Overcoming the Physiopathologic Barriers: Nanoprobes-Mediated Intracranial Glioma Imaging

  • Heng Liu
  • Yu Liu
  • Fengyuan Man
  • Gang LiuEmail author


Malignant glioma is characterized by active angiogenesis, high invasiveness and infiltration, and extremely rapid growth. Accurate visualization of glioma is crucial to the early diagnosis, preoperative localization, intraoperative guidance, and therapeutic evaluation and thus facilitates the clinical decision-making and improves the clinical outcomes of patients. However, conventional contrast agents directed toward intracranial glioma remain challenging, largely attributed to the existence of physiopathologic barriers unique to brain tumors. Remarkable advancements in nanotechnology and nanomedicine open a multidisciplinary field to design various nanoprobes for overcoming the physiopathologic barriers and for improved glioma imaging. This chapter starts with the critical biological challenges facing intracranial glioma. The innovative approaches for enhancing blood-brain barrier permeability and improved glioma targeting ability are presented. It then provides an overview of the unique advantages of nanomaterials for glioma imaging. The advanced applications of nanoprobes in intracranial glioma imaging are reviewed in detail, including magnetic resonance imaging, photoacoustic imaging, fluorescence imaging, multimodality imaging, and intraoperative glioma margin delineation. Finally, the current challenges and perspectives of this field are also discussed.


Malignant glioma Nanoprobe Imaging Blood-brain barrier 



This work was supported by the Major State Basic Research Development Program of China (2017YFA0205201), the National Natural Science Foundation of China (81901872, 81422023, U1705281, and U1505221), the Fundamental Research Funds for the Central Universities (20720160065 and 20720150141), and the Program for New Century Excellent Talents in University, China (NCET-13-0502).


  1. 1.
    Nano R, Lascialfari A, Corti M, Paolini A, Pasi F, Corbella F, et al. New frontiers for astrocytic tumours. Anticancer Res. 2012;32(7):2755–8.PubMedGoogle Scholar
  2. 2.
    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Linz U. Commentary on effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (Lancet Oncol. 2009;10:459–466). Cancer. 2010;116(8):1844–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA. How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology. 2002;59(6):947–9.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Prince MR, Zhang H, Morris M, MacGregor JL, Grossman ME, Silberzweig J, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology. 2008;248(3):807–16.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Quattrocchi CC, van der Molen AJ. Gadolinium retention in the body and brain: is it time for an international joint research effort? Radiology. 2017;282(1):12–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Sun C, Lee JS, Zhang M. Magnetic nanoparticles in MR imaging and drug delivery. Adv Drug Deliv Rev. 2008;60(11):1252–65.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. 2010;64(2):328–63.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Liu H, Zhang J, Chen X, Du XS, Zhang JL, Liu G, et al. Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside. Nanoscale. 2016;8(15):7808–26.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Lesniak MS, Brem H. Targeted therapy for brain tumours. Nat Rev Drug Discov. 2004;3(6):499–508.PubMedCrossRefGoogle Scholar
  11. 11.
    Pardridge WM. Crossing the blood-brain barrier: are we getting it right? Drug Discov Today. 2001;6(1):1–2.PubMedCrossRefGoogle Scholar
  12. 12.
    Pardridge WM. Drug and gene delivery to the brain: the vascular route. Neuron. 2002;36(4):555–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Koo YE, Reddy GR, Bhojani M, Schneider R, Philbert MA, Rehemtulla A, et al. Brain cancer diagnosis and therapy with nanoplatforms. Adv Drug Deliv Rev. 2006;58(14):1556–77.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Vajkoczy P, Menger MD. Vascular microenvironment in gliomas. J Neuro-Oncol. 2000;50(1–2):99–108.CrossRefGoogle Scholar
  15. 15.
    Liu Y, Lu W. Recent advances in brain tumor-targeted nano-drug delivery systems. Expert Opin Drug Deliv. 2012;9(6):671–86.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Sarin H, Kanevsky AS, Wu H, Brimacombe KR, Fung SH, Sousa AA, et al. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells. J Transl Med. 2008;6:80.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Furtado D, Bjornmalm M, Ayton S, Bush AI, Kempe K, Caruso F. Overcoming the blood-brain barrier: the role of nanomaterials in treating neurological diseases. Adv Mater. 2018:e1801362.Google Scholar
  18. 18.
