[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

A New Nano-sized Iron Oxide Particle with High Sensitivity for Cellular Magnetic Resonance Imaging

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

In this study, we investigated the labeling efficiency and magnetic resonance imaging (MRI) signal sensitivity of a newly synthesized, nano-sized iron oxide particle (IOP) coated with polyethylene glycol (PEG), designed by Industrial Technology Research Institute (ITRI).

Procedures

Macrophages, bone-marrow-derived dendritic cells, and mesenchymal stem cells (MSCs) were isolated from rats and labeled by incubating with ITRI-IOP, along with three other iron oxide particles in different sizes and coatings as reference. These labeled cells were characterized with transmission electron microscopy (TEM), light and fluorescence microscopy, phantom MRI, and finally in vivo MRI and ex vivo magnetic resonance microscopy (MRM) of transplanted hearts in rats infused with labeled macrophages.

Results

The longitudinal (r 1) and transverse (r 2) relaxivities of ITRI-IOP are 22.71 and 319.2 s−1 mM−1, respectively. TEM and microscopic images indicate the uptake of multiple ITRI-IOP particles per cell for all cell types. ITRI-IOP provides sensitivity comparable or higher than the other three particles shown in phantom MRI. In vivo MRI and ex vivo MRM detect punctate spots of hypointensity in rejecting hearts, most likely caused by the accumulation of macrophages labeled by ITRI-IOP.

Conclusion

ITRI-IOP, the nano-sized iron oxide particle, shows high efficiency in cell labeling, including both phagocytic and non-phagocytic cells. Furthermore, it provides excellent sensitivity in T2*-weighted MRI, and thus can serve as a promising contrast agent for in vivo cellular MRI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

BN rat:

Brown Norway rat

DA rat:

Dark Agouti rat

DLS:

Dynamic light scattering

ECG:

Electrocardiography

FACS:

Fluorescent-activated cell sorting

FDA:

Food and Drug Administration

MR:

Magnetic resonance

MRI:

Magnetic resonance imaging

MRM:

Magnetic resonance microscopy

MPIO:

Micron-sized superparamagnetic iron oxide particles

MSCs:

Mesenchymal stem cells

PBS:

Phosphate-buffered saline

PEG:

Polyethylene glycol

POD:

Post-operation day

r 1 :

Longitudinal relaxivity

r 2 :

Transverse relaxivity

RES:

Reticuloendothelial system

SPIO:

Superparamagnetic iron oxide particles

T 1 :

Longitudinal relaxation time

T 2 :

Transverse relaxation time

TEM:

Transmission electron microscopy

TE:

Echo time

TR:

Repetition time

USPIO:

Ultrasmall superparamagnetic iron oxide particles

References

  1. Yeh TC, Zhang W, Ildstad ST, Ho C (1995) In vivo dynamic MRI tracking of rat T-cells labeled with superparamagnetic iron-oxide particles. Magn Reson Med 33(2):200–208

    Article  PubMed  CAS  Google Scholar 

  2. Wu YL, Ye Q, Foley LM, Hitchens TK, Sato K, Williams JB, Ho C (2006) In situ labeling of immune cells with iron oxide particles: an approach to detect organ rejection by cellular MRI. Proc Natl Acad Sci USA 103(6):1852–1857

    Article  PubMed  CAS  Google Scholar 

  3. Kiessling F (2008) Noninvasive cell tracking. Handb Exp Pharmacol 185(Pt 2):305–321

    Article  PubMed  CAS  Google Scholar 

  4. Bulte JW, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17(7):484–499

    Article  PubMed  CAS  Google Scholar 

  5. Smirnov P (2009) Cellular magnetic resonance imaging using superparamagnetic anionic iron oxide nanoparticles: applications to in vivo trafficking of lymphocytes and cell-based anticancer therapy. Methods Mol Biol 512:333–353

    Article  PubMed  CAS  Google Scholar 

  6. Baumjohann D, Hess A, Budinsky L, Brune K, Schuler G, Lutz MB (2006) In vivo magnetic resonance imaging of dendritic cell migration into the draining lymph nodes of mice. Eur J Immunol 36(9):2544–2555

    Article  PubMed  CAS  Google Scholar 

  7. Daldrup-Link HE, Rudelius M, Piontek G, Metz S, Brauer R, Debus G, Corot C, Schlegel J, Link TM, Peschel C, Rummeny EJ, Oostendorp RA (2005) Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment. Radiology 234(1):197–205

    Article  PubMed  Google Scholar 

  8. Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, Bryant LH Jr, Bulte JW (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 228(2):480–487

