Fabrication and optimization of verapamil-loaded PEGylated nanoparticles for management of traumatic brain injury: a comparative evaluation

Verapamil (VRP) is a calcium channel blocker described for cardiovascular diseases. The reported antioxidant in addition to anti-inflammatory attributes, could present its potential efficacy for traumatic brain injury (TBI). However, brain drug delivery presents a well-known challenge. The present study aimed to design VRP-loaded PEGylated chitosan nanoparticles (PEG-VRP-NPs) for successful brain delivery after intranasal administration. A central composite design was adopted to optimize levels of Chitosan and PEG4000. The optimized PEG-VRP-NPs were assessed for in-vitro VRP release, and their morphology was observed by Transmission electron microscopy (TEM). The pharmacological effect of the optimized formula as a neuroprotective against TBI was assessed after intranasal administration to rats by measuring oxidative stress markers, inflammatory and apoptotic markers in brain tissues, and histopathological examination. In-vitro release behavior from the optimized formula exhibited a biphasic release pattern of an initial burst release followed by extended release up to 6 h. TEM images of optimized formula confirmed the formation of spherical-shaped nanosized particles. The pharmacological results confirmed the developed nanoparticles' ability to deliver VRP to the brain effectively. The nanoparticles effectively demonstrated neuroprotection through antioxidant, antiapoptotic actions and down-regulation of the TLR4/NOX4/NF-κB signaling pathway. In conclusion, PEG-VRP-NPs formulation showed a novel brain drug delivery of VRP with an improved neuroprotective effect against TBI in rats.