Liposomal itraconazole formulation for the treatment of glioblastoma using inclusion complex with HP-β-CD

  • Sung-Won Yoon
  • Dae Hwan Shin
  • Jin-Seok KimEmail author
Original Article



Itraconazole, which has been widely used as an antifungal-agent, is revisited as an anticancer drug but its low solubility still remains a major hurdle.


Inclusion complex was used to enhance the solubility of itraconazole, followed by encapsulating into liposome for glioblastoma.


Itraconazole-inclusion complex was well formed at 1:1, 1:2 and 1:3 molar ratios of itraconazole: hydroxypropyl-β-cyclodextrin (HP-β-CD) as determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) analyses. Itraconazole-HP-β-CD inclusion complex was then encapsulated in liposome and its size was 120.5 ± 53.1 nm in diameter with 50% encapsulation efficiency. Stem cell-like property, as determined by the population ratio of CD90+/CD133+, was decreased from 3.38 to 1.46% when the U87-MG-TL cells were treated with 100 µM itraconazole/HP-β-CD-loaded liposome. Anti-proliferative effect of itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was slightly better than that of free itraconazole (IC50 of 17 µM vs. 26 µM). Moreover, anti-proliferative effect of Itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was higher than that of free itraconazole when the cells were co-treated with temozolomide (IC50 of 1.58 mM vs. 2.35 mM).


Therefore, itraconazole/HP-β-CD-loaded liposomal formulation could serve as a promising strategy for targeting the glioblastoma multiforme.


Itraconazole Inclusion complex Liposome Glioblastoma multiforme Cyclodextrin 



This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2017R1D1A1B03030849) and the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST, No.2011-0030074).

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.


  1. Cevc G (2012) Rational design of new product candidates: the next generation of highly deformable bilayer vesicles for noninvasive, targeted therapy. J Control Release 160:135–146CrossRefGoogle Scholar
  2. Gharib R, Greige-Gerges H, Fourmentin S, Charcosset C, Auezova L (2015) Liposomes incorporating cyclodextrin–drug inclusion complexes: current state of knowledge. Carbohydr Polym 129:175–186CrossRefGoogle Scholar
  3. Ghorab MK, Adeyeye MC (2001) Enhancement of ibuprofen dissolution via wet granulation with beta-cyclodextrin. Pharm Dev Technol 6:305–314CrossRefGoogle Scholar
  4. Gil A, Chamayou A, Leverd E, Bougaret J, Baron M et al (2004) Evolution of the interaction of a new chemical entity, eflucimibe, with gamma-cyclodextrin during kneading process. Eur J Pharm Sci 23:123–129CrossRefGoogle Scholar
  5. Goke K, Bunjes H (2017) Drug solubility in lipid nanocarriers: Influence of lipid matrix and available interfacial area. Int J Pharm 529:617–628CrossRefGoogle Scholar
  6. Han S-M, Na Y-G, Lee H-S, Son G-H, Jeon S-H et al (2018) Improvement of cellular uptake of hydrophilic molecule, calcein, formulated by liposome. J Pharm Investig 48:595–601CrossRefGoogle Scholar
  7. He J, Liu Y, Zhu T, Zhu J, Dimeco F et al (2012) CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays. Mol Cell Proteom 11:M111 010744CrossRefGoogle Scholar
  8. Kim J, Tang JY, Gong R, Kim J, Lee JJ et al (2010) Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17:388–399CrossRefGoogle Scholar
  9. Lang B, Liu S, McGinity JW, Williams RO 3rd (2016) Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions. Drug Dev Ind Pharm 42:429–445CrossRefGoogle Scholar
  10. Liu R, Li J, Zhang T, Zou L, Chen Y et al (2014) Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy 10:1241–1255CrossRefGoogle Scholar
  11. Miyama T, Takanaga H, Matsuo H, Yamano K, Yamamoto K et al (1998) P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 42:1738–1744CrossRefGoogle Scholar
  12. Nacev BA, Grassi P, Dell A, Haslam SM, Liu JO (2011) The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells. J Biol Chem 286:44045–44056CrossRefGoogle Scholar
  13. Noble GT, Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B (2014) Ligand-targeted liposome design: challenges and fundamental considerations. Trends Biotechnol 32:32–45CrossRefGoogle Scholar
  14. Ohgaki H (2005) Genetic pathways to glioblastomas. Neuropathology 25:1–7CrossRefGoogle Scholar
  15. Parikh T, Sandhu HK, Talele TT, Serajuddin AT (2016) Characterization of solid dispersion of itraconazole prepared by solubilization in concentrated aqueous solutions of weak organic acids and drying. Pharm Res 33:1456–1471CrossRefGoogle Scholar
  16. Reardon DA, Rich JN, Friedman HS, Bigner DD (2006) Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 24:1253–1265CrossRefGoogle Scholar
  17. Sayed S, Elsayed I, Ismail MM (2018) Optimization of beta-cyclodextrin consolidated micellar dispersion for promoting the transcorneal permeation of a practically insoluble drug. Int J Pharm 549:249–260CrossRefGoogle Scholar
  18. Seo J, Kim M-J, Jeon S-O, Oh D-H, Yoon K-H et al (2018) Enhanced topical delivery of fish scale collagen employing negatively surface-modified nanoliposome. J Pharm Investig 48:243–250CrossRefGoogle Scholar
  19. Shin DH, Xuan S, Kim W-Y, Bae G-U, Kim J-S (2014) CD133 antibody-conjugated immunoliposomes encapsulating gemcitabine for targeting glioblastoma stem cells. J Mater Chem B 2:3771–3781CrossRefGoogle Scholar
  20. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401CrossRefGoogle Scholar
  21. Stevens DA (1999) Itraconazole in cyclodextrin solution. Pharmacotherapy 19:603–611CrossRefGoogle Scholar
  22. Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:145–160CrossRefGoogle Scholar
  23. Vieira DB, Gamarra LF (2016) Getting into the brain: liposome-based strategies for effective drug delivery across the blood-brain barrier. Int J Nanomed 11:5381–5414CrossRefGoogle Scholar
  24. Xuan S, Shin DH, Kim J-S (2014) Angiopep-2-conjugated liposomes encapsulating γ-secretase inhibitor for targeting glioblastoma stem cells. J Pharm Investig 44:473–483CrossRefGoogle Scholar
  25. Zhang L, Zhang Q, Wang X, Zhang W, Lin C et al (2015) Drug-in-cyclodextrin-in-liposomes: a novel drug delivery system for flurbiprofen. Int J Pharm 492:40–45CrossRefGoogle Scholar

Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2019

Authors and Affiliations

  1. 1.Drug Information Research Institute (DIRI), College of PharmacySookmyung Women’s UniversitySeoulSouth Korea
  2. 2.College of PharmacyChungbuk National UniversityCheongjuSouth Korea

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