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WIREs Nanomed Nanobiotechnol
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Nanocarrier mediated retinal drug delivery: overcoming ocular barriers to treat posterior eye diseases

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Effective drug delivery to the retina still remains a challenge due to ocular elimination mechanisms and complex barriers that selectively limit the entry of drugs into the eye. To overcome these barriers, frequent intravitreal injections are currently used to achieve high drug concentrations in vitreous and retina. However, these repetitive injections may result in several side effects. Recent advancements in the field of nanoparticle‐based drug delivery could overcome some of these unmet needs and various preclinical studies conducted to date have demonstrated promising results of nanotherapies in the treatment of retinal diseases. Compared to the majority of commercially available ocular implants, the biodegradable nature of most nanoparticles (NPs) avoids the need for surgical implantation and removal after the release of the payload. In addition, the sustained drug release from NPs over an extended period of time reduces the need for frequent intravitreal injections and the risk of associated side effects. The nanometer size and highly modifiable surface properties make NPs excellent candidates for targeted ocular drug delivery. Studies have shown that nanocarriers enhance the intravitreal half‐life and thus bioavailability of a number of drugs including proteins and peptides. In addition, they have shown promising results in delivering genetic material to the retinal tissues by protecting it from possible intravitreal degradation. This review covers the various challenges associated with drug delivery to the posterior segment of the eye, particularly the retina, and highlights the application of nanocarriers to overcome these challenges in context with recent advances in preclinical studies. WIREs Nanomed Nanobiotechnol 2018, 10:e1473. doi: 10.1002/wnan.1473 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Schematic illustration of the routes of ocular drug delivery. (1) Corneal barrier, (2) blood‐aqueous barrier, and (3) blood‐retinal barrier.
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Inhibition of choroidal neovascularization (CNV) in dendrimer 4/ODN‐1 injected rat eyes that were laser photocoagulated 2 months post‐injection. Color fundus photography showing the location of laser lesions (black arrows) in dendrimer 4 without ODN‐1 (a.1) and dendrimer 4 with ODN‐1 (b.1) injected eyes. Corresponding fluorescein angiograms of representative eyes are depicted below at two time points post‐laser photocoagulation, 14 days (a.2, b.2, and 1 month (a.3, b.3). In eyes treated with dendrimer only, strong leakage was detected (white arrows), while in eyes treated with dendrimer 4 plus ODN‐1, leakage remained minimal. (Reprinted with permission from Ref . Copyright 2004 Elsevier)
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Schematic representation of dendrimers for drug delivery applications.
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Short‐term (4 h) trafficking and 48 h biodistribution pattern of plasmid‐gemini surfactant‐phospholipid‐1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (PGL‐DOPE) nanoparticles (NPs) after intravitreal injection. Animals were treated with double labeled NBD‐PE (green) lipid and Cy5‐pDNA (red) 10:1 ρ ± charge ratios PGLDOPE‐N NPs (n = 4). (a) NPs were dispersed throughout the vitreous enroute to the retina 4 h after injection (n = 4). (b) 48 h after intravitreal injection Cy5‐pDNA was observed mainly within the nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform later (IPL) of the retina; limited red fluorescence was observed in the vitreous and around the lens. Retinal cross‐sections were stained with Syto 80 (orange fluorescent nucleic acid stain). (Reprinted with permission from Ref . Copyright 2014 Elsevier)
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Expression of green fluorescent protein (GFP) and retinoschisin in retinas of Rsh‐1 deficient mice 2 weeks after intravitreal administration of the vectors. (a) Confocal images of the retinas. A and E: non‐treated eyes. B–D: eyes treated with hyaluronic acid solid‐lipid nanoparticle (HA‐SLN); F–H: eyes treated with dextran solid‐lipid nanoparticle (DX‐SLN). A, E, B, and F: GFP (green), retinoschisin (red). C and G: GFP (green), rhodopsin (red). D and H: retinoschisin (green), rhodopsin (red). Cell nuclei (RPE, INL, ONL, and GCL) are observed in blue. Scale bar: 100 µm. (b) GFP and (c) retinoschisin levels in the retinal layers. For each protein, data represent the mean value plus standard deviation of six sections per eye (four eyes). (Reprinted with permission from Ref . Copyright 2016 Elsevier)
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Mean fluorescence intensity in different inner ocular tissues (a) 30 min, 4 h, and 12 h after application of negatively charged nanoparticles (NPs) with cathodal iontophoresis and (b) 4 h after application of positively charged NPs with anodal iontophoresis, compared to mock application. T: tissue under the iontophoretic application; P: peripheral tissue. (Reprinted with permission from Ref . Copyright 2008 Elsevier)
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Distribution of human serum albumin nanoparticles (HSA‐NPs) around the retinal vasculature 5 h post‐intravitreal administration. (a) The yellow arrows localize HSA‐NPs at the abluminal surface of the retinal vasculature. (b, c) Immunohistochemistry staining confirming the abluminal distribution of HSA‐NPs. Blue, green, gray, and red represent Von Willebrand Factor positive cells, Müller cells, nuclei, and HSA‐NPs, respectively. ILM, inner limiting membrane; GCL, ganglion cell layer; IPL, inner plexiform layer. (Reprinted with permission from Ref . Copyright 2008 Springer)
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