Intranasal Pacritinib-loaded nanoemulsion for Glioblastoma management: In Vitro, ex Vivo, 3D spheroid and In vivo...

Pacritinib (PAC), a potent inhibitor of JAK2, is currently being explored as a potential therapeutic agent against GBM, which is an aggressive and vascularized brain tumor, resistant to many therapies. The therapeutic potential of PAC is hindered due to its poor water solubility and low brain bioavailability. In the current study, a PAC-loaded nanoemulsion (PAC-NE) was formulated to deliver the drug through the intranasal (IN) route for better solubilization, nasal absorption, and brain targeting. The optimized formulation of PAC-NE exhibited a mean droplet size of 18.78 ± 0.4 nm and a polydispersity index (PDI) value of 0.183 ± 0.007, representing a highly homogenous and uniform NE, which is appropriate for nasal administration. In vitro evaluation of the anticancer efficacy in 2D cell culture and 3D tumor spheroid model (3DS) proved that PAC-NE greatly improved the cellular uptake, cytotoxicity, and tumor spheroid inhibition activity compared with free PAC. In addition, ex vivo nasal permeation was greatly improved by the optimized formulation, showing a flux value of 1.27 ± 0.06 µg/cm²/h and a permeability coefficient value of 2.4 × 10⁻⁷ ± 0.19 cm/s, which were significantly higher than that of the plain drug. Moreover, the histopathological examination demonstrated no sign of damage to the nasal mucosa. Pharmacokinetics analysis following IN application revealed that the optimized NE depicted greater brain-targeting ability, where there was an improvement in %DTE by 1.99-fold and in %DTP by 2.75-fold in comparison to free PAC. Overall, from the above observations, it can be concluded that PAC-NE is a non-invasive delivery system which shows promising results for better brain delivery thereby supporting the clinical translation of PAC for GBM therapy.