   Bullok, K.E., Gammon, S.T., Violini, S., Prantner, A.M., Villalobos, V.M., Sharma, V. and PiwnicaWorms, D. (2006) Permeation Peptide Conjugates for in Vivo Molecular Imaging Applications. Molecular Imaging, 5, 115.

[29]   Heckl, S., Debus, J., Jenne, J., Pipkorn, R., Waldeck, W., Spring, H., Rastert, R., von der Lieth, C.W. and Braun, K. (2002) CNNGd(3+) Enables Cell Nucleus Molecular Imaging of Prostate Cancer Cells: The Last 600 nm. Cancer Re search, 62, 70187024.

[30]   Writer, M.J., Kyrtatos, P.G., Bienemann, A.S., Pugh, J.A., Lowe, A.S., VillegasLlerena, C., Kenny, G.D., White, E.A., Gill, S.S., McLeod, C.W., Lythgoe, M.F. and Hart, S.L. (2012) Lipid Peptide Nanocomplexes for Gene Delivery and Magnetic Resonance Imaging in the Brain. Journal of Controlled Release, 162, 340348.

[31]   Digilio, G., Menchise, V., Gianolio, E., Catanzaro, V., Carrera, C., Napolitano, R., Fedeli, F. and Aime, S. (2010) Ex ofacial Protein Thiols as a Route for the Internalization of Gd(III)Based Complexes for Magnetic Resonance Imaging Cell Labeling. Journal of Medicinal Chemistry, 53, 48774890.

[32]   Bellin, M.F. and Van Der Molen, A.J. (2008) Extracellular GadoliniumBased Contrast Media: An Overview. Euro pean Journal of Radiology, 66, 160167.

[33]   Hasebroock, K.M. and Serkova, N.J. (2009) Toxicity of MRI and CT Contrast Agents. Expert Opinion on Drug Meta bolism & Toxicology, 5, 403416.

[34]   DaSilva, M., Deming, M.O., Fligiel, S.E., Dame, M.K., Johnson, K.J., Swartz, R.D. and Varani, J. (2010) Responses of Human Skin in Organ Culture and Human Skin Fibroblasts to a GadoliniumBased MRI Contrast Agent: Comparison of Skin from Patients with EndStage Renal Disease and Skin from Healthy Subjects. Investigative Radiology, 45, 733739.

[35]   Pan, D., Caruthers, S.D., Senpan, A., Schmieder, A.H., Wickline, S.A. and Lanza, G.M. (2010) Revisiting an Old Fri end: ManganeseBased MRI Contrast Agents. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Published Online.

[36]   Létourneau, M., Tremblay, M., Faucher, L., Rojas, D., Chevallier, P., Gossuin, Y., Lagueux, J. and Fortin, M.A. (2012) MnOLabeled Cells: Positive Contrast Enhancement in MRI. The Journal of Physical Chemistry B, 116, 1322813238.

[37]   Yamada, M., Gurney, P.T., Chung, J., Kundu, P., Drukker, M., Smith, A.K., Weissman, I.L., Nishimura, D., Robbins, R.C. and Yang, P.C. (2009) ManganeseGuided Cellular MRI of Human Embryonic Stem Cell and Human Bone Mar row Stromal Cell Viability. Magnetic Resonance in Medicine, 62, 10471054.

[38]   Gilad, A.A., Walczak, P., McMahon, M.T., Na, H.B., Lee, J.H., An, K., Hyeon, T., van Zijl, P.C. and Bulte, J.W. (2008) MR Tracking of Transplanted Cells with “Positive Contrast” Using Manganese Oxide Nanoparticles. Magnetic Resonance in Medicine, 60, 17.

[39]   Srinivas, M., BoehmSturm, P., Figdor, C.G., de Vries, I.J. and Hoehn, M. (2012) Labeling Cells for in Vivo Tracking Using 19F MRI. Biomaterials, 33, 88308840.

[40]   Zhong, J., Mills, P.H., Hitchens, T.K. and Ahrens, E.T. (2013) Accelerated Fluorine19 MRI Cell Tracking Using Compressed Sensing. Magnetic Resonance in Medicine, 69, 16831690.

