Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme


The blood-brain barrier (BBB) impedes the efficient delivery of systemically administered drugs to brain tumors, thus reducing the therapeutic efficacy. To overcome the limitations of intravascular delivery, convention-enhanced delivery (CED) was introduced to infuse drugs directly into the brain tumor using a catheter with a continuous positive pressure. However, tissue distribution and retention of the infused drugs are significantly hindered by microenvironmental factors of the tumor such as the extracellular matrix and lymphatic drainage system in the brain. Here, we leveraged a liposomal formulation to simultaneously improve tissue distribution and retention of drugs infused in the brain tumor via the CED method. Various liposomal formulations with different surface charge, PEGylation, and transition temperature (Tm) were prepared to test the cellular uptake in vitro, and the tissue distribution and retention in the brain. In in vitro studies, PEGylated liposomal formulations with a positive surface charge and high Tm showed the most efficient cellular uptake among the tested formulations. In in vivo studies, the liposomal formulations were infused directly into the brain via the CED method. PEGylated liposomal formulations with a positive surface charge and high Tm showed more efficient distribution and retention in both normal and tumor tissues while only-PEGylated formulations displayed rapid clearance from the tissues to cervical lymph nodes. Furthermore, we demonstrated that the CED of liposomal everolimus prepared with the PEGylated formulation with a positive surface charge and high Tm resulted in superior therapeutic effects for glioblastoma treatment compared to other formulations.

Graphical abstract

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, Duong N, et al. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proc Natl Acad Sci U S A. 2013;110:11751–6.

    CAS  PubMed Central  Google Scholar 

  2. 2.

    Allard E, Passirani C, Benoit JP. Convection-enhanced delivery of nanocarriers for the treatment of brain tumors. Biomaterials. 2009;30:2302–18.

    CAS  Google Scholar 

  3. 3.

    Stupp R, Mason WP, van den Bent M, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    CAS  Google Scholar 

  4. 4.

    Dong X. Current strategies for brain drug delivery. Theranostics. 2018;8:1481–93.

    CAS  PubMed Central  Google Scholar 

  5. 5.

    Dhermain FG, Hau P, Lanfermann H, Jacobs AH, van den Bent MJ. Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol. 2010;9:906–20.

    Google Scholar 

  6. 6.

    van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 2015;19:1–12.

    Google Scholar 

  7. 7.

    Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release. 2012;161:264–73.

    CAS  Google Scholar 

  8. 8.

    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A. 1994;91:2076–80.

    CAS  PubMed Central  Google Scholar 

  9. 9.

    Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro-oncology. 2010;12:871–81.

    CAS  PubMed Central  Google Scholar 

  10. 10.

    Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Nass D, et al. Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg. 2004;100:472–9.

    CAS  Google Scholar 

  11. 11.

    Mittermeyer G, Christine CW, Rosenbluth KH, Baker SL, Starr P, Larson P, et al. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum Gene Ther. 2012;23:377–81.

    CAS  PubMed Central  Google Scholar 

  12. 12.

    Souweidane MM, Kramer K, Pandit-Taskar N, Zhou Z, Haque S, Zanzonico P, et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial. Lancet Neurol. 2018;19:1040–50.

    Google Scholar 

  13. 13.

    Laske DW, Youle RJ, Oldfield EH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med. 1997;3:1362–8.

    CAS  Google Scholar 

  14. 14.

    Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol. 2000;164:2–14.

    CAS  Google Scholar 

  15. 15.

    Nguyen JB, Sanchez-Pernaute R, Cunningham J, Bankiewicz KS. Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain. Neuroreport. 2001;12:1961–4.

    CAS  Google Scholar 

  16. 16.

    Stiles DK, Zhang Z, Ge P, Nelson B, Grondin R, Ai Y, et al. Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp Neurol. 2012;233:463–71.

    CAS  Google Scholar 

  17. 17.

    Yang W, et al. Convection-enhanced delivery of boronated epidermal growth factor for molecular targeting of EGF receptor-positive gliomas. Cancer Res. 2002;62:6552–8.

    CAS  Google Scholar 

  18. 18.

    Hadjipanayis CG, Machaidze R, Kaluzova M, Wang L, Schuette AJ, Chen H, et al. EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res. 2010;70:6303–12.

    CAS  PubMed Central  Google Scholar 

  19. 19.

    Mamot C, Nguyen JB, Pourdehnad M, Hadaczek P, Saito R, Bringas JR, et al. Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery. J Neuro-Oncol. 2004;68:1–9.

    Google Scholar 

  20. 20.

    Saito R, Bringas JR, McKnight TR, Wendland MF, Mamot C, Drummond DC, et al. Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res. 2004;64:2572–9.

    CAS  Google Scholar 

  21. 21.

    Nance E, Zhang C, Shih TY, Xu Q, Schuster BS, Hanes J. Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration. ACS Nano. 2014;8:10655–64.

    CAS  PubMed Central  Google Scholar 

  22. 22.

    Xi G, Robinson E, Mania-Farnell B, Vanin EF, Shim KW, Takao T, et al. Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine. 2014;10:381–91.

    CAS  Google Scholar 

  23. 23.

    Thorne RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A. 2006;103:5567–72.

    CAS  PubMed Central  Google Scholar 

  24. 24.

    Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 2012;7:5577–91.

    PubMed Central  Google Scholar 

  25. 25.

    Nance EA, et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med. 2012;4:149ra119.

    PubMed Central  Google Scholar 

  26. 26.

    Mishra S, Webster P, Davis ME. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol. 2004;83:97–111.

    CAS  Google Scholar 

  27. 27.

    Weller RO, Djuanda E, Yow HY, Carare RO. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol. 2009;117:1–14.