    Article  PubMed  Google Scholar 

  9. Arbab AS, Bashaw LA, Miller BR, Jordan EK, Bulte JW, Frank JA (2003) Intracytoplasmic tagging of cells with ferumoxides and transfection agent for cellular magnetic resonance imaging after cell transplantation: methods and techniques. Transplantation 76(7):1123–1130

    Article  PubMed  CAS  Google Scholar 

  10. Kanno S, Wu YJ, Lee PC, Dodd SJ, Williams M, Griffith BP, Ho C (2001) Macrophage accumulation associated with rat cardiac allograft rejection detected by magnetic resonance imaging with ultrasmall superparamagnetic iron oxide particles. Circulation 104(8):934–938

    Article  PubMed  CAS  Google Scholar 

  11. Ye Q, Yang D, Williams M, Williams DS, Pluempitiwiriyawej C, Moura JM, Ho C (2002) In vivo detection of acute rat renal allograft rejection by MRI with USPIO particles. Kidney Int 61(3):1124–1135

    Article  PubMed  Google Scholar 

  12. Ho C, Hitchens TK (2004) A non-invasive approach to detecting organ rejection by MRI: monitoring the accumulation of immune cells at the transplanted organ. Curr Pharm Biotechnol 5(6):551–566

    Article  PubMed  CAS  Google Scholar 

  13. Penno E, Johnsson C, Johansson L, Ahlstrom H (2006) Macrophage uptake of ultra-small iron oxide particles for magnetic resonance imaging in experimental acute cardiac transplant rejection. Acta Radiol 47(3):264–271

    Article  PubMed  CAS  Google Scholar 

  14. Hauger O, Grenier N, Deminere C, Lasseur C, Delmas Y, Merville P, Combe C (2007) USPIO-enhanced MR imaging of macrophage infiltration in native and transplanted kidneys: initial results in humans. Eur Radiol 17(11):2898–2907

    Article  PubMed  Google Scholar 

  15. Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP (2004) MRI detection of single particles for cellular imaging. Proc Natl Acad Sci USA 101(30):10901–10906

    Article  PubMed  CAS  Google Scholar 

  16. Shapiro EM, Skrtic S, Koretsky AP (2005) Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn Reson Med 53(2):329–338

    Article  PubMed  Google Scholar 

  17. Josephson L, Tung CH, Moore A, Weissleder R (1999) High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug Chem 10(2):186–191

    Article  PubMed  CAS  Google Scholar 

  18. Montet-Abou K, Montet X, Weissleder R, Josephson L (2007) Cell internalization of magnetic nanoparticles using transfection agents. Mol Imaging 6(1):1–9

    PubMed  CAS  Google Scholar 

  19. Ahrens ET, Feili-Hariri M, Xu H, Genove G, Morel PA (2003) Receptor-mediated endocytosis of iron-oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging. Magn Reson Med 49(6):1006–1013

    Article  PubMed  CAS  Google Scholar 

  20. Tai JH, Foster P, Rosales A, Feng B, Hasilo C, Martinez V, Ramadan S, Snir J, Melling CW, Dhanvantari S, Rutt B, White DJ (2006) Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla. Diabetes 55(11):2931–2938

    Article  PubMed  CAS  Google Scholar 

  21. Walczak P, Ruiz-Cabello J, Kedziorek DA, Gilad AA, Lin S, Barnett B, Qin L, Levitsky H, Bulte JW (2006) Magnetoelectroporation: improved labeling of neural stem cells and leukocytes for cellular magnetic resonance imaging using a single FDA-approved agent. Nanomedicine 2(2):89–94

    Article  PubMed  CAS  Google Scholar 

  22. Chang W-H, Hsieh W-Y, Huang H-H, Wang S-J. Biocompatible polymer and magnetic nanoparticles with biocompatibility. Patent Application Number: P54960092WO, data of filing: April 23, 2008

  23. Dodd SJ, Williams M, Suhan JP, Williams DS, Koretsky AP, Ho C (1999) Detection of single mammalian cells by high-resolution magnetic resonance imaging. Biophys J 76(1 Pt 1):103–109

    Article  PubMed  CAS  Google Scholar 

  24. Riemer J, Hoepken HH, Czerwinska H, Robinson SR, Dringen R (2004) Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem 331(2):370–375

    Article  PubMed  CAS  Google Scholar 

  25. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1(3):1458–1461

    Article  PubMed  CAS  Google Scholar 

  26. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  PubMed  CAS  Google Scholar 

  27. Shapiro EM, Sharer K, Skrtic S, Koretsky AP (2006) In vivo detection of single cells by MRI. Magn Reson Med 55(2):242–249

    Article  PubMed  Google Scholar 

  28. Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK, Zywicke H, Miller B, van Gelderen P, Moskowitz BM, Duncan ID, Frank JA (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19(12):1141–1147

