Pharmacokinetics and Effects of Nanoceria in Normal and P23H Degenerative Rat Retinas

Abstract

Purpose: : Cerium oxide nanoparticles (nanoceria or CNPs) are potent antioxidants in vitro and in vivo. They possess regenerative radical scavenging activities that mimic catalytic reactions by super oxide dismutase and catalase. Previously, we demonstrated that CNPs offered neuroprotection in two rodent retinal degeneration models: the on-demand light-induced, and the tubby photoreceptor degeneration models. However, the pharmacokinetics and tissue deposition of CNPs after intravitreal injection remains unknown. In this study, we determined the distribution and retention of CNPs after a single intravitreal injection. We also determined whether the presence of CNPs in ocular tissues has negative effects in retinal function and morphology. To further establish CNPs as potential ophthalmic therapeutics, we assessed the ability of CNPs to extend the functional life span of defective photoreceptor cells in the P23H rat.

Methods: : We used the highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) to determine the quantity of CNPs in different ocular tissues after a single intravitreal injection. Negative effects on ocular function due to CNPs were evaluated by electroretinography (ERG) and quantitative tissue morphology at 12, 60, and 120 days post injection. For photoreceptor cell protection studies, postnatal day (P) 25 Tg(P23H)1Lav rats were injected with either saline or different amounts of CNPs and killed on P53 for ERG and morphometric assessment.

Results: : We discovered that 93% of the injected CNPs were found in the retina one hour after intravitreal injection. At 120 days, 75% of the CNPs were still retained in the retina and no reduction of retinal function was observed at a dosage 100X the lowest effective dose. We also observed more rod photoreceptor cells survived in the P23H rats after a single intravitreal injection of CNPs at the 1mM dosage.

Conclusions: : CNPs are rapidly taken up by cells in the retina and are preferentially retained there. CNPs acting as radical scavengers prolong the life span of the defective photoreceptor cells of P23H rat, a model for an autosomal dominant retinitis pigmentosa. These data demonstrated that CNPs do not turn over in the retina and may be therapeutically beneficial for treating blinding eye diseases over prolonged periods.

Keywords: antioxidants • oxidation/oxidative or free radical damage • transgenics/knock-outs