QbD-based intranasal pH-sensitive Ibrutinib liposomes for glioblastoma management: in vitro, ex vivo, and in vivo pharmacokinetics and brain distribution assessment.

Ibrutinib (IBR), a potent Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated promising anticancer potential; however, its poor solubility, limited bioavailability and restricted permeability across the blood-brain barrier (BBB) significantly constrain its therapeutic application in glioblastoma (GBM). For GBM therapy, overcoming the formidable BBB remains a major obstacle. In the current research, a pH-sensitive liposomal formulation encapsulating IBR (IBR-LIPO) was developed to facilitate direct nose-to-brain (N2B) delivery and enhance brain targeting. The optimized IBR-LIPO depicted a spherical morphology with a mean particle size below 200 nm, as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The optimized formulation depicted a zeta potential of -31.8 ± 0.95 indicating good stability. The formulation depicted an entrapment efficiency and drug loading of 85.46 ± 1.35% and 4.5 ± 0.34% respectively. The incorporation of cholesteryl hemisuccinate (CHS) conferred pH-responsive behavior, resulting in controlled yet initial-burst release profile in acidic conditions. Ex vivo nasal permeation and toxicity studies revealed a 2.54-fold enhancement in the nasal permeation with no signs of toxicity. In vitro evaluation using 2D and 3D cell culture revealed significantly improved cytotoxicity of IBR-LIPO compared to the free drug. In vivo pharmacokinetic analysis depicted enhanced brain delivery with a 2.30-fold enhancement in drug targeting efficiency (%DTE) and a 2.39-fold increase in direct transport percentage (%DTP) and a higher drug targeting index (DTI) over free IBR following intranasal (IN) administration. Collectively, these findings highlight IBR-LIPO as a promising nanocarrier for efficient N2B delivery and targeted GBM therapy.