Repeated Topical Administration of 3 nm Cerium Oxide Nanoparticles Reverts Disease Atrophic Phenotype and Arrests Neovascular Degeneration in AMD Mouse Models

Abstract

Increased oxidative stress in the retina and retinal pigment epithelium is implicated in age-related macular degeneration (AMD). Antioxidant cerium oxide nanoparticles (CeO2NPs) have been used to treat degenerative retinal pathologies in animal models, although their delivery route is not ideal for chronic patient treatment. In this work, we prepared a formulation for ocular topical delivery that contains small (3 nm), nonaggregated biocompatible CeO2NPs. In vitro results indicate the biocompatible and protective character of the CeO2NPs, reducing oxidative stress in ARPE19 cells and inhibiting neovascularization related to pathological angiogenesis in both HUVEC and in in vitro models of neovascular growth. In the in vivo experiments, we observed the capacity of CeO2NPs to reach the retina after topical delivery and a subsequent reversion of the altered retinal transcriptome of the retinal degenerative mouse model DKOrd8 toward that of healthy control mice, together with signs of decreased inflammation and arrest of degeneration. Furthermore, CeO2NP eye drops’ treatment reduced laser-induced choroidal neovascular lesions in mice by lowering VEGF and increasing PEDF levels. These results indicate that CeO2NP eye drops are a beneficial antioxidant and neuroprotective treatment for both dry and wet forms of AMD disease.

Exploring the Long-Term Tissue Accumulation and Excretion of 3 nm Cerium Oxide Nanoparticles after Single Dose Administration

“…Sodium citrate (SC) was used as a complexing and stabilizing agent, and TMAOH was used as a base. A stable colloidal solution of ~3 nm non-aggregated naked surface NPs was obtained [ 25 ] and described in Figure 2 . Note that a precise description of NP features is critical in controlling the interactions at the nano–bio interface [ 73 ].…”

“…Finally, as an inorganic catalyst, it can be used many times without being consumed, which allows it to work rather permanently at very low doses, offering chronic protection with a single administration. Accordingly, nanoceria efficacy has successfully been tested in a wide variety of disease models, mainly in inflammatory-related pathologies such as cardiac diseases [ 20 ], brain ischemia [ 21 , 22 , 23 ], diabetes [ 24 ], retinal dysfunction [ 25 , 26 ], liver inflammation [ 27 , 28 ], cancer [ 29 ], anaphylactic shock [ 30 , 31 , 32 ], acute [ 33 ] and chronic glaucoma [ 34 ], radiation-induced injuries [ 35 , 36 ], and neurodegeneration [ 37 , 38 ]. This ability of nanoceria to reduce ROS is crucial, because it avoids the direct damage derived from free radicals.…”

Nano-based ocular drug delivery systems: an insight into the preclinical/clinical studies and their potential in the treatment of posterior ocular diseases

“…Recently, a lot of nano-based drug delivery systems have been developed to overcome the limitations of conventional eye drops and deliver drugs to the retina. 37–63 These advanced delivery systems have shown promising outcomes in the ocular disease models both in vitro and in vivo by increasing the retention time of drugs on the cornea, enhancing drug penetration, or promoting drug delivery to the posterior segment of the eye through the corneal or conjunctival–scleral pathway. Herein, we provide a summary of preclinical research on novel nano-based drug delivery systems for topical delivery to the posterior segment of the eye in the recent five years (Table 3).…”

“…5). 52 Gold nanoparticles possess several advantages, such as relatively small size, high biocompatibility, antioxidant and antiangiogenic features. 68 nanoparticles for topical instillation to reach the retina.…”

Conservation of the enzyme-like activity and biocompatibility of CeO2 nanozymes in simulated body fluids

“…[4][5][6] Amongst them, cerium oxide NZs (CeO 2 NZs) are some of the most widely studied due to their potential of mimicking the activity of several key endogenous enzymes such as superoxide dismutase (SOD), 7 catalase, 8 and peroxidase. 9 CeO 2 NZs have been reported to have protective and therapeutic effects in different medical conditions such as hepatic diseases, 10 neurodegeneration, 11 retinal degeneration, 12,13 cardiopathies, 14 ischemia, 15,16 and different tumours. [17][18][19] Their enzyme-mimetic behaviour is attributed to their ability to participate in redox reactions through a well-described regenerative cycle between the Ce-oxidized (Ce 4+ ) and Ce-reduced (Ce 3+ ) states due to the presence of oxygen vacancies in the crystal lattice when the size of the particle is reduced to the nanometer scale.…”