Chitosan/Cyclodextrin Nanospheres for Potential Nose-to-Brain Targeting of Idebenone

Idebenone (IDE) is a powerful antioxidant that is potentially active towards cerebral diseases, but its low water solubility and fast first pass metabolism reduce its accumulation in the brain, making it ineffective. In this work, we developed cyclodextrin-based chitosan nanospheres (CS NPs) as potential carriers for nose-to-brain targeting of IDE. Sulfobutylether-beta-cyclodextrin (SBE-beta-CD) was used as a polyanion for chitosan (CS) and as a complexing agent for IDE, permitting its encapsulation into nanospheres (NPs) produced in an aqueous solution. Overloading NPs were obtained by adding the soluble IDE/hydroxypropyl-beta-CD (IDE/HP-beta-CD) inclusion complex into the CS or SBE-beta-CD solutions. We obtained homogeneous CS NPs with a hydrodynamic radius of about 140 nm, positive zeta potential (about +28 mV), and good encapsulation efficiency and drug loading, particularly for overloaded NPs. A biphasic release of IDE, finished within 48 h, was observed from overloaded NPs, whilst non-overloaded CS NPs produced a prolonged release, without a burst effect. In vitro biological studies showed the ability of CS NPs to preserve the antioxidant activity of IDE on U373 culture cells. Furthermore, Fourier transform infrared spectroscopy (FT-IR) demonstrated the ability of CS NPs to interact with the excised bovine nasal mucosa, improving the permeation of the drug and potentially favoring its accumulation in the brain.