Intranasal delivery of poly (d-glucosamine) encrusted self-assembled lipidic nanovesicles to enhanced brain uptake of thymoquinone for management of Glioblastoma Multiforme

Abstract

Glioblastoma Multiforme (GBM) is a grade IV primary malignant brain tumour, which is highly infiltrative and exhibits a poor prognosis which results in high mortality. Low solubility and stability are the major hurdles faced while developing drug delivery systems for the treatment of GBM. Therefore, this study focuses on the enhancement of brain uptake of thymoquinone (TH) by formulating poly (d-glucosamine) self-assembled lipidic nanovesicles for intranasal delivery using 3-level and 3-factor central composite design (CCD). The nanovesicles were formulated using thin film hydration technique and were spherical with the particle size of 129.13 ± 2.3 nm and 32.4 ± 2.4 mV of zeta potential. The formulation exhibited high entrapment and drug loading of TH i.e., 95.07 ± 0.8 % and 8.91 ± 0.2 % respectively. The nanovesicles attained a sustained release of TH of 89.62 ± 2.9 % in 48 h with improved drug permeation of 41.89 ± 1.61 % in 12 h from nasal mucosa with enhanced mucoadhesion of 72.98 ± 1.78 %. The in-vitro cellular studies indicated the high anticancer potential of TH by lowering the cell viability to 32.90 ± 0.91 % at 25 μg/mL (IC50;21.10 μg/mL) and high radical scavenging of 69.35 ± 1.91 % (IC50;18.10 μg/mL) and improved cellular uptake of 48.71 ± 0.10ng/100 cells. Greater bioavailability of TH in CNS (∼3 folds that of IV solution) was observed along with a high drug-targeting percentage (98.1 ± 3.90 %) and drug-targeting index (11.67 ± 1.87 %) post-intranasal administration of the formulation. Quantitative uptake of the formulation was estimated using fluorescence imaging, which showed higher uptake in tissues of the brain. The formulation was having very less hemolysis (<8 %). Hence the formulated carriers can be a promising tool for the treatment of GBM.