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Preclinical 19F MRI cell tracking at 3 Tesla

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Abstract

Purpose

To develop methods for fluorine-19 (19F) MRI cell tracking in mice on a 3 Tesla clinical scanner. Compared to iron-based cell tracking, 19F MRI has lower sensitivity and, consequently, preclinical 19F cell tracking has only been performed at relatively high magnetic field strengths (> 3 T). Here, we focus on using 19F MRI to detect macrophages in tumors; macrophage density is an indication of tumor aggressiveness and, therefore, 19F MRI could be used as an imaging biomarker.

Methods

Perfluorocarbon (PFC)-labeled macrophages were imaged at 3 T and NMR spectroscopy was performed to validate 19F spin quantification. In vivo 19F MRI was performed on tumor-bearing mice, post-PFC at both 9.4 T and 3 T. 3 T MRI utilized varying NEX and 19F images were analyzed two different ways for 19F quantification.

Results

As few as 25,000 cells could be detected as cell pellets at 3 T. 19F quantification in cell pellets by 3 T MRI agreed with NMR spectroscopy. 19F signal was observed in the liver, spleen and tumor in all mice at 9.4 T and 3 T and there was no significant difference in 19F spin quantification.

Conclusion

This study demonstrates the ability to detect and quantify 19F signal in murine tumors using 19F MRI at 3 T.

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References

  1. Balducci A, Helfer BM, Ahrens ET, O’Hanlon CF 3rd, Wesa AK (2012) Visualizing arthritic inflammation and therapeutic response by fluorine-19 magnetic resonance imaging (19F MRI). J Inflamm (Lond) 9:24

    Article  CAS  Google Scholar 

  2. Shin SH, Kadayakkara DK, Bulte JWM (2017) In vivo (19)F MR imaging cell tracking of inflammatory macrophages and site-specific development of colitis-associated dysplasia. Radiology 282:194–201

    Article  PubMed  Google Scholar 

  3. Zhong J, Narsinh K, Morel PA, Xu H, Ahrens ET (2015) In vivo quantification of inflammation in experimental autoimmune encephalomyelitis rats using fluorine-19 magnetic resonance imaging reveals immune cell recruitment outside the nervous system. PLoS One 10:e0140238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Makela AV, Gaudet JM, Foster PJ (2017) Quantifying tumor associated macrophages in breast cancer: a comparison of iron and fluorine-based MRI cell tracking. Sci Rep 7:42109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Makela AV, Foster PJ (2018) Imaging macrophage distribution and density in mammary tumors and lung metastases using fluorine-19 MRI cell tracking. Magn Reson Med 80:1138–1147

    Article  CAS  PubMed  Google Scholar 

  6. Khurana A, Chapelin F, Xu H, Acevedo JR, Molinolo A, Nguyen Q, Ahrens ET (2018) Visualization of macrophage recruitment in head and neck carcinoma model using fluorine-19 magnetic resonance imaging. Magn Reson Med 79:1972–1980

    Article  CAS  PubMed  Google Scholar 

  7. Shin SH, Park SH, Kang SH, Kim SW, Kim M, Kim D (2017) Fluorine-19 magnetic resonance imaging and positron emission tomography of tumor-associated macrophages and tumor metabolism. Contrast Media Mol Imaging 2017:4896310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Srinivas M, Boehm-Sturm P, Figdor CG, de Vries IJ, Hoehn M (2012) Labeling cells for in vivo tracking using (19)F MRI. Biomaterials 33:8830–8840

    Article  CAS  PubMed  Google Scholar 

  9. Taylor AJ, Granwehr J, Lesbats C, Krupa JL, Six JS, Pavlovskaya GE, Thomas NR, Auer DP, Meersmann T, Faas HM (2016) Probe-specific procedure to estimate sensitivity and detection limits for 19F magnetic resonance imaging. PLoS One 11:e0163704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Temme S, Grapentin C, Quast C, Jacoby C, Grandoch M, Ding Z, Owenier C, Mayenfels F, Fischer JW, Schubert R, Schrader J, Flogel U (2015) Noninvasive imaging of early venous thrombosis by 19F magnetic resonance imaging with targeted perfluorocarbon nanoemulsions. Circulation 131:1405–1414

    Article  CAS  PubMed  Google Scholar 

  11. Ebner B, Behm P, Jacoby C, Burghoff S, French BA, Schrader J, Flogel U (2010) Early assessment of pulmonary inflammation by 19F MRI in vivo. Circ Cardiovasc Imaging 3:202–210

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hitchens TK, Ye Q, Eytan DF, Janjic JM, Ahrens ET, Ho C (2011) 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells. Magn Reson Med 65:1144–1153

    Article  PubMed  PubMed Central  Google Scholar 

  13. Flögel U, Su S, Kreideweiß I, Ding Z, Galbarz L, Fu J, Jacoby C, Witzke O, Schrader J (2011) Noninvasive detection of graft rejection by in vivo 19F MRI in the early stage. Am J Transplant 11:235–244

    Article  PubMed  Google Scholar 

  14. Srinivas M, Morel PA, Ernst LA, Laidlaw DH, Ahrens ET (2007) Fluorine-19 MRI for visualization and quantification of cell migration in a diabetes model. Magn Reson Med 58:725–734

    Article  CAS  PubMed  Google Scholar 

  15. Gaudet JM, Ribot EJ, Chen Y, Gilbert KM, Foster PJ (2015) Tracking the fate of stem cell implants with fluorine-19 MRI. PLoS One 10:e0118544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tiainen S, Tumelius R, Rilla K, Hämäläinen K, Tammi M, Tammi R, Kosma VM, Oikari S, Auvinen P (2015) High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology 66:873–883

