Ferumoxytol Can Be Used for Quantitative Magnetic Particle Imaging of Transplanted Stem Cells

Abstract

Purpose

To evaluate, if clinically translatable ferumoxytol nanoparticles can be used for in vivo detection and quantification of stem cell transplants with magnetic particle imaging (MPI).

Procedures

Mesenchymal stem cells (MSCs) were labeled with ferumoxytol or ferucarbotran and underwent MPI, magnetic resonance imaging (MRI), Prussian blue staining, and inductively coupled plasma (ICP) spectrometry. Unlabeled, ferumoxytol, and ferucarbotran-labeled MSCs were implanted in calvarial defects of eight mice and underwent MPI, MRI, and histopathology. The iron concentration calculated according to the MPI signal intensity and T2 relaxation times of the three different groups were compared using an analysis of variance (ANOVA) with Bonferroni correction, and a p < 0.05.

Results

Compared to unlabeled controls, ferumoxytol- and ferucarbotran-labeled MSC showed significantly increased iron content, MPI signal and MRI signal. The ferumoxytol MPI signal was approximately 4× weaker compared to ferucarbotran at equimolar concentrations (p = 0.0003) and approximately 1.5× weaker for labeled cells when using optimized labeling protocols (p = 0.002). In vivo, the MPI signal of ferumoxytol-labeled MSC decreased significantly between day 1 and day 14 (p = 0.0124). This was confirmed by histopathology where we observed a decrease in Prussian blue stain of MSCs at the transplant site. The MRI signal of the same transplants did not change significantly during this observation period (p = 0.93).

Conclusion

Ferumoxytol nanoparticles can be used for in vivo detection of stem cell transplants with MPI and provide quantitative information not attainable with MRI.

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

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

References

  1. 1.

    Brooks PM (2002) Impact of osteoarthritis on individuals and society: how much disability? Social consequences and health economic implications. Curr Opin Rheumatol 14:573–577

    Article  PubMed  Google Scholar 

  2. 2.

    Chimutengwende-Gordon M, Khan WS (2012) Advances in the use of stem cells and tissue engineering applications in bone repair. Curr Stem Cell Res Ther 7:122–126

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Ciapetti G, Granchi D, Baldini N (2012) The combined use of mesenchymal stromal cells and scaffolds for bone repair. Curr Pharm Design 18:1796–1820

    Article  CAS  Google Scholar 

  4. 4.

    Jorgensen C, Gordeladze J, Noel D (2004) Tissue engineering through autologous mesenchymal stem cells. Curr Opin Biotechnol 15:406–410

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Buza JA 3rd, Einhorn T (2016) Bone healing in 2016. Clin Cases Miner Bone Metab 13:101–105

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hodgetts SI, Beilharz MW, Scalzo AA, Grounds MD (2000) Why do cultured transplanted myoblasts die in vivo? DNA quantification shows enhanced survival of donor male myoblasts in host mice depleted of CD4+ and CD8+ cells or Nk1.1+ cells. Cell Transplant 9:489–502

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Rando TA, Pavlath GK, Blau HM (1995) The fate of myoblasts following transplantation into mature muscle. Exp Cell Res 220:383–389

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:9–20

    Article  CAS  Google Scholar 

  9. 9.

    Le Blanc K, Ringden O (2005) Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Trans 11:321–334

    Article  CAS  Google Scholar 

  10. 10.

    Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I (2009) Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc 17:1289–1297

    Article  PubMed  Google Scholar 

  11. 11.

    Hyun J, Grova M, Nejadnik H, Lo D, Morrison S, Montoro D, Chung M, Zimmermann A, Walmsley GG, Lee M, Daldrup-Link H, Wan DC, Longaker MT (2013) Enhancing in vivo survival of adipose-derived stromal cells through Bcl-2 overexpression using a minicircle vector. Stem Cells Transl Med 2:690–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bulte JW, Walczak P, Janowski M, Krishnan KM, Arami H, Halkola A, Gleich B, Rahmer J (2015) Quantitative “hot spot” imaging of transplanted stem cells using superparamagnetic tracers and magnetic particle imaging (MPI). Tomography 1:91–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zheng B, von See MP, Yu E, Gunel B, Lu K, Vazin T, Schaffer DV, Goodwill PW, Conolly SM (2016) Quantitative magnetic particle imaging monitors the transplantation, biodistribution, and clearance of stem cells in vivo. Theranostics 6:291–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gleich B, Weizenecker J (2005) Tomographic imaging using the nonlinear response of magnetic particles. Nature 435:1214–1217

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Hope MD, Hope TA, Zhu C, Faraji F, Haraldsson H, Ordovas KG, Saloner D (2015) Vascular imaging with ferumoxytol as a contrast agent. Am J Roentgenol 205:W366–W373

    Article  Google Scholar 

  16. 16.

