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. 2007 Jul;4(3):428–433. doi: 10.1016/j.nurt.2007.05.010

Cellular magnetic resonance imaging: Nanometer and micrometer size particles for noninvasive cell localization

Jonathan R Slotkin 1, Kevin S Cahill 1, Suzanne A Tharin 1, Erik M Shapiro 2,✉
PMCID: PMC7479728  PMID: 17599708

Summary

The use of nanometer and micrometer-sized superparamagnetic iron oxide particles as cellular contrast agents allows for the noninvasive detection of labeled cells on high-resolution magnetic resonance images. The development and application of these techniques to neurologic disorders is likely to accelerate the development of cell transplantation therapies and allow for the detailed study of in vivo cellular biology. This review summarizes the early development of iron oxide—based cellular contrast agents and the more recent application of this technology to noninvasive imaging of cellular transplants. The ability of this technique to allow for the noninvasive detection of in vivo transplants on the single-cell level is highlighted.

Key Words: Stem cells, magnetic resonance imaging, single-cell imaging, superparamagnetic contrast agents, iron oxide, brain

Footnotes

Both authors contributed equally to this work.

References

  • 1.Rapalino O, Lazarov-Spiegler O, Agranov E, et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 1998;4:814–821. doi: 10.1038/nm0798-814. [DOI] [PubMed] [Google Scholar]
  • 2.Dunning MD, Lakatos A, Loizou L, et al. Superparamagnetic iron oxide-labeled Schwann cells and olfactory ensheathing cells can be traced in vivo by magnetic resonance imaging and retain functional properties after transplantation into the CNS. J Neurosci. 2004;24:9799–9810. doi: 10.1523/JNEUROSCI.3126-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Anderson SA, Shukaliak-Quandt J, Jordan EK, et al. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol. 2004;55:654–659. doi: 10.1002/ana.20066. [DOI] [PubMed] [Google Scholar]
  • 4.Bulte JW, Douglas T, Witwer B, et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol. 2001;19:1141–1147. doi: 10.1038/nbt1201-1141. [DOI] [PubMed] [Google Scholar]
  • 5.Arbab AS, Bashaw LA, Miller BR, et al. Characterization of biophysical and metabolic properties of cells labeled with super-paramagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology. 2003;229:838–846. doi: 10.1148/radiol.2293021215. [DOI] [PubMed] [Google Scholar]
  • 6.Arbab AS, Jordan EK, Wilson LB, Yocum GT, Lewis BK, Frank JA. In vivo trafficking and targeted delivery of magnetically labeled stem cells. Hum Gene Ther. 2004;15:351–360. doi: 10.1089/104303404322959506. [DOI] [PubMed] [Google Scholar]
  • 7.Frank JA, Miller BR, Arbab AS, et al. Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology. 2003;228:480–487. doi: 10.1148/radiol.2281020638. [DOI] [PubMed] [Google Scholar]
  • 8.Hayakawa J, Migita M, Ueda T, Shimada T, Fukunaga Y. Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells: a useful model for studying the behavior of bone marrow cells in regeneration in vivo. Int J Hematol. 2003;77:456–462. doi: 10.1007/BF02986613. [DOI] [PubMed] [Google Scholar]
  • 9.Bulte JW, Zhang S, van Gelderen P, et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci U S A. 1999;96:15256–15261. doi: 10.1073/pnas.96.26.15256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Josephson L, Tung CH, Moore A, Weissleder R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug Chem. 1999;10:186–191. doi: 10.1021/bc980125h. [DOI] [PubMed] [Google Scholar]
