SPION and doxorubicin-loaded polymeric nanocarriers for glioblastoma theranostics


Glioma is a type of cancer with a very poor prognosis with a survival of around 15 months in the case of glioblastoma multiforme (GBM). In order to advance in personalized medicine, we developed polymeric nanoparticles (PNP) loaded with both SPION (superparamagnetic iron oxide nanoparticles) and doxorubicin (DOX). The former being used for its potential to accumulate the PNP in the tumor under a strong magnetic field and the later for its therapeutic potential. The emulsion solvent and evaporation method was selected to develop monodisperse PNP with high loading efficiency in both SPION and DOX. Once injected in mice, a significant accumulation of the PNP was observed within the tumoral tissue under static magnetic field as observed by MRI leading to a reduction of tumor growth rate.

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  1. 1.

    De Vleeschouwer S. Glioblastoma. Codon Publications. 2017. https://doi.org/10.15586/CODON.GLIOBLASTOMA.2017.

    Article  Google Scholar 

  2. 2.

    Gaikwad PS, Banerjee R. Nanotechnology-based strategies as novel therapies in gliomas. Ther Deliv. 2018;9:571–92. https://doi.org/10.4155/tde-2018-0022.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Valenciano EV, De Fisiología D, De Medicina E, Universidad D, Rica DC, Costarricense C, Social DS, Jose S, Rica C, Ángel M, Miranda E, De Medicina E, Universidad D, Rica DC, Costarricense C, Social DS, Jose S, Rica C. Importancia de Células Madre Tumorales y Cultivos de Neuroesferas en Neurooncología. Neuroeje. 2012;25:55–60.

    Google Scholar 

  4. 4.

    Malinovskaya Y, Melnikov P, Baklaushev V, Gabashvili A, Osipova N, Mantrov S, Ermolenko Y, Maksimenko O, Gorshkova M, Balabanyan V, Kreuter J, Gelperina S. Delivery of doxorubicin-loaded PLGA nanoparticles into U87 human glioblastoma cells. Int J Pharm. 2017;524:77–90. https://doi.org/10.1016/J.IJPHARM.2017.03.049.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target. 2002;10:317–25. https://doi.org/10.1080/10611860290031877.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Neves AR, Queiroz JF, Reis S. Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. J Nanobiotechnology. 2016. https://doi.org/10.1186/s12951-016-0177-x.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Pinzón-Daza M, Garzón R, Couraud P, Romero I, Weksler B, Ghigo D, Bosia A, Riganti C. The association of statins plus LDL receptor-targeted liposome-encapsulated doxorubicin increases in vitro drug delivery across blood-brain barrier cells. Br J Pharmacol. 2012;167:1431–47. https://doi.org/10.1111/j.1476-5381.2012.02103.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Battaglia L, Gallarate M, Peira E, Chirio D, Muntoni E, Biasibetti E, Capucchio MT, Valazza A, Panciani PP, Lanotte M, Schiffer D, Annovazzi L, Caldera V, Mellai M, Riganti C. Solid Lipid Nanoparticles for potential doxorubicin delivery in glioblastoma treatment: preliminary in vitro studies. J Pharm Sci. 2014;103:2157–65. https://doi.org/10.1002/jps.24002.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    C. Rousselle, P. Clair, J.M. Lefauconnier, M. Kaczorek, J.M. Scherrmann, J. Temsamani, New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy., Mol. Pharmacol. 57 (2000) 679–86. http://www.ncbi.nlm.nih.gov/pubmed/10727512 (accessed January 10, 2017).

  10. 10.

    Luque-Michel E, Sebastian V, Larrea A, Marquina C, Blanco-Prieto MJ. Co-encapsulation of superparamagnetic nanoparticles and doxorubicin in PLGA nanocarriers: development, characterization and in vitro antitumor efficacy in glioma cells. Eur J Pharm Biopharm. 2019. https://doi.org/10.1016/j.ejpb.2019.10.004.

    Article  PubMed  Google Scholar 

  11. 11.

    Luque-Michel E, Imbuluzqueta E, Sebastián V, Blanco-Prieto MJ. Clinical advances of nanocarrier-based cancer therapy and diagnostics. Expert Opin Drug Deliv. 2017;14:75–92. https://doi.org/10.1080/17425247.2016.1205585.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Israel LL, Galstyan A, Holler E, Ljubimova JY. Magnetic iron oxide nanoparticles for imaging, targeting and treatment of primary and metastatic tumors of the brain. J Control Release. 2020;320:45–62. https://doi.org/10.1016/j.jconrel.2020.01.009.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bin Shen W, Anastasiadis P, Nguyen B, Yarnell D, Yarowsky PJ, Frenkel V, Fishman PS. Magnetic enhancement of stem cell–targeted delivery into the brain following MR-guided focused ultrasound for opening the blood–brain barrier. Cell Transplant. 2017;26:1235–1246. https://doi.org/10.1177/0963689717715824.