[41]   Janjic, J.M. and Ahrens, E.T. (2009) FluorineContaining Nanoemulsions for MRI Cell Tracking. Wiley Interdiscipli nary Reviews: Nanomedicine and Nanobiotechnology, 1, 492501.

[42]   BoehmSturm, P., Mengler, L., Wecker, S., Hoehn, M. and Kallur, T. (2011) In Vivo Tracking of Human Neural Stem Cells with 19F Magnetic Resonance Imaging. PLoS ONE, 6, Article ID: e29040.

[43]   Ahrens, E.T., Flores, R., Xu, H. and Morel, P.A. (2005) In Vivo Imaging Platform for Tracking Immunotherapeutic Cells. Nature Biotechnology, 23, 983987.

[44]   Partlow, K.C., Chen, J., Brant, J.A., Neubauer, A.M., Meyerrose, T.E., Creer, M.H., Nolta, J.A., Caruthers, S.D., Lanza, G.M. and Wickline, S.A. (2007) 19F Magnetic Resonance Imaging for Stem/Progenitor Cell Tracking with Multiple Unique Perfluorocarbon Nanobeacons. The FASEB Journal, 21, 16471654.

[45]   Anbari, K.K., Garino, J.P. and Mackenzie, C.F. (2004) Hemoglobin Substitutes. European Spine Journal, 13, S76S82.

[46]   Liu, G., Li, Y. and Pagel, M.D. (2007) Design and Characterization of New Irreversible Responsive PARACEST MRI Contrast Agent That Detects Nitric Oxide. Magnetic Resonance in Medicine, 58, 12491256.

[47]   Hingorani, D. and Pagel, M.D. (2012) An EnzymeResponsive PARACEST MRI Contrast Agent That “Turns on” after Catalysis. Proceedings of the International Society for Magnetic Resonance in Medicine, 20, 486.

[48]   Ferrauto, G., Castelli, D.D., Terreno, E. and Aime, S. (2013) In Vivo MRI Visualization of Different Cell Populations Labeled with PARACEST Agents. Magnetic Resonance in Medicine, 69, 17031711.

[49]   Weissleder, R., Stark, D.D., Compton, C.C., Wittenberg, J. and Ferrucci, J.T. (1987) FerriteEnhanced MR Imaging of Hepatic Lymphoma: An Experimental Study in Rats. American Journal of Roentgenology, 149, 11611165.

[50]   Weissleder, R., Hahn, P.F., Stark, D.D., Rummeny, E., Wittenberg, J. and Ferrucci, J.T. (1987) MR Imaging of Splenic Metastases: FerriteEnhanced Detection in Rats. American Journal of Roentgenology, 149, 723726.

[51]   Weissleder, R., Hahn, P.F., Stark, D.D., Elizondo, G., Saini, S., Todd, L.E., Wittenberg, J. and Ferrucci, J.T. (1988) Superparamagnetic Iron Oxide: Enhanced Detection of Focal Splenic Tumors with MR Imaging. Radiology, 169, 399403.

[52]   Lodhia, J., Mandarano, G., Ferris, N.J., Eu, P. and Cowell, S.F. (2010) Development and Use of Iron Oxide Nanopar ticles (Part 1): Synthesis of Iron Oxide Nanoparticles for MRI. Biomedical Imaging and Intervention Journal, 6, e12.

[53]   Thorekm, D.L. and Tsourkas, A. (2008) Size, Charge and Concentration Dependent Uptake of Iron Oxide Particles by NonPhagocytic Cells. Biomaterials, 29, 35833590.

[54]   Weissleder, R., Stark, D.D., Engelstad, B.L., Bacon, B.R., Compton, C.C., White, D.L., Jacobs, P. and Lewis, J. (1989) Superparamagnetic Iron Oxide: Pharmacokinetics and Toxicity. American Journal of Roentgenology, 152, 167173.

[55]   Raynal, I., Prigent, P., Peyramaure, S., Najid, A., Rebuzzi, C. and Corot, C. (2004) Macrophage Endocytosis of Super paramagnetic Iron Oxide Nanoparticles: Mechanisms and Comparison of Ferumoxides and Ferumoxtran10. Investiga tive Radiology, 39, 5663.

