Abstract

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Interferon (IFN)-beta constitutes one of the first-line therapies to treat MS, but has limited efficacy due to the injectable systemic administration, short half-life, and limited CNS access. To address these limitations, we developed IFN-beta-loaded chitosan/sulfobutylether-beta-cyclodextrin nanoparticles (IFN-beta-NPs) for delivery of IFN-beta into the CNS via the intranasal (i.n.) route. The nanoparticles (NPs) (approximate to 200 nm, polydispersity approximate to 0.1, and zeta potential approximate to 20 mV) were prepared by mixing two aqueous solutions and associated human or murine IFN-beta with high efficiency (90%). Functional in vitro assays showed that IFN-beta-NPs were safe and that IFN-beta was steadily released while retaining biological activity. Biodistribution analysis showed an early and high fluorescence in the brain after nasal administration of fluorescent probe-loaded NPs. Remarkably, mice developing experimental autoimmune encephalomyelitis (EAE), an experimental model of MS, exhibited a significant improvement of clinical symptoms in response to intranasal IFN-beta-NPs (inIFN-beta-NPs), whereas a similar dose of intranasal or systemic free IFN-beta had no effect. Importantly, inIFN-beta-NPs treatment was equally effective despite a reduction of 78% in the total amount of weekly administered IFN-beta. Spinal cords obtained from inIFN-beta-NPs-treated EAE mice showed fewer inflammatory foci and demyelination, lower expression of antigen-presenting and costimulatory proteins on CD11b(+) cells, and lower astrocyte and microglia activation than control mice. Therefore, IFN-beta treatment at tested doses was effective in promoting clinical recovery and control of neuroinflammation in EAE only when associated with NPs. Overall, inIFN beta-NPs represent a potential, effective, non-invasive, and low-cost therapy for MS.