    Liu H, Chen X, Xue W, Chu C, Liu Y, Tong H, et al. Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging. Int J Nanomedicine. 2016;11:5099–108.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Liu H, Chu C, Liu Y, Pang X, Wu Y, Zhou Z, et al. Novel Intrapolymerization doped manganese-eumelanin coordination nanocomposites with ultrahigh relaxivity and their application in tumor theranostics. Adv Sci. 2018; Scholar
  20. 20.
    Cao C, Wang X, Cai Y, Sun L, Tian L, Wu H, et al. Targeted in vivo imaging of microscopic tumors with ferritin-based nanoprobes across biological barriers. Adv Mater. 2014;26(16):2566–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen N, Shao C, Qu Y, Li S, Gu W, Zheng T, et al. Folic acid-conjugated MnO nanoparticles as a T1 contrast agent for magnetic resonance imaging of tiny brain gliomas. ACS Appl Mater Interfaces. 2014;6(22):19850–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Yan H, Wang L, Wang J, Weng X, Lei H, Wang X, et al. Two-order targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain barrier. ACS Nano. 2012;6(1):410–20.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Zhang J, Chen N, Wang H, Gu W, Liu K, Ai P, et al. Dual-targeting superparamagnetic iron oxide nanoprobes with high and low target density for brain glioma imaging. J Colloid Interface Sci. 2016;469:86–92.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Jiang W, Xie H, Ghoorah D, Shang Y, Shi H, Liu F, et al. Conjugation of functionalized SPIONs with transferrin for targeting and imaging brain glial tumors in rat model. PLoS One. 2012;7(5):e37376.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Luo B, Wang S, Rao R, Liu X, Xu H, Wu Y, et al. Conjugation magnetic PAEEP-PLLA nanoparticles with Lactoferrin as a specific targeting MRI contrast agent for detection of brain Glioma in rats. Nanoscale Res Lett. 2016;11(1):227.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Xie H, Zhu Y, Jiang W, Zhou Q, Yang H, Gu N, et al. Lactoferrin-conjugated superparamagnetic iron oxide nanoparticles as a specific MRI contrast agent for detection of brain glioma in vivo. Biomaterials. 2011;32(2):495–502.PubMedCrossRefGoogle Scholar
  27. 27.
    Abakumov MA, Shein SA, Vishvasrao H, Nukolova NV, Sokol’ski-Papkov M, Sandalova TO, et al. Visualization of experimental glioma C6 by MRI with magnetic nanoparticles conjugated with monoclonal antibodies to vascular endothelial growth factor. Bull Exp Biol Med. 2012;154(2):274–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Towner RA, Smith N, Asano Y, He T, Doblas S, Saunders D, et al. Molecular magnetic resonance imaging approaches used to aid in the understanding of angiogenesis in vivo: implications for tissue engineering. Tissue Eng Part A. 2010;16(2):357–64.PubMedCrossRefGoogle Scholar
  29. 29.
    de Oliveira EA, Lazovic J, Guo L, Soto H, Faintuch BL, Akhtari M, et al. Evaluation of Magnetonanoparticles conjugated with new angiogenesis peptides in intracranial Glioma tumors by MRI. Appl Biochem Biotechnol. 2017;183(1):265–79.PubMedCrossRefGoogle Scholar
  30. 30.
    Richard S, Boucher M, Lalatonne Y, Meriaux S, Motte L. Iron oxide nanoparticle surface decorated with cRGD peptides for magnetic resonance imaging of brain tumors. Biochim Biophys Acta Gen Subj. 2017;1861(6):1515–20.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Tomanek B, Iqbal U, Blasiak B, Abulrob A, Albaghdadi H, Matyas JR, et al. Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging. Neuro-Oncology. 2012;14(1):53–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Shevtsov MA, Nikolaev BP, Yakovleva LY, Marchenko YY, Dobrodumov AV, Mikhrina AL, et al. Superparamagnetic iron oxide nanoparticles conjugated with epidermal growth factor (SPION-EGF) for targeting brain tumors. Int J Nanomedicine. 2014;9:273–87.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Mu K, Zhang S, Ai T, Jiang J, Yao Y, Jiang L, et al. Monoclonal antibody-conjugated superparamagnetic iron oxide nanoparticles for imaging of epidermal growth factor receptor-targeted cells and gliomas. Mol Imaging. 2015;14CrossRefGoogle Scholar
  34. 34.
    Shevtsov MA, Yakovleva LY, Nikolaev BP, Marchenko YY, Dobrodumov AV, Onokhin KV, et al. Tumor targeting using magnetic nanoparticle Hsp70 conjugate in a model of C6 glioma. Neuro-Oncology. 2014;16(1):38–49.PubMedCrossRefGoogle Scholar
  35. 35.