[56]   Arbab, A.S., Yocum, G.T., Kalish, H., Jordan, E.K., Anderson, S.A., Khakoo, A.Y., Read, E.J. and Frank, J.A. (2004) Efficient Magnetic Cell Labeling with Protamine Sulfate Complexed to Ferumoxides for Cellular MRI. Blood, 104, 12171223.

[57]   Baumjohann, D., Hess, A., Budinsky, L., Brune, K., Schuler, G. and Lutz, M.B. (2006) In Vivo Magnetic Resonance Imaging of Dendritic Cell Migration into the Draining lymph Nodes of Mice. European Journal of Immunology, 36, 25442555.

[58]   Schlorf, T., Meincke, M., Kossel, E., Glüer, C.C., Jansen, O. and Mentlein, R. (2010) Biological Properties of Iron Oxide Nanoparticles for Cellular and Molecular Magnetic Resonance Imaging. International Journal of Molecular Sci ences, 12, 1223.

[59]   Chen, J., Wang, F., Zhang, Y., Jin, X., Zhang, L., Feng, Y., Lin, X. and Yang, L. (2012) In Vivo Tracking of Superpa ramagnetic Iron Oxide Nanoparticle Labeled Chondrocytes in Large Animal Model. Annals of Biomedical Engineering, 40, 25682578.

[60]   Lee, J.H., Jung, M.J., Hwang, Y.H., Lee, Y.J., Lee, S., Lee, D.Y. and Shin, H. (2012) HeparinCoated Superparamag netic Iron Oxide for in Vivo MR Imaging of Human MSCs. Biomaterials, 33, 48614871.

[61]   Luchetti, A., Milani, D., Ruffini, F., Galli, R., Falini, A., Quattrini, A., Scotti, G., Comi, G., Martino, G., Furlan, R. and Politi, L.S. (2012) Monoclonal Antibodies Conjugated with Superparamagnetic Iron Oxide Particles Allow Magnetic Resonance Imaging Detection of Lymphocytes in the Mouse Brain. Molecular Imaging, 11, 114125.

[62]   Saha, S., Yang, X.B., Tanner, S., Curran, S., Wood, D. and Kirkham, J. (2013) The Effects of Iron Oxide Incorporation on the Chondrogenic Potential of Three Human Cell Types. Journal of Tissue Engineering and Regenerative Medicine, 7, 461469.

[63]   Farrell, E., Wielopolski, P., Pavljasevic, P., van Tiel, S., Jahr, H., Verhaar, J., Weinans, H., Krestin, G., O’Brien, F.J., van Osch, G. and Bernsen, M. (2008) Effects of Iron Oxide Incorporation for Long Term Cell Tracking on MSC Dif ferentiation in Vitro and in Vivo. Biochemical and Biophysical Research Communications, 369, 10761081.

[64]   Liu, T., Zhou, H., Xia, R., Liao, J., Wu, C., Wang, H., Ai, H., Bi, F. and Gao, F. (2012) Tracking Tumor Cells in Lym phatics in a Mice Xenograft Model by Magnetic Resonance Imaging. Molecular Imaging, 11, 451460.

[65]   Struys, T., KetkarAtre, A., Gervois, P., Leten, C., Hilkens, P., Martens, W., Bronckaers, A., Dresselaers, T., Politis, C., Lambrichts, I. and Himmelreich, U. (2013) Magnetic Resonance Imaging of Human Dental Pulp Stem Cells in Vitro and in Vivo. Cell Transplantation, 22, 18131829.

[66]   Lu, S.S., Liu, S., Zu, Q.Q., Xu, X.Q., Yu, J., Wang, J.W., Zhang, Y. and Shi, H.B. (2013) In Vivo MR Imaging of In traarterially Delivered Magnetically Labeled Mesenchymal Stem Cells in a Canine Stroke Model. PLoS ONE, 8, Ar ticle ID: e54963.

[67]   Mathiasen, A.B., Hansen, L., Friis, T., Thomsen, C., Bhakoo, K. and Kastrup, J. (2013) Optimal Labeling Dose, Labe ling Time, and Magnetic Resonance Imaging Detection Limits of Ultrasmall Superparamagnetic IronOxide Nanopar ticle Labeled Mesenchymal Stromal Cells. Stem Cells International, 2013, Article ID: 353105.

