Skip to main content

In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI



The development of theranostic nanocarriers as an innovative therapy against cancer has been improved by targeting properties in order to optimize the drug delivery to safely achieve its desired therapeutic effect. The aim of this paper is to evaluate the magnetic targeting (MT) efficiency of ultra-magnetic liposomes (UML) into CT26 murine colon tumor by magnetic resonance imaging (MRI).


Dynamic susceptibility contrast MRI was applied to assess the bloodstream circulation time. A novel semi-quantitative method called %I0.25, based on the intensity distribution in T2*-weighted MRI images was developed to compare the accumulation of T2 contrast agent in tumors with or without MT. To evaluate the efficiency of magnetic targeting, the percentage of pixels under the intensity value I0.25 (I0.25 = 0.25(Imax − Imin)) was calculated on the intensity distribution histogram.


This innovative method of processing MRI images showed the MT efficiency by a %I0.25 that was significantly higher in tumors using MT compared to passive accumulation, from 15.3 to 28.6 %. This methodology was validated by ex vivo methods with an iron concentration that is 3-fold higher in tumors using MT.


We have developed a method that allows a semi-quantitative evaluation of targeting efficiency in tumors, which could be applied to different T2 contrast agents.

This is a preview of subscription content, access via your institution.

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


  1. 1.

    Shi J, Kantoff PW, Wooster R, Farokhzad OC (2016) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Mura S, Nicolas J, Couvreur P (2013) Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12:991–1003

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Lammers T, Aime S, Hennink WE, Storm G, Kiessling F (2011) Theranostic nanomedicine. Acc Chem Res 44:1029–1038

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Soenen SJ, Velde GV, Ketkar-Atre A, Himmelreich U, de Cuyper M (2011) Magnetoliposomes as magnetic resonance imaging contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:197–211

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Pattni BS, Chupin VV, Torchilin VP (2015) New developments in liposomal drug delivery. Chem Rev 115:10938–10966

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Amstad E, Kohlbrecher J, Müller E et al (2011) Triggered release from liposomes through magnetic actuation of Iron oxide nanoparticle containing membranes. Nano Lett 11:1664–1670

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Mikhaylov G, Mikac U, Magaeva AA, Itin VI, Naiden EP, Psakhye I, Babes L, Reinheckel T, Peters C, Zeiser R, Bogyo M, Turk V, Psakhye SG, Turk B, Vasiljeva O (2011) Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment. Nat Nano Technol 6:594–602

    Article  CAS  Google Scholar 

  8. 8.

    Béalle G, Di Corato R, Kolosnjaj-Tabi J et al (2012) Ultra magnetic liposomes for MR imaging, targeting, and hyperthermia. Langmuir 28:11834–11842

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Marie H, Lemaire L, Franconi F, Lajnef S, Frapart YM, Nicolas V, Frébourg G, Trichet M, Ménager C, Lesieur S (2015) Superparamagnetic liposomes for MRI monitoring and external magnetic field-induced selective targeting of malignant brain tumors. Adv Funct Mater 25:1258–1269

    Article  CAS  Google Scholar 

  10. 10.

    Fernandez-Sanchez ME, Barbier S, Whitehead J et al (2015) Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523:92–95

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Ramniceanu G, Doan BT, Vezignol C, Graillot A, Loubat C, Mignet N, Berret JF (2016) Delayed hepatic uptake of multi-phosphonic acid poly(ethylene glycol) coated iron oxide measured by real-time magnetic resonance imaging. RSC Adv 6:63788–63800

    Article  CAS  Google Scholar 

  12. 12.

    Hernando D, Levin YS, Sirlin CB, Reeder SB (2014) Quantification of liver iron with MRI: state of the art and remaining challenges. J Magn Reson Imaging 40:1003–1021

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Massart R (1981) Preparation of aqueous magnetic liquids in alkaline and acidic media. IEEE Trans Magn 17:1247–1248

    Article  Google Scholar 

  14. 14.

    Jarzyna PA, Skajaa T, Gianella A, Cormode DP, Samber DD, Dickson SD, Chen W, Griffioen AW, Fayad ZA, Mulder WJM (2009) Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging. Biomaterials 30:6947–6954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Wilhelm C, Gazeau F, Bacri JC (2002) Magnetophoresis and ferromagnetic resonance of magnetically labeled cells. Eur Biophys J 31:118–125

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Heijman E, de Graaf W, Niessen P, Nauerth A, van Eys G, de Graaf L, Nicolay K, Strijkers GJ (2007) Comparison between prospective and retrospective triggering for mouse cardiac MRI. NMR Biomed 20:439–447

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Bovens SM, te Boekhorst BC, den Ouden K et al (2011) Evaluation of infarcted murine heart function: comparison of prospectively triggered with self-gated MRI. NMR Biomed 24:307–315

    Article  PubMed  Google Scholar 

  18. 18.

    Seguin J, Doan BT, Latorre Ossa H, Jugé L, Gennisson JL, Tanter M, Scherman D, Chabot GG, Mignet N (2013) Evaluation of nonradiative clinical imaging techniques for the longitudinal assessment of tumour growth in murine CT26 colon carcinoma. Int J Mol Imaging 2013:1–13

    Article  Google Scholar 

  19. 19.

    Weatherall E, Willmott GR (2015) Applications of tunable resistive pulse sensing. Analyst 140:3318–3334

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Martina MS, Fortin JP, Ménager C, Clément O, Barratt G, Grabielle-Madelmont C, Gazeau F, Cabuil V, Lesieur S (2005) Generation of superparamagnetic liposomes revealed as highly efficient MRI contrast agents for in vivo imaging. J Am Chem Soc 127:10676–10685

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Bulte JWM, de Cuyper M, Despres D, Frank JA (1999) Preparation, relaxometry, and biokinetics of PEGylated magnetoliposomes as MR contrast agent. J Magn Magn Mater 194:204–209

    Article  CAS  Google Scholar 

  22. 22.