    Netto JP, Iliff J, Stanimirovic D, Krohn KA, Hamilton B, Varallyay C, Gahramanov S, Daldrup-Link H, d’Esterre C, Zlokovic B, Sair H, Lee Y, Taheri S, Jain R, Panigrahy A, Reich DS, Drewes LR, Castillo M, Neuwelt EA (2018) Neurovascular unit: basic and clinical imaging with emphasis on advantages of ferumoxytol. Neurosurgery 82:770–780

    Article  PubMed  Google Scholar 

  17. 17.

    Nejadnik H, Taghavi-Garmestani SM, Madsen SJ, Li K, Zanganeh S, Yang P, Mahmoudi M, Daldrup-Link HE (2018) The protein corona around nanoparticles facilitates stem cell labeling for clinical MR imaging. Radiology 286:938–947

    Article  PubMed  Google Scholar 

  18. 18.

    Song G, Chen M, Zhang Y, Cui L, Qu H, Zheng X, Wintermark M, Liu Z, Rao J (2018) Janus Iron oxides@ semiconducting polymer nanoparticle tracer for cell tracking by magnetic particle imaging. Nano Lett 18:182–189

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Castaneda RT, Khurana A, Khan R, Daldrup-Link HE (2011) Labeling stem cells with ferumoxytol, an FDA-approved Iron oxide nanoparticle. J Visualized Exp. https://doi.org/10.3791/3482

  20. 20.

    Bullivant JP, Zhao S, Willenberg BJ, Kozissnik B, Batich C, Dobson J (2013) Materials characterization of Feraheme/ferumoxytol and preliminary evaluation of its potential for magnetic fluid hyperthermia. Int J Mol Sci 14:17501–17510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Coyne DW (2009) Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease. Expert Opin Pharmacother 10:2563–2568

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Bashir MR, Bhatti L, Marin D, Nelson RC (2015) Emerging applications for ferumoxytol as a contrast agent in MRI. J Magn Reson Imaging 41:884–898

    Article  PubMed  Google Scholar 

  23. 23.

    Nejadnik H, Lenkov O, Gassert F, Fretwell D, Lam I, Daldrup-Link HE (2016) Macrophage phagocytosis alters the MRI signal of ferumoxytol-labeled mesenchymal stromal cells in cartilage defects. Sci Rep 6:25897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wang Y-XJ (2011) Superparamagnetic iron oxide based MRI contrast agents: current status of clinical application. Quant Imaging Med Surg 1:35–40

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Reimer P, Rummeny EJ, Daldrup HE, Balzer T, Tombach B, Berns T, Peters PE (1995) Clinical results with Resovist: a phase 2 clinical trial. Radiology 195:489–496

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    VivoTrax™ Super-paramagnetic iron oxide tracer for pre-clinical Magnetic Resonance and Magnetic Particle Imaging. https://www.magneticinsight.com/vivotrax/ (accessed 12/20/2017)

  27. 27.

    Ferguson RM, Khandhar AP, Kemp SJ, Arami H, Saritas EU, Croft LR, Konkle J, Goodwill PW, Halkola A, Rahmer J, Borgert J, Conolly SM, Krishnan KM (2015) Magnetic particle imaging with tailored Iron oxide nanoparticle tracers. IEEE Trans Med Imaging 34:1077–1084

    Article  PubMed  Google Scholar 

  28. 28.

    Goodwill PW, Tamrazian A, Croft LR, Lu CD, Johnson EM, Pidaparthi R, Ferguson RM, Khandhar AP, Krishnan KM, Conolly SM (2011) Ferrohydrodynamic relaxometry for magnetic particle imaging. Appl Phys Lett 98:262502

    Article  CAS  Google Scholar 

  29. 29.

    Panagiotopoulos N, Duschka RL, Ahlborg M, Bringout G, Debbeler C, Graeser M, Kaethner C, Lüdtke-Buzug K, Medimagh H, Stelzner J, Buzug TM, Barkhausen J, Vogt FM, Haegele J (2015) Magnetic particle imaging: current developments and future directions. Int J Nanomedicine 10:3097–3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Mason EE, Cooley CZ, Cauley SF et al (2017) Design analysis of an MPI human functional brain scanner. Int J Magn Part Imaging 3. https://doi.org/10.18416/ijmpi.2017.1703008

  31. 31.