[68]   Richards, J.M., Shaw, C.A., Lang, N.N., Williams, M.C., Semple, S.I., MacGillivray, T.J., Gray, C., Crawford, J.H., Alam, S.R., Atkinson, A.P., Forrest, E.K., Bienek, C., Mills, N.L., Burdess, A., Dhaliwal, K., Simpson, A.J., Wallace, W.A., Hill, A.T., Roddie, P.H., McKillop, G., Connolly, T.A., Feuerstein, G.Z., Barclay, G.R., Turner, M.L. and Newby, D.E. (2012) In Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide: Feasibility and Safety In Humans. Circulation: Cardiovascular Imaging, 5, 509517.

[69]   Kang, J.H. and Chung, J.K. (2008) MolecularGenetic Imaging Based on Reporter Gene Expression. Journal of Nuc lear Medicine, 49, 164S179S.

[70]   Choi, Y., Kim, H.S., Cho, K.W., Lee, K.M., Yi, Y.J., Eun, S.J., Kim, H.J., Woo, J., Choi, S.H., Whangbo, T.K., Choi, C., Noh, D.Y. and Moon, W.K. (2013) Noninvasive Identification of Viable Cell Populations in DocetaxelTreated Breast Tumors Using FerritinBased Magnetic Resonance Imaging. PLoS ONE, 8, Article ID: e52931.

[71]   Iordanova, B., Hitchens, T.K., Robison, C.S. and Ahrens, E.T. (2013) Engineered Mitochondrial Ferritin as a Magnetic Resonance Imaging Reporter in Mouse Olfactory Epithelium. PLoS ONE, 8, Article ID: e72720.

[72]   BarShir, A., Liu, G., Chan, K., Oskolkov, N., Song, X., Yadav, N.N., Walczak, P., McMahon, M.T., van Zijl, P.C., Bulte, J.W. and Gilad, A.A. (2014) Human Protamine1 as an MRI Reporter Gene Based on Chemical Exchange. ACS Chemical Biology, 9, 134138.

[73]   Gilad, A.A., McMahon, M.T., Walczak, P., Winnard, P.T., Raman, V., van Laarhoven, H.W., Skoglund, C.M., Bulte, J.W. and van Zij, P.C. (2007) Artificial Reporter Gene Providing MRI Contrast Based on Proton Exchange. Nature Bi otechnology, 25, 217219.

[74]   Zhang, S.J. and Wu, J.C. (2007) Comparison of Imaging Techniques for Tracking Cardiac Stem Cell Therapy. The Journal of Nuclear Medicine, 48, 19161919.

[75]   James, N.S., Chen, Y., Joshi, P., Ohulchanskyy, T.Y., Ethirajan, M., Henary, M., Strekowsk, L. and Pandey, R.K. (2013) Evaluation of Polymethine Dyes as Potential Probes for Near Infrared Fluorescence Imaging of Tumors: Part1. Theranostics, 3, 692702.

[76]   ReschGenger, U., Grabolle, M., CavaliereJaricot, S., Nitschke, R. and Nann, T. (2008) Quantum Dots versus Organic Dyes as Fluorescent Labels. Nature Methods, 5, 763775.

[77]   Santra, S. and Malhotra, A. (2011) Fluorescent Nanoparticle Probes for Imaging of Cancer. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Published Online.

[78]   Hoi, H., Howe, E.S., Ding, Y., Zhang, W., Baird, M.A., Sell, B.R., Allen, J.R., Davidson, M.W. and Campbell, R.E. (2013) An Engineered Monomeric Zoanthus sp. Yellow Fluorescent Protein. Chemistry & Biology, 20, 12031205.

[79]   Goto, K., Kato, G., Kawahara, I., Luo, Y., Obata, K., Misawa, H., Ishikawa, T., Kuniyasu, H., Nabekura, J. and Takaki, M. (2013) In Vivo Imaging of Enteric Neurogenesis in the Deep Tissue of Mouse Small Intestine. PLoS ONE, 8, Ar ticle ID: e54814.

[80]   Shcherbo, D., Merzlyak, E.M., Chepurnykh, T.V., Fradkov, A.F., Ermakova, G.V., Solovieva, E.A., Lukyanov, K.A., Bogdanova, E.A., Zaraisky, A.G., Lukyanov, S. and Chudakov, D.M. (2007) Bright FarRed Fluorescent Protein for WholeBody Imaging. Nature Methods, 4, 741746.