  14. 14.

    Qiu Y, Tong S, Zhang L, Sakurai Y, Myers DR, Hong L, Lam WA, Bao G. Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions. Nat Commun. 2017;8:15594. https://doi.org/10.1038/ncomms15594.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD, Muldoon LL, Neuwelt EA. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab. 2010;30:15–35. https://doi.org/10.1038/jcbfm.2009.192.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Li H, Jin H, Wan W, Wu C, Wei L. Cancer nanomedicine: mechanisms, obstacles and strategies. Nanomedicine. 2018;13:1639–56. https://doi.org/10.2217/nnm-2018-0007.

    Article  PubMed  Google Scholar 

  17. 17.

    Lemaire L, Nel J, Franconi F, Bastiat G, Saulnier P. Perfluorocarbon-loaded lipid nanocapsules to assess the dependence of U87-human glioblastoma tumor pO2 on in vitro expansion conditions. PLoS ONE. 2016;11:e0165479. https://doi.org/10.1371/journal.pone.0165479.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Marie H, Lemaire L, Franconi F, Lajnef S, Frapart Y-M, Nicolas V, Frébourg G, Trichet M, Ménager C, Lesieur S. Superparamagnetic liposomes for MRI monitoring and external magnetic field-induced selective targeting of malignant brain tumors. Adv Funct Mater. 2015;25:1258–69. https://doi.org/10.1002/adfm.201402289.

    CAS  Article  Google Scholar 

  19. 19.

    Luque-Michel E, Larrea A, Lahuerta C, Sebastian V, Imbuluzqueta E, Arruebo M, Blanco-Prieto MJ, Santamaria J. A simple approach to obtain hybrid Au-loaded polymeric nanoparticles with a tunable metal load. Nanoscale. 2016;8:6495–506. https://doi.org/10.1039/c5nr06850a.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Fischer K, Schmidt M. Pitfalls and novel applications of particle sizing by dynamic light scattering. Biomaterials. 2016;98:79–91. https://doi.org/10.1016/J.BIOMATERIALS.2016.05.003.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Chertok B, David AE, Huang Y, Yang VC. Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics. J Control Release. 2007;122:315–23. https://doi.org/10.1016/j.jconrel.2007.05.030.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zhou J, Zhang J, Gao W. Enhanced and selective delivery of enzyme therapy to 9L-glioma tumor via magnetic targeting of PEG-modified, β-glucosidase-conjugated iron oxide nanoparticles. Int J Nanomedicine. 2014;9:2905–17. https://doi.org/10.2147/IJN.S59556.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Lemaire L, Franconi F, Siegler B, Legendre C, Garcion E. In vitro expansion of U87-MG human glioblastoma cells under hypoxic conditions affects glucose metabolism and subsequent in vivo growth. Tumor Biol. 2015;36:7699–710. https://doi.org/10.1007/s13277-015-3458-3.

    CAS  Article  Google Scholar 

  24. 24.

    Peiris PM, Abramowski A, Mcginnity J, Doolittle E, Toy R, Gopalakrishnan R, Shah S, Bauer L, Ghaghada KB, Hoimes C, Brady-Kalnay SM, Basilion JP, Griswold MA, Karathanasis E. Treatment of invasive brain tumors using a chain-like nanoparticle. Cancer Res. 2015;75:1356–65. https://doi.org/10.1158/0008-5472.CAN-14-1540.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Schleich N, Po C, Jacobs D, Ucakar B, Gallez B, Danhier F, Préat V. Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy. J Control Release. 2014;194:82–91. https://doi.org/10.1016/J.JCONREL.2014.07.059.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Clavreul A, Roger E, Pourbaghi-Masouleh M, Lemaire L, Tétaud C, Menei P. Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma. Drug Deliv. 2018;25:1756–65. https://doi.org/10.1080/10717544.2018.1507061.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sun Z, Yan X, Liu Y, Huang L, Kong C, Qu X. Application of dual targeting drug delivery system for the improvement of anti-glioma efficacy of doxorubicin. Oncotarget. 2017;8:58823–34.

    Article  Google Scholar 

  28. 28.