    Shevtsov MA, Nikolaev BP, Yakovleva LY, Dobrodumov AV, Zhakhov AV, Mikhrina AL, et al. Recombinant interleukin-1 receptor antagonist conjugated to superparamagnetic iron oxide nanoparticles for theranostic targeting of experimental glioblastoma. Neoplasia. 2015;17(1):32–42.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Perera VS, Covarrubias G, Lorkowski M, Atukorale P, Rao A, Raghunathan S, et al. One-pot synthesis of nanochain particles for targeting brain tumors. Nanoscale. 2017;9(27):9659–67.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Qiu LH, Zhang JW, Li SP, Xie C, Yao ZW, Feng XY. Molecular imaging of angiogenesis to delineate the tumor margins in glioma rat model with endoglin-targeted paramagnetic liposomes using 3T MRI. J Magn Reson Imaging: JMRI. 2015;41(4):1056–64.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Liu X, Madhankumar AB, Miller PA, Duck KA, Hafenstein S, Rizk E, et al. MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA. Neuro-Oncology. 2016;18(5):691–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Lu W, Melancon MP, Xiong C, Huang Q, Elliott A, Song S, et al. Effects of photoacoustic imaging and photothermal ablation therapy mediated by targeted hollow gold nanospheres in an orthotopic mouse xenograft model of glioma. Cancer Res. 2011;71(19):6116–21.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Chen J, Liu C, Hu D, Wang F, Wu H, Gong X, et al. Single-layer MoS2 nanosheets with amplified photoacoustic effect for highly sensitive photoacoustic imaging of orthotopic brain tumors. Adv Funct Mater. 2016; Scholar
  41. 41.
    Liu C, Chen J, Zhu Y, Gong X, Zheng R, Chen N, et al. Highly sensitive MoS2-Indocyanine green hybrid for Photoacoustic imaging of Orthotopic brain Glioma at deep site. Nano-Micro Lett. 2018;10(3):48.CrossRefGoogle Scholar
  42. 42.
    Fan Q, Cheng K, Yang Z, Zhang R, Yang M, Hu X, et al. Perylene-diimide-based nanoparticles as highly efficient photoacoustic agents for deep brain tumor imaging in living mice. Adv Mater. 2015;27(5):843–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Guo B, Sheng Z, Hu D, Liu C, Zheng H, Liu B. Through scalp and skull NIR-II photothermal therapy of deep Orthotopic brain tumors with precise photoacoustic imaging guidance. Adv Mater. 2018;30(35):e1802591.PubMedCrossRefGoogle Scholar
  44. 44.
    Nurmikko A. What future for quantum dot-based light emitters? Nat Nanotechnol. 2015;10(12):1001–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Tang J, Huang N, Zhang X, Zhou T, Tan Y, Pi J, et al. Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma. Int J Nanomedicine. 2017;12:3899–911.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Huang N, Cheng S, Zhang X, Tian Q, Pi J, Tang J, et al. Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood-brain barrier and targeted fluorescence imaging of glioma and tumor vasculature. Nanomedicine. 2017;13(1):83–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang Y, Meng Y, Wang S, Li C, Shi W, Chen J, et al. Direct solvent-derived polymer-coated nitrogen-doped carbon Nanodots with high water solubility for targeted fluorescence imaging of Glioma. Small. 2015;11(29):3575–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Zheng M, Ruan S, Liu S, Sun T, Qu D, Zhao H, et al. Self-targeting fluorescent carbon dots for diagnosis of brain Cancer cells. ACS Nano. 2015;9(11):11455–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Prodi L, Rampazzo E, Rastrelli F, Speghini A, Zaccheroni N. Imaging agents based on lanthanide doped nanoparticles. Chem Soc Rev. 2015;44(14):4922–52.PubMedCrossRefGoogle Scholar
  50. 50.
    Ni D, Zhang J, Bu W, Xing H, Han F, Xiao Q, et al. Dual-targeting upconversion nanoprobes across the blood-brain barrier for magnetic resonance/fluorescence imaging of intracranial glioblastoma. ACS Nano. 2014;8(2):1231–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Sheng Z, Guo B, Hu D, Xu S, Wu W, Liew WH, et al. Bright aggregation-induced-emission dots for targeted synergetic NIR-II fluorescence and NIR-I Photoacoustic imaging of Orthotopic brain tumors. Adv Mater. 2018;30:e1800766.CrossRefGoogle Scholar
  52. 52.