[81]   Welsh, D.K. and Noguchi, T. (2012) Cellular Bioluminescence Imaging. Cold Spring Harb Protocols, 2012, 1028.

[82]   Rahmim, A. and Zaidi, H. (2008) PET versus SPECT: Strengths, Limitations and Challenges. Nuclear Medicine Com munications, 29, 193207.

[83]   Massoud, T.F. and Gambhir, S.S. (2003) Molecular Imaging in Living Subjects: Seeing Fundamental Biological Pro cesses in a New Light. Genes & Development, 17, 545580.

[84]   Nutt, R. (2002) 1999 ICP Distinguished Scientist Award. The History of Positron Emission Tomography. Molecular Imaging & Biology, 4, 1126.

[85]   Tegnebratt, T., Lu, L., Lee, L., Meresse, V., Tessier, J., Ishii, N., Harada, N., Pisa, P. and StoneElander, S. (2013) [18F]FDGPET Imaging Is an Early NonInvasive Pharmacodynamic Biomarker for a FirstinClass Dual MEK/Raf Inhibitor, RO5126766 (CH5126766), in Preclinical Xenograft Models. EJNMMI Research, 3, 67.

[86]   Gholamrezanezhad, A., Mirpour, S., Ardekani, J.M., Bagheri, M., Alimoghadam, K., Yarmand, S. and Malekzadeh, R. (2009) Cytotoxicity of 111InOxine on Mesenchymal Stem Cells: A TimeDependent Adverse Effect. Nuclear Medici ne Communication, 30, 210216.

[87]   Ponomarev, V., Doubrovin, M., Shavrin, A., Serganova, I., Beresten, T., Ageyeva, L., Cai, C., Balatoni, J., Alauddin, M. and Gelovani, J. (2007) A HumanDerived Reporter Gene for Noninvasive Imaging in Humans: Mitochondrial Thymidine Kinase Type 2. The Journal of Nuclear Medicine, 48, 819826.

[88]   McCracken, M.N., Gschweng, E.H., NairGill, E., McLaughlin, J., Cooper, A.R., Riedinger, M., Cheng, D., Nosala, C., Kohn, D.B. and Witte, O.N. (2013) LongTerm in Vivo Monitoring of Mouse and Human Hematopoietic Stem Cell Engraftment with a Human Positron Emission Tomography Reporter Gene. Proceedings of the National Academy of Sciences of the United States of America, 110, 18571062.

[89]   Brader, P., Serganova, I. and Blasberg, R.G. (2013) Noninvasive Molecular Imaging Using Reporter Genes. The Journal of Nuclear Medicine, 54, 167172.

[90]   Yaghoubi, S.S., Jensen, M.C., Satyamurthy, N., Budhiraja, S., Paik, D., Czernin, J. and Gambhir, S.S. (2009) Noninvasive Detection of Therapeutic Cytolytic T Cells with 18FFHBG PET in a Patient with Glioma. Nature Clinical Practi ce Oncology, 6, 5358.

[91]   Qin, C., Lan, X., He, J., Xia, X., Tian, Y., Pei, Z., Yuan, H. and Zhang, Y. (2013) An in Vitro and in Vivo Evaluation of a Reporter Gene/Probe System hERL/18FFES. PLoS ONE, 8, Article ID: e61911.

[92]   Nam, S.Y., Ricles, L.M., Suggs, L.J. and Emelianov, S.Y. (2012) In Vivo Ultrasound and Photoacoustic Monitoring of Mesenchymal Stem Cells Labeled with Gold Nanotracers. PLoS ONE, 7, Article ID: e37267.

[93]   Wang, L.V. and Hu, S. (2012) Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs. Science, 335, 14581462.

[94]   Yang, X.M., Stein, E.W., Ashkenazi, S. and Wang, L.H.V. (2009) Nanoparticles for Photoacoustic Imaging. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 1, 360368.

[95]   Greco, A., Mancini, M., Gargiulo, S., Gramanzini, M., Claudio, P.P., Brunetti, A. and Salvatore, M. (2012) Ultrasound Biomicroscopy in Small Animal Research: Applications in Molecular and Preclinical Imaging. Journal of Biomedicine and Biotechnology, 2012, Article ID: 519238.