Dexamethasone sodium phosphate-loaded biodegradable nanoparticles for treating experimental autoimmune uveitis

Abstract

Purpose : Autoimmune uveitis, featured by the intraocular inflammation, is a leading cause of visual impairment and blindness. It is challenging to treat the disease, especially in intermediate, posterior- and pan-uveitis that affect the retina and choroid. We have developed biodegradable polymeric nanoparticles (NP) loaded with water-soluble dexamethasone sodium phosphate (DSP), or DSP-NP, to treat experimental autoimmune uveitis (EAU) following subconjunctival (SC) injection.

Methods : DSP-NP were prepared by a nanoprecipitation method, and characterized in terms of particle size, surface charge, particle morphology, drug loading and drug release in vitro. The drug levels in the ocular tissues and blood were determined by measuring the radioactivity of [H³]-labelled DSP following SC injection of DSP-NP in rats. EAU was induced by interphotoreceptor retinoid binding protein (IRBP) in rats. EAU rats were treated at post-immunization day (PID) 8 with a 30 µL SC injection of: (1) DSP-NP (6 mg DSP/mL), (2) DSP free drug (6 mg DSP/mL), (3) PBS. Animals were followed until PID18. Clinical evaluation, slit lamp and fundus imaging, histopathological analysis, electroretinography (ERG), mRNA expression level of inflammatory cytokines (IL17, TNFα, IL2) in retina and iris were performed.

Results : The DSP-NP exhibited a drug loading of 6wt.% and a diameter of 210 nm (Fig1A). DSP-NP sustained the release of DSP in vitro for about 2 weeks (Fig1B). DSP effectively reached the vitreous following the SC injection and sustained DSP levels in the vitreous were maintained for at least 2 weeks (Fig1C). We found the SC injection of DSP-NP significantly reduced EAU inflammation in comparison to DSP and PBS treated groups, evidenced by a significantly reduced clinical disease score, decreased expression of various inflammatory cytokines, and preserved retinal structure and function (Fig1D-G).

Conclusions : By delivering DSP-NP through SC injection, this strategy may provide sufficient intraocular drug levels for prolonged period, reduced drug administration frequency, improved patient compliance and increased therapeutic efficacy to treat autoimmune uveitis. DSP-NP were made from all Generally Regarded As Safe materials, facilitating the future translational use.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Figure1: (A-C) Characterization of DSP-NP; (D-G) Efficacy of treating EAU using SC injection of DSP-NP.