SYM-18-04

Triterpenoid micellar nanoparticles for the treatment of glioblastoma: potential inhibition of the PI3K/Akt signalling pathway

P Pirotta, YSW Wah, R Rohanizadeh, JR Hanrahan and RH Roubin

Faculty of Pharmacy, The University of Sydney, NSW, Australia

Glioma is the most common type of malignant brain tumour. Glioblastoma, the most aggressive type of glioma, accounts for half of all glioma cases and is associated with a high mortality rate. Current standard therapy for glioblastoma is inadequate due to tumour resistance and recurrence. Recent efforts in producing targeted therapies for glioblastoma have also faced challenges due to the blood brain barrier and the tumour heterogeneity of glioblastomas. As a result, there is a need for novel treatment strategies. A pentacyclic triterpenoid, ursolic acid (UA) and derivatives, are well known to possess a wide range of anti-cancer effects. With its multifaceted action, selective toxicity, chemosensitising effect and ability to penetrate the blood brain barrier, UA is believed to have a potential role in the treatment of glioblastoma. However, the limited aqueous solubility and non-specific bio-distribution of UA have been obstacles to its clinical application. An effective method for delivering UA has yet to be developed that would further elucidate the precise mechanism of UA in treating glioblastoma. We have synthesised UA into nanoparticles using micelles. We then characterised these nanoparticles to determine their physical properties, before determining their cellular uptake, in vitro cytotoxicity and effectiveness. We significantly improve UA solubility, stability, and bioavailability in vitro (P<0.05). We also significantly improve the anti-glioblastoma effects of the UA micellar nanoparticles comparable to a standard chemotherapeutic agent, vincristine (P<0.05). We hypothesise that UA may be inhibiting the PI3K/Akt signalling pathway, which plays a major role in mediating the responses of glioblastoma cells to UA, and the potential use of UA in treating glioblastoma.