Formulation and evaluation of itraconazole liposomes for Hedgehog pathway inhibition

Abstract

Itraconazole (ITZ) is an FDA-approved antifungal agent that has recently been explored for novel biological properties. In particular, ITZ was identified as a potent inhibitor of the hedgehog (Hh) pathway, a cell signalling pathway that has been linked to a variety of cancers and accounts for ∼25% of paediatric medulloblastoma (MB) cases. To date, there is not a targeted therapeutic option for paediatric MB, resulting in long-term side effects such as hormone deficiency, organ damage and secondary cancers. A primary obstacle for developing targeted therapy for brain ailments is the presence of the blood–brain barrier (BBB), which protects the brain from potentially harmful substances. Due to its size and hydrophobicity, ITZ does not penetrate the BBB. Alternatively, liposomes are being increasingly used within the clinic to increase drug bioavailability, target specificity and BBB permeability. With this in mind, we have successfully developed ITZ-containing liposomes with an optimal size for BBB penetration (<100 nm) and encapsulation efficiency (∼95%) by utilizing a continuous manufacturing approach—turbulent coaxial jet in co-flow. Our preliminary in vitro data demonstrate that these liposomes inhibit the Hh pathway, albeit at a reduced level in comparison to free ITZ. (196/250 words)

Keywords:

• Hedgehog
• cancer
• medulloblastoma
• itraconazole
• liposome
• drug repurposing
• blood–brain barrier

Acknowledgements

ASZ-001 cells were provided by Dr. Ervin Epstein (Children’s Hospital Oakland Research Institute).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We gratefully acknowledge support of this work by the National Institutes of Health/National Cancer Institute [CA190617]. J. R. P. gratefully acknowledges financial support from the Division of Medicinal Chemistry of the American Chemical Society (MEDI Pre-doctoral Fellowship).