    Article  PubMed  Google Scholar 

  17. Yuan Z-Y, Luo R-Z, Peng R-J, Wang S-S, Xue C (2014) High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. Onco Targets Ther 7:1475–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gwak JM, Jang MH, Il Kim D, Seo AN, Park SY (2015) Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One 10:1–14

    Article  CAS  Google Scholar 

  19. Reigstad I, Smeland HYH, Skogstrand T, Sortland K, Schmid MC, Reed RK, Stuhr L (2016) Stromal integrin α11β1 affects RM11 prostate and 4T1 breast xenograft tumors differently. PLoS One 11:e0151663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wong CW, Song C, Grimes MM, Fu W, Dewhirst MW, Muschel RJ, Al-Mehdi A-B (2002) Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 161:749–753

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gudbjartsson H, Patz S (1995) The rician distribution of noisy MRI data. Magn Reson Med 34:910–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 103:1852–1857

    Article  CAS  PubMed  Google Scholar 

  23. Zarif L, Postel M, Trevino L, Riess JG, Valla A, Follana R (1994) Biodistribution and excretion of a mixed fluorocarbon-hydrocarbon “dowel” emulsion as determined by 19F NMR. Artif Cells Blood Substit Immobil Biotechnol 22:1193–1198

    Article  CAS  PubMed  Google Scholar 

  24. Ahrens ET, Zhong J (2013) In vivo MRI cell tracking using perfluorocarbon probes and fluorine-19 detection. NMR Biomed 26:860–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H (2015) Nanoparticle uptake: the phagocyte problem. Nano Today 10:487–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khurana A, Chapelin F, Xu H, Acevedo JR, Molinolo A, Nguyen Q, Ahrens ET (2017) Visualization of macrophage recruitment in head and neck carcinoma model using fluorine-19 magnetic resonance imaging. Magn Reson Med 79:1972–1980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weibel S, Basse-Luesebrink TC, Hess M, Hofmann E, Seubert C, Langbein-Laugwitz J, Gentschev I, Sturm VJF, Ye Y, Kampf T, Jakob PM, Szalay AA (2013) Imaging of intratumoral inflammation during oncolytic virotherapy of tumors by 19F-magnetic resonance imaging (MRI). PLoS One 8:e56317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Balducci A, Wen Y, Zhang Y, Helfer BM, Hitchens TK, Meng WS, Wesa AK, Janjic JM (2013) A novel probe for the non-invasive detection of tumor-associated inflammation. Oncoimmunology 2:e23034

    Article  PubMed  PubMed Central  Google Scholar 

  30. Daldrup-Link HE, Golovko D, Ruffell B, Denardo DG, Castaneda R, Ansari C, Rao J, Tikhomirov GA, Wendland MF, Corot C, Coussens LM (2011) MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin Cancer Res 17:5695–5704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi Q, Pisani LJ, Lee YK, Messing S, Ansari C, Bhaumik S, Lowery L, Lee BD, Meyer DE, Daldrup-Link HE (2013) Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses. Contrast Media Mol Imaging 8:281–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Leimgruber A, Berger C, Cortez-Retamozo V, Etzrodt M, Newton AP, Waterman P, Figueiredo JL, Kohler RH, Elpek N, Mempel TR, Swirski FK, Nahrendorf M, Weissleder R, Pittet MJ (2009) Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle. Neoplasia 11:459-IN4

    Article  CAS  Google Scholar 

  33. Ahrens ET, Young W-B, Xu H, Pusateri LK (2011) Rapid quantification of inflammation in tissue samples using perfluorocarbon emulsion and fluorine-19 nuclear magnetic resonance. Biotechniques 50:229–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ahrens ET, Helfer BM, O’Hanlon CF, Schirda C (2014) Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19 MRI. Magn Reson Med 72:1696–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gocheva V, Wang H-W, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656

    Article  CAS  PubMed  Google Scholar 

  37. Hill HDW, Richards RE (1968) Limits of measurement in magnetic resonance. J Phys E 1:977

    Article  Google Scholar 

  38. Haase A, Odoj F, Von Kienlin M, Warnking J, Fidler F, Weisser A, Nittka M, Rommel E, Lanz T, Kalusche B, Griswold M (2000) NMR probeheads for in vivo applications. Concepts Magn Reson 12:361–388

    Article  CAS  Google Scholar 

  39. Morita Y, Zhang R, Leslie M, Adhikari S, Hasan N, Chervoneva I, Rui H, Tanaka T (2017) Pathologic evaluation of tumor-associated macrophage density and vessel inflammation in invasive breast carcinomas. Oncol Lett 14:2111–2118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the following sources of funding for AVM: Natural Sciences and Engineering Research Council, Molecular Imaging Graduate Program (Western University), Translational Breast Cancer Research Unit, Cancer Research and Technology Transfer Program and Canadian Cancer Society.

Funding

This study was funded by: Canadian Institute for Health Research.

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Authors and Affiliations

Authors

Contributions

AVM study conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript and critical revision. PJF study conception and design, drafting of manuscript and critical revision.

Corresponding author

Correspondence to Ashley V. Makela.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Makela, A.V., Foster, P.J. Preclinical 19F MRI cell tracking at 3 Tesla. Magn Reson Mater Phy 32, 123–132 (2019). https://doi.org/10.1007/s10334-018-0715-7

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