Purchase this article with an account.
Y. De Kozak, K. Andrieux, H. Villarroya, C. Klein, M. Naud, B. Thillaye-Goldenberg, E. Garcia, P. Couvreur; Effect of Systemic and Intraocular Treatment with Tamoxifen-Loaded Nanoparticles on Experimental Autoimmune Uveoretinitis (EAU) in Lewis Rats . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4306.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Tamoxifen, an anti-estrogen used for treatment of breast cancer, has shown its efficacy for prevention of experimental autoimmune diseases. To overcome systemic side effects, tamoxifen was encapsulated within polyethylene glycol (PEG)-coated nanoparticles and its effect on EAU was investigated. Methods: We first studied the ocular biodistribution of nanoparticles during EAU induced with S-Ag (40µg) in male and female Lewis rats. 0.2µm polystyrene nanoparticles-Fluoresbrite (NP-F) (Polyscience, Germany) coated with a copolymer made of poly(MePEG-co-hexadecylcyanoacrylate) 1:4 were injected intravenously (IV) (0.4ml/rat, n=5 rats) or intravitreally (IVT) (10µl/eye, n=7 rats) on the day of disease onset. Eyes were taken at 8 and 24 hours, and 3 and 9 days, to evaluate fluorescence on cryostat sections. To determine the effect of tamoxifen on EAU, the drug was encapsulated in biodegradable nanoparticles poly (PEGCA-co-HDCA) (NP-TAM) (20mg/ml) and injected either IV (n=4 rats) or IVT (n=8 rats) on day 13 after immunization (i.e. one day before expected disease onset in controls injected with empty nanoparticles). Rats were examined clinically from day 10. At days 16-17 (i.e. 2-3 days after disease onset in controls), histopathology and immunohistochemistry with confocal microscopy, using antibodies specific for glia (GFAP), inflammatory cells (ED1, ED2, OX42, OX62) and MHC class II (OX6), were performed. RT-PCR was undertaken on enucleated eyes to determine chemokine mRNA expression. Results: 24 hours after IV injection of NP-F, numerous inflammatory cells containing phagocytosed NP-F infiltrated ocular tissues of rats with EAU. From 8 hours to 9 days after IVT injection of NP-F, free NP-F were distributed through ocular tissues, and also concentrated in resident and inflammatory cells. Injection of free tamoxifen did not influence the course of EAU. In contrast, in both male and female rats, IV and IVT injection of NP-TAM resulted in significant inhibition of clinical and histological EAU. Diminished infiltration by OX6+ inflammatory cells and low expression of RANTES and MIP-1α mRNA were noted in ocular tissues from treated rats. Conclusions: These data support the use of tamoxifen as an anti-inflammatory drug for ocular inflammation. Intraocular injection of nanoparticles may be an effective method of local drug delivery with the advantage of diminished side effects related to the systemic release of a drug.
This PDF is available to Subscribers Only