Abstract

Purpose: The leading risk factor for glaucoma is age, yet elevated IOP is the only modifiable risk factor and the major therapeutic target. Current IOP-reducing treatments in the form of eyedrops have proven only marginally effective, notably due to lack of patient compliance. To explore other potentially more effective methods of administering drugs to the eye, we examined the feasibility of nanoparticle-encapsulated brimonidine in mice with elevated IOP. Methods: Nanoparticle distribution was examined in C57BL/6 retina after intravitreal injection of DiO-infused nanoparticles. Retinal ganglion cell (RGC) uptake of DiO was quantified by counting phosphorylated heavy-chain neurofilament (SMI31)+ RGCs also positive for DiO. To determine the efficacy of brimonidine-loaded nanoparticles, C57BL/6 mice underwent microbead injection into the anterior chamber of both eyes to induce IOP elevation. Mice then received a single intravitreal injection of brimonidine nanoparticles into one eye and PBS in the other. IOP was measured in both eyes up to 10 days post-injection. Results: With increasing time of exposure to DiO-infused nanoparticles, retinas exhibited an increasing amount of DiO deposition. Retinal area stained by DiO increased 3.1-fold by 14 days and 8.1-fold by 28 days compared to the 3 day timepoint. RGC uptake of DiO was observed as on average 40% of SMI31+ cells in the ganglion cell layer also contained DiO. In mice with elevated IOP, brimonidine nanoparticle treatment resulted in a reduction of IOP to near baseline levels over the course of 10 days, whereas the IOP of the control eyes remained elevated. Conclusions: The increasing deposition of DiO on the retina with time implies nanoparticles were retained in the vitreal chamber for a period of weeks. DiO uptake by RGCs indicates that the nanoparticles passed the inner limiting membrane, a major barrier to many therapeutic compounds. Finally, the reduction of IOP by nanoparticle-encapsulated brimonidine suggests that intravitreal injections of therapeutically-loaded nanoparticles may be an ideal vehicle for long-term drug delivery to the eye in glaucoma.