    Khurana A, Nejadnik H, Chapelin F, Lenkov O, Gawande R, Lee S, Gupta SN, Aflakian N, Derugin N, Messing S, Lin G, Lue TF, Pisani L, Daldrup-Link HE (2013) Ferumoxytol: a new, clinically applicable label for stem-cell tracking in arthritic joints with MRI. Nanomed 8:1969–1983

    Article  CAS  Google Scholar 

  32. 32.

    Daldrup-Link HE, Chan C, Lenkov O, Taghavigarmestani S, Nazekati T, Nejadnik H, Chapelin F, Khurana A, Tong X, Yang F, Pisani L, Longaker M, Gambhir SS (2017) Detection of stem cell transplant rejection with ferumoxytol MR imaging: correlation of MR imaging findings with those at Intravital microscopy. Radiology 284:495–507

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Nguyen PK, Riegler J, Wu JC (2014) Stem cell imaging: from bench to bedside. Cell Stem Cell 14:431–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Henning TD, Wendland MF, Golovko D, Sutton EJ, Sennino B, Malek F, Bauer JS, McDonald DM, Daldrup-Link H (2009) Relaxation effects of ferucarbotran-labeled mesenchymal stem cells at 1.5T and 3T: discrimination of viable from lysed cells. Magn Reson Med 62:325–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Tromsdorf UI, Bigall NC, Kaul MG, Bruns OT, Nikolic MS, Mollwitz B, Sperling RA, Reimer R, Hohenberg H, Parak WJ, Förster S, Beisiegel U, Adam G, Weller H (2007) Size and surface effects on the MRI Relaxivity of manganese ferrite nanoparticle contrast agents. Nano Lett 7:2422–2427

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Tay ZW, Hensley DW, Vreeland EC, Zheng B, Conolly SM (2017) The relaxation wall: experimental limits to improving MPI spatial resolution by increasing nanoparticle core size. Biomed Phys Eng Express 3:035003

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ferguson RM, Minard KR, Krishnan KM (2009) Optimization of nanoparticle core size for magnetic particle imaging. J Magn Magn Mater 321:1548–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Goodwill PW, Konkle JJ, Zheng B et al (2012) Projection x-space magnetic particle imaging. IEEE Trans Med Imaging 31:1076–1085

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Tay ZHD, et al. (2017) Eight fold improvement in magnetic particle imaging resolution with pulsed drive waveform. [Abstract]

  40. 40.

    Zheng B, Yu E, Orendorff R, Lu K, Konkle JJ, Tay ZW, Hensley D, Zhou XY, Chandrasekharan P, Saritas EU, Goodwill PW, Hazle JD, Conolly SM (2017) Seeing SPIOs directly in vivo with magnetic particle imaging. Mol Imaging Biol 19:385–390

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lu KGP, Zheng B, Conolly S. (2017) Multi-channel Acquisition for Isotropic Resolution in Magnetic Particle Imaging. [abstract]. 1P

  42. 42.

    Konkle JJ, Goodwill PW, Hensley DW, Orendorff RD, Lustig M, Conolly SM (2015) A convex formulation for magnetic particle imaging x-space reconstruction. PLoS One 10:e0140137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Lu KGP, Zheng B, Conolly S (2015) Reshaping the 2D MPI PSF to be isotropic and sharp using vector acquisition and equalization [abstract]. 1P

  44. 44.

    Khurana A, Chapelin F, Beck G, Lenkov OD, Donig J, Nejadnik H, Messing S, Derugin N, Chan RCF, Gaur A, Sennino B, McDonald DM, Kempen PJ, Tikhomirov GA, Rao J, Daldrup-Link HE (2013) Iron administration before stem cell harvest enables MR imaging tracking after transplantation. Radiology 269:186–197

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Aghighi M, Theruvath AJ, Pareek A, Pisani LL, Alford R, Muehe AM, Sethi TK, Holdsworth SJ, Hazard FK, Gratzinger D, Luna-Fineman S, Advani R, Spunt SL, Daldrup-Link HE (2018) Magnetic resonance imaging of tumor associated macrophages: clinical translation. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-0673

Download references

Funding

This work was supported by a grant from the Musculoskeletal Transplant Foundation and a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant no. 4R01AR054458-09.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Heike E. Daldrup-Link.

Ethics declarations

Conflict of Interest

Prachi Pandit holds equity interest in Magnetic Insight Inc.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nejadnik, H., Pandit, P., Lenkov, O. et al. Ferumoxytol Can Be Used for Quantitative Magnetic Particle Imaging of Transplanted Stem Cells. Mol Imaging Biol 21, 465–472 (2019). https://doi.org/10.1007/s11307-018-1276-x

Download citation

Key Words

  • Stem cell
  • MRI
  • MPI
  • Molecular imaging