    Lorenzato C, Oerlemans C, van Elk M, Geerts WJC, Denis de Senneville B, Moonen C, Bos C (2016) MRI monitoring of nanocarrier accumulation and release using gadolinium-SPIO co-labelled thermosensitive liposomes: Gd-TSM for nanocarrier localization and monitoring of release using MRI. Contrast Media Mol Imaging 11:184–194

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Larsen BA, Haag MA, Serkova NJ, Shroyer KR, Stoldt CR (2008) Controlled aggregation of superparamagnetic iron oxide nanoparticles for the development of molecular magnetic resonance imaging probes. Nanotechnology 19:265102

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Seguin J, Nicolazzi C, Mignet N, Scherman D, Chabot GG (2012) Vascular density and endothelial cell expression of integrin alpha v beta 3 and E-selectin in murine tumours. Tumor Biol 33:1709–1717

    Article  CAS  Google Scholar 

  25. 25.

    Malinge J, Géraudie B, Savel P, Nataf V, Prignon A, Provost C, Zhang Y, Ou P, Kerrou K, Talbot JN, Siaugue JM, Sollogoub M, Ménager C (2017) Liposomes for PET and MR imaging and for dual targeting (magnetic field/glucose moiety): synthesis, properties, and in vivo studies. Mol Pharm 14:406–414

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Seo JW, Zhang H, Kukis DL, Meares CF, Ferrara KW (2008) A novel method to label preformed liposomes with 64Cu for positron emission tomography (PET). Imaging. Bioconjug Chem 19:2577–2584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Petersen AL, Binderup T, Rasmussen P, Henriksen JR, Elema DR, Kjær A, Andresen TL (2011) 64Cu loaded liposomes as positron emission tomography imaging agents. Biomaterials 32:2334–2341

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Phillips WT, Goins BA, Bao A (2009) Radioactive liposomes. Wiley Interdiscip Rev Nanomed Nanobiotech 1:69–83

    Article  CAS  Google Scholar 

  29. 29.

    Klotz E, König M (1999) Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke. Eur J Radiol 30:170–184

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Pesnel S, Akkoul S, Ledée R, Leconge R, Pillon A, Kruczynski A, Harba R, Lerondel S, le Pape A (2011) Use of an image restoration process to improve spatial resolution in bioluminescence imaging. Mol Imaging 10:446–452

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Haacke EM, Brown RW, Thompson MR, et al. (2014) Magnetic properties of tissues: theory and measurement. In: Magnetic resonance imaging: Physical Principles and Sequence Design. Ed. John Wiley & Sons. New York: Wiley-Liss, pp 741–779

  32. 32.

    Oakes JM, Breen EC, Scadeng M, Tchantchou GS, Darquenne C (2014) MRI-based measurements of aerosol deposition in the lung of healthy and elastase-treated rats. J Appl Physiol 116:1561–1568

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, Yang VC (2008) Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials 29:487–496

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Melemenidis S, Jefferson A, Ruparelia N, Akhtar AM, Xie J, Allen D, Hamilton A, Larkin JR, Perez-Balderas F, Smart SC, Muschel RJ, Chen X, Sibson NR, Choudhury RP (2015) Molecular magnetic resonance imaging of angiogenesis in vivo using polyvalent cyclic RGD-Iron oxide microparticle conjugates. Theranostics 5:515–529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Wang Y, Liu T (2015) Quantitative susceptibility mapping (QSM): decoding MRI data for a tissue magnetic biomarker: QSM. Magnet Reson Med 73:82–101

    Article  CAS  Google Scholar 

  36. 36.

    Schleich N, Po C, Jacobs D, Ucakar B, Gallez B, Danhier F, Préat V (2014) Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy. J Control Release 194:82–91

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Chen J, Ke X, He Z et al (2012) A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer. Int J Nanomedicine 7:5053–5065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    de Smet M, Heijman E, Langereis S, Hijnen NM, Grüll H (2011) Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. J Control Release 150:102–110

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Di Corato R, Béalle G, Kolosnjaj-Tabi J et al (2015) Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with Photoresponsive magnetic liposomes. ACS Nano 9:2904–2916

    Article  CAS  PubMed  Google Scholar 

Download references


This work was supported by the LabEx MiChem part of French state funds managed by the ANR within Le Programme Investissements d’Avenir under reference ANR-11-IDEX-0004-02. In vivo imaging was performed at the Life Imaging Facility of Paris Descartes University (LIOPA from the Plateform Imageries du Vivant – PIV) and partly supported by CNRS and ENSCP, ANR LightLab program.

We are grateful to Institut Français Weizmann for a postdoctoral grant (GR), Emmanuel Aubry from ALIPP6 for ICP analysis, Claire Wilhelm for magnetophoresis experiments, Cellular Imaging facility Imagic of Institut Cochin for confocal microscopy, and to Jean-Michel Guigner for CryoTEM.

Author information



Corresponding authors

Correspondence to Christine Ménager or Bich-Thuy Doan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material


(PDF 583 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thébault, C.J., Ramniceanu, G., Michel, A. et al. In Vivo Evaluation of Magnetic Targeting in Mice Colon Tumors with Ultra-Magnetic Liposomes Monitored by MRI. Mol Imaging Biol 21, 269–278 (2019).

Download citation

Key words

  • MRI
  • Magnetic targeting
  • Magnetic nanoparticle
  • Liposome
  • Image analysis method
  • Tumor