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S. Raghava, S. Sundaram, E. R. Escobar, H. F. Edelhauser, U. B. Kompella; Particle Surface Functionalization for Enhanced Nanoparticle Delivery to the Anterior and the Posterior Segments of the Eye. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5798.
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To enhance nanoparticle delivery to cornea and conjunctiva of the anterior segment and retinal pigment epithelium of the posterior segment of the eye.
Anionic fluospheres < 100 nm in diameter (NP) were conjugated to deslorelin (deslorelin-NP), a nonapeptide luteinizing hormone releasing hormone (LHRH) agonist, and transferrin (transferrin-NP). Nanoparticle drop was topically administered to a novel ex vivo bovine eye model and the nanoparticles in corneal epithelium, stroma, and endothelium were quantified at 5 and 60 min. The uptake of nanoparticles into cultured human retinal epithelial cells (ARPE-19) was studied by exposing nanoparticle suspension to confluent cells and quantifying the uptake at 3 h using spectrofluorometry. Further, the transport of nanoparticles over 4 h was studied using excised bovine cornea and conjunctiva mounted in Ussing chambers. Confocal microscopy was employed to visualize nanoparticles within various layers of cornea, conjunctiva, and ARPE-19 cells. Real time PCR and western blot were carried out to determine the expression of LHRH and transferrin receptors in cornea and conjunctiva.
Deslorelin and transferrin conjugation enhanced corneal epithelial uptake of nanoparticles by 3- and 4.5 fold at 5 min and by 4.5- and 3.8 fold at 60 min. The total corneal uptake in 5 min was approximately 2.4, 9, and 16% with plain, deslorelin functionalized, and transferrin functionalized particles, respectively. In all groups, the nanoparticle uptake per unit tissue weight was in the order: corneal epithelium > stroma > endothelium with the levels in aqueous humor being undetectable even at 1 h. Deslorelin and transferrin conjugation significantly enhanced the 4 h uptake and transport of nanoparticles across excised bovine cornea as well as conjunctiva. The retinal pigment epithelial cell uptake of deslorelin-NP and transferrin-NP was significantly greater than unconjugated NP. The uptake enhancement was reduced in the presence of free ligand and at 4 °C. Real time PCR and western blot indicated the expression of receptors for LHRH and transferrin in bovine corneal epithelium and conjunctiva.
Surface functionalized nanoparticles in an eye drop allow as much as 16% dose delivery to the cornea within 5 min. This approach is useful for cells of the posterior segment as well. The delivery enhancement involves the interaction of ligands on nanoparticles with cell surface receptors.
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