    Article  PubMed  CAS  Google Scholar 

  29. Schafer R, Kehlbach R, Wiskirchen J, Bantleon R, Pintaske J, Brehm BR, Gerber A, Wolburg H, Claussen CD, Northoff H (2007) Transferrin receptor upregulation: in vitro labeling of rat mesenchymal stem cells with superparamagnetic iron oxide. Radiology 244(2):514–523

    Article  PubMed  Google Scholar 

  30. Korosoglou G, Weiss RG, Kedziorek DA, Walczak P, Gilson WD, Schar M, Sosnovik DE, Kraitchman DL, Boston RC, Bulte JW, Weissleder R, Stuber M (2008) Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using “positive contrast” magnetic resonance imaging. J Am Coll Cardiol 52(6):483–491

    Article  PubMed  CAS  Google Scholar 

  31. Gupta AK, Wells S (2004) Surface-modified superparamagnetic nanoparticles for drug delivery: preparation, characterization, and cytotoxicity studies. IEEE Trans Nanobioscience 3(1):66–73

    Article  PubMed  Google Scholar 

  32. Zhang Y, Kohler N, Zhang M (2002) Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials 23(7):1553–1561

    Article  PubMed  CAS  Google Scholar 

  33. Hamm J, Pulito R, Benedetto S, Barberis L, Hirsch E, Poli V, Silengo L (2008) Magnetically enriched bone marrow-derived macrophages loaded in vitro with iron oxide can migrate to inflammation sites in mice. NMR Biomed 21(2):120–128

    Article  PubMed  Google Scholar 

  34. Pouliquen D, Le Jeune JJ, Perdrisot R, Ermias A, Jallet P (1991) Iron oxide nanoparticles for use as an MRI contrast agent: pharmacokinetics and metabolism. Magn Reson Imaging 9(3):275–283

    Article  PubMed  CAS  Google Scholar 

  35. Majumdar S, Zoghbi SS, Gore JC (1990) Pharmacokinetics of superparamagnetic iron-oxide MR contrast agents in the rat. Invest Radiol 25(7):771–777

    Article  PubMed  CAS  Google Scholar 

  36. Thorek DL, Tsourkas A (2008) Size, charge and concentration dependent uptake of iron oxide particles by non-phagocytic cells. Biomaterials 29(26):3583–3590

    Article  PubMed  CAS  Google Scholar 

  37. Choi H, Choi SR, Zhou R, Kung HF, Chen IW (2004) Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery. Acad Radiol 11(9):996–1004

    Article  PubMed  Google Scholar 

  38. Slotkin JR, Cahill KS, Tharin SA, Shapiro EM (2007) Cellular magnetic resonance imaging: nanometer and micrometer size particles for noninvasive cell localization. Neurotherapeutics 4(3):428–433

    Article  PubMed  Google Scholar 

  39. Yeh TC, Zhang W, Ildstad ST, Ho C (1993) Intracellular labeling of T-cells with superparamagnetic contrast agents. Magn Reson Med 30(5):617–625

    Article  PubMed  CAS  Google Scholar 

  40. Islam T, Wolf G (2009) The pharmacokinetics of the lymphotropic nanoparticle MRI contrast agent ferumoxtran-10. Cancer Biomark 5(2):69–73

    PubMed  CAS  Google Scholar 

  41. Ye Q, Wu YL, Foley LM, Hitchens TK, Eytan DF, Shirwan H, Ho C (2008) Longitudinal tracking of recipient macrophages in a rat chronic cardiac allograft rejection model with noninvasive magnetic resonance imaging using micrometer-sized paramagnetic iron oxide particles. Circulation 118(2):149–156

    Article  PubMed  Google Scholar 

  42. Oude Engberink RD, van der Pol SM, Dopp EA, de Vries HE, Blezer EL (2007) Comparison of SPIO and USPIO for in vitro labeling of human monocytes: MR detection and cell function. Radiology 243(2):467–474

    Article  PubMed  Google Scholar 

  43. Salaklang J, Steitz B, Finka A, O’Neil CP, Moniatte M, van der Vlies AJ, Giorgio TD, Hofmann H, Hubbell JA, Petri-Fink A (2008) Superparamagnetic nanoparticles as a powerful systems biology characterization tool in the physiological context. Angew Chem Int Ed Engl 47(41):7857–7860

    Article  PubMed  CAS  Google Scholar 

  44. Matuszewski L, Persigehl T, Wall A, Meier N, Bieker R, Kooijman H, Tombach B, Mesters R, Berdel WE, Heindel W, Bremer C (2007) Assessment of bone marrow angiogenesis in patients with acute myeloid leukemia by using contrast-enhanced MR imaging with clinically approved iron oxides: initial experience. Radiology 242(1):217–224