    Louie A. Multimodality imaging probes: design and challenges. Chem Rev. 2010;110(5):3146–95.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jiang L, Zhou Q, Mu K, Xie H, Zhu Y, Zhu W, et al. pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin for MR and fluorescence imaging of glioma in rats. Biomaterials. 2013;34(30):7418–28.PubMedCrossRefGoogle Scholar
  54. 54.
    Du Y, Qian M, Li C, Jiang H, Yang Y, Huang R. Facile marriage of Gd(3+) to polymer-coated carbon nanodots with enhanced biocompatibility for targeted MR/fluorescence imaging of glioma. Int J Pharm. 2018;552(1–2):84–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Gonawala S, Ali MM. Application of Dendrimer-based nanoparticles in Glioma imaging. J Nanomed Nanotechnol. 2017;8(3):444.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Chen N, Shao C, Li S, Wang Z, Qu Y, Gu W, et al. Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas. J Colloid Interface Sci. 2015;457:27–34.PubMedCrossRefGoogle Scholar
  57. 57.
    Sun L, Joh DY, Al-Zaki A, Stangl M, Murty S, Davis JJ, et al. Theranostic application of mixed gold and Superparamagnetic Iron Oxide nanoparticle micelles in glioblastoma Multiforme. J Biomed Nanotechnol. 2016;12(2):347–56.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Blanco VM, Chu Z, LaSance K, Gray BD, Pak KY, Rider T, et al. Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles. Oncotarget. 2016;7(22):32866–75.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Shang W, Zeng C, Du Y, Hui H, Liang X, Chi C, et al. Core-Shell gold Nanorod@Metal-Organic framework nanoprobes for multimodality diagnosis of Glioma. Adv Mater. 2017;29(3). CrossRefGoogle Scholar
  60. 60.
    Xiao N, Gu W, Wang H, Deng Y, Shi X, Ye L. T1-T2 dual-modal MRI of brain gliomas using PEGylated Gd-doped iron oxide nanoparticles. J Colloid Interface Sci. 2014;417:159–65.PubMedCrossRefGoogle Scholar
  61. 61.
    Shevtsov M, Nikolaev B, Marchenko Y, Yakovleva L, Skvortsov N, Mazur A, et al. Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs). Int J Nanomedicine. 2018;13:1471–82.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Liu XL, Ng CT, Chandrasekharan P, Yang HT, Zhao LY, Peng E, et al. Synthesis of ferromagnetic Fe0.6 Mn0.4 O Nanoflowers as a new class of magnetic Theranostic platform for in vivo T1 -T2 dual-mode magnetic resonance imaging and magnetic hyperthermia therapy. Adv Healthc Mater. 2016;5(16):2092–104.PubMedCrossRefGoogle Scholar
  63. 63.
    Ni D, Shen Z, Zhang J, Zhang C, Wu R, Liu J, et al. Integrating anatomic and functional dual-mode magnetic resonance imaging: design and applicability of a bifunctional contrast agent. ACS Nano. 2016;10(3):3783–90.PubMedCrossRefGoogle Scholar
  64. 64.
    Yang L, Shao B, Zhang X, Cheng Q, Lin T, Liu E. Multifunctional upconversion nanoparticles for targeted dual-modal imaging in rat glioma xenograft. J Biomater Appl. 2016;31(3):400–10.PubMedCrossRefGoogle Scholar
  65. 65.
    Gao X, Yue Q, Liu Z, Ke M, Zhou X, Li S, et al. Guiding brain-tumor surgery via blood-brain-barrier-permeable gold Nanoprobes with acid-triggered MRI/SERRS signals. Adv Mater. 2017 Jun;29(21). Epub 2017 Mar 15.CrossRefGoogle Scholar
  66. 66.
    Neuschmelting V, Harmsen S, Beziere N, Lockau H, Hsu HT, Huang R, et al. Dual-modality surface-enhanced resonance Raman scattering and multispectral Optoacoustic tomography nanoparticle approach for brain tumor delineation. Small. 2018;14(23):e1800740.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kircher MF, de la Zerda A, Jokerst JV, Zavaleta CL, Kempen PJ, Mittra E, et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med. 2012;18(5):829–34.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of RadiologyPLA Rocket Force Characteristic Medical CenterBeijingChina
  2. 2.Department of Ultrasound, Southwest HospitalArmy Medical UniversityChongqingChina
  3. 3.State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina

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