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Giannaccini M
,
Giannini M
,
Calatayud MP
,
Goya GF
,
Cuschieri A
,
Dente L
,
Raffa V
.
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One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterioreye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterioreye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species.
Figure 1. Distribution of MNPs 24 h after IVT injection in the left eye of Xenopus embryos. (aâe) Prussian Blue staining on paraffin section. The arrow points to blue labeled MNPs. CNS, central nervous system; E, eye; N, notochord; P, pharynx; H, heart; S, somites; Pr, pronephros; G, gut; (f) Iron content assay on explanted eyes. CL, contralateral eye (non-injected); INJ, injected eyes; K, wild type eyes. Scale bar, 50 μm. n = 3, ** p < 0.001, t-test.
Figure 2. Cryostat sections of Xenopus embryos 1 day after injection. (a) Merged image of bright field (showing the pigmented RPE) and red fluorescence field (showing MNPs as red spots); (b) Image from a bleached section merging the bright field (showing MNPs as dark blue spots by Prussian Blue staining) and fluorescence field (showing fluorescent blue nuclei by Hoechst staining). White arrows point some MNPs. C, choroid; RPE, retinal pigmented epithelium; PR, photoreceptors; INL, inner nuclear cell layer. Scale bar, 50 μm.
Figure 3. Prussian Blue staining on paraffin section of Xenopus embryos. (a) 5 min after injection; (b) 30 min after injection; (c) 1 h after injection; (d) 6 h after injection; (e) 24 h after injection; (f) Graphical representation of MNP localization in eye regions of the embryo population. VC, vitreous chamber; NR, neural retina; RPE, retinal pigmented epithelium. n = 45 each time point. MNPs are blue labeled. Scale bar, 50 μm.
Figure 4. Prussian Blue staining on paraffin section of Xenopus embryos at different time points from MNPs injection. MNPs are blue labeled. n = 45 each time point. (a) Three days after injection; (b) five days after injection; (c) 10 days after injection; (d) 20 days after injection. Arrowheads point to MNP localization in interdigitated RPE microvilli with the outer segment of photoreceptors; arrow points to MNPs derived from RPE rupture, during manipulation (details in the material and methods section). Scale bar, 50 μm.
Figure 5. (a) TEM images of MNP; (b) TEM images of MNPâ; (c) TEM images of MNP+; (d) TEM images of MNPs.
Figure 6. Prussian Blue staining on paraffin section of Xenopus embryos one day after injection. Particles are blue labeled. n = 45 each group. (a) Lefteye injected with MNP−; (b) Lefteye injected with MNP+; (c) Lefteye injected with MNPs; (d) Graphical representation of MNP, MNP+, MNP− and MNPs localization in eye regions of the embryo population. VC, vitreous chamber; NR, neural retina; RPE, retinal pigmented epithelium. Scale bar, 50 μm.
Figure 7. Prussian Blue staining on paraffin section of Xenopus embryos one day after injection. Particles are blue labeled. n =45 each group. (a) Left eye injected with MNPâ; (b) Left eye injected with MNP+; (c) Left eye injected with MNPs. H, heart; CNS, central nervous system; S, somites; N, notochord; G, gut. Scale bar, 50 μm.
Figure 8. Prussian Blue staining (without pararosaniline counterstaining) on paraffin section of zebrafish embryos one day from injection. MNPs are blue labeled. Scale bar, 50 μm. n = 45.
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