    CAS  Google Scholar 

  28. 28.

    Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol. 2008;18:253–66.

    CAS  Google Scholar 

  29. 29.

    Rottenberg DA, Ginos JZ, Kearfott KG, Junck L, Dhawan V, Jarden JO. In vivo measurement of brain tumor pH using [11C]DMO and positron emission tomography. Ann Neurol. 1985;17:70–9.

    CAS  Google Scholar 

  30. 30.

    Mindell JA. Lysosomal acidification mechanisms. Annu Rev Physiol. 2012;74:69–86.

    CAS  Google Scholar 

  31. 31.

    Ramachandran M, Yu D, Dyczynski M, Baskaran S, Zhang L, Lulla A, et al. Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically delivered triple microRNA-detargeted oncolytic Semliki Forest virus. Clin Cancer Res. 2017;23:1519–30.

    CAS  Google Scholar 

  32. 32.

    Wei J, Marisetty A, Schrand B, Gabrusiewicz K, Hashimoto Y, Ott M, et al. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J Clin Invest. 2019;129:137–49.

    Google Scholar 

  33. 33.

    Belmans J, van Woensel M, Creyns B, Dejaegher J, Bullens DM, van Gool SW. Immunotherapy with subcutaneous immunogenic autologous tumor lysate increases murine glioblastoma survival. Sci Rep. 2017;7:13902.

    PubMed Central  Google Scholar 

  34. 34.

    Enríquez Pérez J, Kopecky J, Visse E, Darabi A, Siesjö P. Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas. BMC Cancer. 2020;20:7.

    PubMed Central  Google Scholar 

  35. 35.

    IYENGAR S, SCHWARTZ D. Failure of inositol trispyrophosphate to enhance highly effective radiotherapy of GL261 glioblastoma in mice. Anticancer Res. 2017;37:1121–5.

    CAS  Google Scholar 

  36. 36.

    Zhang T, Yan Y, Wang X, Xiong Z, Lin F, Wu R, et al. Three-dimensional gelatin and gelatin/hyaluronan hydrogel structures for traumatic brain injury. J Bioact Compat Polym. 2007;22:19–29.

    Google Scholar 

  37. 37.

    Wu S, Xu R, Duan B, Jiang P. Three-dimensional hyaluronic acid hydrogel-based models for in vitro human iPSC-derived NPC culture and differentiation. J Mater Chem B. 2017;5:3870–8.

    CAS  PubMed Central  Google Scholar 

  38. 38.

    Xiao W, Zhang R, Sohrabi A, Ehsanipour A, Sun S, Liang J, et al. Brain-mimetic 3D culture platforms allow investigation of cooperative effects of extracellular matrix features on therapeutic resistance in glioblastoma. Cancer Res. 2018;78:1358–70.

    CAS  Google Scholar 

  39. 39.

    Engelhardt B, Carare RO, Bechmann I, Flügel A, Laman JD, Weller RO. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 2016;132:317–38.

    CAS  PubMed Central  Google Scholar 

  40. 40.

    Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127:3210–9.

    PubMed Central  Google Scholar 

  41. 41.

    Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019;572:62–6.

    CAS  Google Scholar 

  42. 42.

    Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31:326–41.

    CAS  PubMed Central  Google Scholar 

  43. 43.

    Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.

    CAS  Google Scholar 

  44. 44.

    Hu Y, Xie J, Tong YW, Wang CH. Effect of PEG conformation and particle size on the cellular uptake efficiency of nanoparticles with the HepG2 cells. J Control Release. 2007;118:7–17.

    CAS  Google Scholar 

  45. 45.

    Oyewumi MO, Yokel RA, Jay M, Coakley T, Mumper RJ. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release. 2004;95:613–26.

    CAS  Google Scholar 

  46. 46.

    Song E, Gaudin A, King AR, Seo YE, Suh HW, Deng Y, et al. Surface chemistry governs cellular tropism of nanoparticles in the brain. Nat Commun. 2017;8:15322.

    CAS  PubMed Central  Google Scholar 

  47. 47.

    Ferrer VP, Moura Neto V, Mentlein R. Glioma infiltration and extracellular matrix: key players and modulators. Glia. 2018;66:1542–65.

    Google Scholar 

  48. 48.

    Oohashi T, Edamatsu M, Bekku Y, Carulli D. The hyaluronan and proteoglycan link proteins: organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity. Exp Neurol. 2015;274:134–44.

    CAS  Google Scholar 

  49. 49.

    Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ. Proteoglycans and their roles in brain cancer. FEBS J. 2013;280:2399–417.

    CAS  PubMed Central  Google Scholar 

  50. 50.

    Kim WY, Lee HY. Brain angiogenesis in developmental and pathological processes: mechanism and therapeutic intervention in brain tumors. FEBS J. 2009;276:4653–64.

    CAS  PubMed Central  Google Scholar 

  51. 51.

    Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol. 2018;135:311–36.

    CAS  PubMed Central  Google Scholar 

Download references


This work was supported by the Basic Science Research Program (Grant No. NRF-2017R1E1A1A01074847) through the National Research Foundation funded by the Ministry of Science and ICT, Republic of Korea.

Author information



Corresponding author

Correspondence to Ji-Ho Park.

Ethics declarations

All animal experiments were performed with approval from the KAIST Institutional Animal Care and Use Committee (IACUC).

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material


(PDF 13.2 mb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Han, Y., Park, JH. Convection-enhanced delivery of liposomal drugs for effective treatment of glioblastoma multiforme. Drug Deliv. and Transl. Res. 10, 1876–1887 (2020).

Download citation


  • Cervical lymph node
  • Chemotherapy
  • Convection-enhanced delivery
  • Glioblastoma
  • Liposome