    Article  PubMed  Google Scholar 

  45. Arbab AS, Yocum GT, Kalish H, Jordan EK, Anderson SA, Khakoo AY, Read EJ, Frank JA (2004) Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104(4):1217–1223

    Article  PubMed  CAS  Google Scholar 

  46. Wilhelm C, Billotey C, Roger J, Pons JN, Bacri JC, Gazeau F (2003) Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials 24(6):1001–1011

    Article  PubMed  CAS  Google Scholar 

  47. Yamazaki M, Ito T (1990) Deformation and instability in membrane structure of phospholipid vesicles caused by osmophobic association: mechanical stress model for the mechanism of poly(ethylene glycol)-induced membrane fusion. Biochemistry 29(5):1309–1314

    Article  PubMed  CAS  Google Scholar 

  48. de Vries IJ, Lesterhuis WJ, Barentsz JO, Verdijk P, van Krieken JH, Boerman OC, Oyen WJ, Bonenkamp JJ, Boezeman JB, Adema GJ, Bulte JW, Scheenen TW, Punt CJ, Heerschap A, Figdor CG (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 23(11):1407–1413

    Article  PubMed  Google Scholar 

  49. Shapiro EM, Medford-Davis LN, Fahmy TM, Dunbar CE, Koretsky AP (2007) Antibody-mediated cell labeling of peripheral T cells with micron-sized iron oxide particles (MPIOs) allows single cell detection by MRI. Contrast Media Mol Imaging 2(3):147–153

    Article  PubMed  CAS  Google Scholar 

  50. Tavill AS, Bacon BR (1986) Hemochromatosis: how much iron is too much? Hepatology 6(1):142–145

    Article  PubMed  CAS  Google Scholar 

  51. Weissleder R, Stark DD, Engelstad BL, Bacon BR, Compton CC, White DL, Jacobs P, Lewis J (1989) Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol 152(1):167–173

    PubMed  CAS  Google Scholar 

  52. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V (2008) Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 5(2):316–327

    Article  PubMed  CAS  Google Scholar 

  53. Moghimi SM, Szebeni J (2003) Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 42(6):463–478

    Article  PubMed  CAS  Google Scholar 

  54. Reimer P, Balzer T (2003) Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol 13(6):1266–1276

    PubMed  Google Scholar 

  55. Di Marco M, Sadun C, Port M, Guilbert I, Couvreur P, Dubernet C (2007) Physicochemical characterization of ultrasmall superparamagnetic iron oxide particles (USPIO) for biomedical application as MRI contrast agents. Int J Nanomedicine 2(4):609–622

    PubMed  Google Scholar 

  56. Luciani N, Wilhelm C, Gazeau F (2010) The role of cell-released microvesicles in the intercellular transfer of magnetic nanoparticles in the monocyte/macrophage system. Biomaterials 31(27):7061–7069

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mr. Joseph P. Suhan, Department of Biological Sciences, Carnegie Mellon University, for excellent technical assistance in the TEM measurements. We also thank Dr. Steve R. Roffler of the Institute of Biomedical Sciences, Academia Sinica, Taiwan for kindly providing us with his anti-PEG AGP3 antibody (SR-66). C.-L. Chen, W.-Y. Hsieh, H.-H. Shen, and S.-J. Wang are supported by the Industrial Technology Research Institute, Taiwan. We also acknowledge the research support from NIH grants (R01HL-081349 and P41EB-00197 to C. Ho).

Conflicts of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Biomedical Engineering Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan

    Chih-Lung Chen & Hsin-Hsin Shen

  2. Pittsburgh NMR Center for Biomedical Research and Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Ave, Pittsburgh, PA, 15213, USA

    Haosen Zhang, Qing Ye, T. Kevin Hitchens, Li Liu, Yi-Jen Wu, Lesley M. Foley & Chien Ho

  3. Material and Chemical Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan

    Wen-Yuan Hsieh & Shian-Jy Wang

Authors
  1. Chih-Lung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haosen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Yuan Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Kevin Hitchens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hsin-Hsin Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi-Jen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lesley M. Foley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shian-Jy Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chien Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chien Ho.

Additional information

Chih-Lung Chen and Haosen Zhang contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, CL., Zhang, H., Ye, Q. et al. A New Nano-sized Iron Oxide Particle with High Sensitivity for Cellular Magnetic Resonance Imaging. Mol Imaging Biol 13, 825–839 (2011). https://doi.org/10.1007/s11307-010-0430-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-010-0430-x

Key words

Search

Navigation