    Zhang Y, Zhai M, Chen Z, Han X, Yu F, Li Z, Xie X, Han C, Yu L, Yang Y, Mei X. Dual-modified liposome codelivery of doxorubicin and vincristine improve targeting and therapeutic efficacy of glioma. Drug Deliv. 2017;24:1045–55. https://doi.org/10.1080/10717544.2017.1344334.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Li Y, Baiyang L, Leran B, Zhen W, Yandong X, Baixiang D, Dandan Z, Yufu Z, Jun L, Rutong Y, Hongmei L. Reduction-responsive PEtOz-SS-PCL micelle with tailored size to overcome blood–brain barrier and enhance doxorubicin antiglioma effect. Drug Deliv. 2017;24:1782–90. https://doi.org/10.1080/10717544.2017.1402218.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Belhadj Z, Ying M, Cao X, Hu X, Zhan C, Wei X, Gao J, Wang X, Yan Z, Lu W. Design of Y-shaped targeting material for liposome-based multifunctional glioblastoma-targeted drug delivery. J Control Release. 2017;255:132–41. https://doi.org/10.1016/j.jconrel.2017.04.006.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Fang Y, Jiang Y, Zou Y, Meng F, Zhang J, Deng C, Sun H, Zhong Z. Targeted glioma chemotherapy by cyclic RGD peptide-functionalized reversibly core-crosslinked multifunctional poly(ethylene glycol)- b -poly(ε-caprolactone) micelles. Acta Biomater. 2017;50:396–406. https://doi.org/10.1016/j.actbio.2017.01.007.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Liu S, Guo Y, Huang R, Li J, Huang S, Kuang Y, Han L, Jiang C. Gene and doxorubicin co-delivery system for targeting therapy of glioma. Biomaterials. 2012;33:4907–16. https://doi.org/10.1016/J.BIOMATERIALS.2012.03.031.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Chen Y, Huang Y, Liu W, Gao F, Fang X. c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma. Int J Nanomedicine. 2016;11:1629. https://doi.org/10.2147/IJN.S104162.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ucakar B, Joudiou N, Bianco J, Danhier P, Danhier F. Magnetic targeting of paclitaxel-loaded poly (lactic-co-glycolic acid )-based nanoparticles for the treatment of glioblastoma. Int J Nanomedicine. 2018;13:4509–21.

    Article  Google Scholar 

  35. 35.

    Ganipineni LP, Ucakar B, Joudiou N, Riva R, Jérôme C, Gallez B, Danhier F, Préat V. Paclitaxel-loaded multifunctional nanoparticles for the targeted treatment of glioblastoma. J Drug Target. 2019;27:614–23. https://doi.org/10.1080/1061186X.2019.1567738.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Shen W-B, Anastasiadis P, Nguyen B, Yarnell D, Yarowsky PJ, Frenkel V, Fishman PS. Magnetic enhancement of stem cell-targeted delivery into the brain following MR-guided focused ultrasound for opening the blood-brain barrier. Cell Transplant. 2017;26:1235–46. https://doi.org/10.1177/0963689717715824.

    Article  PubMed  PubMed Central  Google Scholar 

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The authors would like to thank Angers Hospital & University Animal Facility (SCAHU), Plateforme de Recherche en Imagerie et Spectroscopie Multimodales (PRISM-IRM-Angers) for providing access to their facilities.


This work was supported by the Fundación Caja Navarra and Navarra Government [grant number 411001-41210-4800-322302].

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Conceptualization: Laurent Lemaire and Maria J. Blanco-Prieto; investigation: Edurne Luque-Michel; writing—original draft preparation: Edurne Luque-Michel; writing—review and editing: Laurent Lemaire and Maria J. Blanco-Prieto; funding acquisition: María J. Blanco-Prieto. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Maria J. Blanco-Prieto.

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Ethics approval and consent to participate: all institutional and national guidelines for the care and use of laboratory animals were followed. Animal care and use were in accordance with the regulations of the French Ministry of Agriculture and approved by the Pays de la Loire Ethics in Animal Experimentation Committee under project number 01858.03.

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Luque-Michel, E., Lemaire, L. & Blanco-Prieto, M.J. SPION and doxorubicin-loaded polymeric nanocarriers for glioblastoma theranostics. Drug Deliv. and Transl. Res. 11, 515–523 (2021). https://doi.org/10.1007/s13346-020-00880-8

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  • Tween 80
  • MRI
  • Tumor doubling time
  • Glioma
  • U87-MG
  • PLGA