  • 11.Lewin M, Carlesso N, Tung CH, et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol. 2000;18:410–414. doi: 10.1038/74464. [DOI] [PubMed] [Google Scholar]
  • 12.Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L. Ultrasmail superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology. 1990;175:489–493. doi: 10.1148/radiology.175.2.2326474. [DOI] [PubMed] [Google Scholar]
  • 13.Shen T, Weissleder R, Papisov M, Bogdanov A, Brady TJ. Monocrystalline iron oxide nanocompounds (MION): physico-chemical properties. Magn Reson Med. 1993;29:599–604. doi: 10.1002/mrm.1910290504. [DOI] [PubMed] [Google Scholar]
  • 14.Moore A, Grimm J, Han B, Santamaria P. Tracking the recruitment of diabetogenic CD8 + T-cells to the pancreas in real time. Diabetes. 2004;53:1459–1466. doi: 10.2337/diabetes.53.6.1459. [DOI] [PubMed] [Google Scholar]
  • 15.Jirak D, Kriz J, Herynek V, et al. MRI of transplanted pancreatic islets. Magn Reson Med. 2004;52:1228–1233. doi: 10.1002/mrm.20282. [DOI] [PubMed] [Google Scholar]
  • 16.Bulte JW, Duncan ID, Frank JA. In vivo magnetic resonance tracking of magnetically labeled cells after transplantation. J Cereb Blood Flow Metab. 2002;22:899–907. doi: 10.1097/00004647-200208000-00001. [DOI] [PubMed] [Google Scholar]
  • 17.Brown MA, Semelka RC. MRI: basic principles and applications. 2nd ed. New York: Wiley-Liss; 1999. [Google Scholar]
  • 18.Wang YX, Hussain SM, Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol. 2001;11:2319–2331. doi: 10.1007/s003300100908. [DOI] [PubMed] [Google Scholar]
  • 19.Wood ML, Hardy PA. Proton relaxation enhancement. J Magn Reson Imaging. 1993;3:149–156. doi: 10.1002/jmri.1880030127. [DOI] [PubMed] [Google Scholar]
  • 20.Schoepf U, Marecos EM, Melder RJ, Jain RK, Weissleder R. Intracellular magnetic labeling of lymphocytes for in vivo trafficking studies. Biotechniques. 1998;24:642–646. doi: 10.2144/98244rr01. [DOI] [PubMed] [Google Scholar]
  • 21.Dodd CH, Hsu HC, Chu WJ, et al. 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. doi: 10.1016/S0022-1759(01)00433-1. [DOI] [PubMed] [Google Scholar]
  • 22.Dennig J, Duncan E. Gene transfer into eukaryotic cells using activated polyamidoamine dendrimers. J Biotechnol. 2002;90:339–347. doi: 10.1016/s1389-0352(01)00066-6. [DOI] [PubMed] [Google Scholar]
  • 23.Shah DS, Sakthivel T, Toth I, Florence AT, Wilderspin AF. DNA transfection and transfected cell viability using amphipathic asymmetric dendrimers. Int J Pharm. 2000;208:41–48. doi: 10.1016/S0378-5173(00)00534-2. [DOI] [PubMed] [Google Scholar]
  • 24.Yoo H, Juliano RL. Enhanced delivery of antisense oligonucleotides with fluorophore-conjugated PAMAM dendrimers. Nucleic Acids Res. 2000;28:4225–4231. doi: 10.1093/nar/28.21.4225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Hudde T, Rayner SA, Comer RM, et al. Activated polyamidoamine dendrimers, a non-viral vector for gene transfer to the corneal endothelium. Gene Ther. 1999;6:939–943. doi: 10.1038/sj.gt.3300886. [DOI] [PubMed] [Google Scholar]
  • 26.Kukowska-Latallo JF, Bielinska AU, Johnson J, Spindler R, Tomalia DA, Baker JR. Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. Proc Natl Acad Sci U S A. 1996;93:4897–4902. doi: 10.1073/pnas.93.10.4897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Bulte JW, Douglas T, Witwer B, et al. Monitoring stem cell therapy in vivo using magnetodendrimers as a new class of cellular MR contrast agents. Acad Radiol. 2002;9(Suppl 2):S332–S335. doi: 10.1016/S1076-6332(03)80221-0. [DOI] [PubMed] [Google Scholar]
  • 28.Walter GA, Cahill KS, Huard J, et al. Noninvasive monitoring of stem cell transfer for muscle disorders. Magn Reson Med. 2004;51:273–277. doi: 10.1002/mrm.10684. [DOI] [PubMed] [Google Scholar]
  • 29.Frank JA, Zywicke H, Jordan EK, et al. Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. Acad Radiol. 2002;9(Suppl 2):S484–S487. doi: 10.1016/S1076-6332(03)80271-4. [DOI] [PubMed] [Google Scholar]
  • 30.Kalish H, Arbab AS, Miller BR, et al. Combination of transfection agents and magnetic resonance contrast agents for cellular imaging: relationship between relaxivities, electrostatic forces, and chemical composition. Magn Reson Med. 2003;50:275–282. doi: 10.1002/mrm.10556. [DOI] [PubMed] [Google Scholar]
  • 31.Cahill KS, Gaidosh G, Huard J, Silver X, Byrne BJ, Walter GA. Noninvasive monitoring and tracking of muscle stem cell transplants. Transplantation. 2004;78:1626–1633. doi: 10.1097/01.TP.0000145528.51525.8B. [DOI] [PubMed] [Google Scholar]
  • 32.Dodd SJ, Williams M, Suhan JP, Williams DS, Koretsky AP, Ho C. Detection of single mammalian cells by high-resolution magnetic resonance imaging. Biophys J. 1999;76:103–109. doi: 10.1016/S0006-3495(99)77182-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Hoehn M, Kustermann E, Blunk J, et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci U S A. 2002;99:16267–16272. doi: 10.1073/pnas.242435499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Foster-Gareau P, Heyn C, Alejski A, Rutt BK. Imaging single mammalian cells with a 1.5 T clinical MRI scanner. Magn Reson Med. 2003;49:968–971. doi: 10.1002/mrm.10417. [DOI] [PubMed] [Google Scholar]
  • 35.Heyn C, Ronald JA, Mackenzie LT, et al. In vivo magnetic resonance imaging of single cells in mouse brain with optical validation. Magn Reson Med. 2006;55:23–29. doi: 10.1002/mrm.20747. [DOI] [PubMed] [Google Scholar]
  • 36.Hinds KA, Hill JM, Shapiro EM, et al. Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood. 2003;102:867–872. doi: 10.1182/blood-2002-12-3669. [DOI] [PubMed] [Google Scholar]
  • 37.Shapiro EM, Skrtic S, Koretsky AP. Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn Reson Med. 2005;53:329–338. doi: 10.1002/mrm.20342. [DOI] [PubMed] [Google Scholar]
  • 38.Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP. MRI detection of single particles for cellular imaging. Proc Natl Acad Sci U S A. 2004;101:10901–10906. doi: 10.1073/pnas.0403918101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Shapiro EM, Sharer K, Skrtic S, Koretsky AP. In vivo detection of single cells by MRI. Magn Reson Med. 2006;55:242–249. doi: 10.1002/mrm.20718. [DOI] [PubMed] [Google Scholar]
  • 40.Shapiro EM, Gonzalez-Perez O, Manuel Garcia-Verdugo J, Alvarez-Buylla A, Koretsky AP. Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain. Neuroimage. 2006;32:1150–1157. doi: 10.1016/j.neuroimage.2006.04.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Louie AY, Huber MM, Ahrens ET, et al. In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol. 2000;18:321–325. doi: 10.1038/73780. [DOI] [PubMed] [Google Scholar]
  • 42.Cohen B, Ziv K, Plaks V, et al. MRI detection of transcriptional regulation of gene expression in transgenic mice. Nat Med. 2007;13:498–503. doi: 10.1038/nm1497. [DOI] [PubMed] [Google Scholar]
  • 43.Genove G, DeMarco U, Xu H, Goins WF, Ahrens ET. A new transgene reporter for in vivo magnetic resonance imaging. Nat Med. 2005;11:450–454. doi: 10.1038/nm1208. [DOI] [PubMed] [Google Scholar]

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